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1.  Anti-tau antibodies that block tau aggregate seeding in vitro markedly decrease pathology and improve cognition in vivo 
Neuron  2013;80(2):402-414.
Summary
Tau aggregation occurs in neurodegenerative diseases including Alzheimer's disease and many other disorders collectively termed tauopathies. Trans-cellular propagation of tau pathology, mediated by extracellular tau aggregates, may underlie pathogenesis of these conditions. P301S tau transgenic mice express mutant human tau protein, and develop progressive tau pathology. Using a cell-based biosensor assay, we screened anti-tau monoclonal antibodies for their ability to block seeding activity present in P301S brain lysates. We infused 3 effective antibodies or controls into the lateral ventricle of P301S mice for 3 months. The antibodies markedly reduced hyperphosphorylated, aggregated, and insoluble tau. They also blocked development of tau seeding activity detected in brain lysates using the biosensor assay, reduced microglial activation, and improved cognitive deficits. These data imply a central role for extracellular tau aggregates in the development of pathology. They also suggest immunotherapy specifically designed to block trans-cellular aggregate propagation will be a productive treatment strategy.
doi:10.1016/j.neuron.2013.07.046
PMCID: PMC3924573  PMID: 24075978
2.  Tuberculin Skin Tests versus Interferon-Gamma Release Assays in Tuberculosis Screening among Immigrant Visa Applicants 
Objective. Use of tuberculin skin tests (TSTs) and interferon gamma release assays (IGRAs) as part of tuberculosis (TB) screening among immigrants from high TB-burden countries has not been fully evaluated. Methods. Prevalence of Mycobacterium tuberculosis infection (MTBI) based on TST, or the QuantiFERON-TB Gold test (QFT-G), was determined among immigrant applicants in Vietnam bound for the United States (US); factors associated with test results and discordance were assessed; predictive values of TST and QFT-G for identifying chest radiographs (CXRs) consistent with TB were calculated. Results. Of 1,246 immigrant visa applicants studied, 57.9% were TST positive, 28.3% were QFT-G positive, and test agreement was 59.4%. Increasing age was associated with positive TST results, positive QFT-G results, TST-positive but QFT-G-negative discordance, and abnormal CXRs consistent with TB. Positive predictive values of TST and QFT-G for an abnormal CXR were 25.9% and 25.6%, respectively. Conclusion. The estimated prevalence of MTBI among US-bound visa applicants in Vietnam based on TST was twice that based on QFT-G, and 14 times higher than a TST-based estimate of MTBI prevalence reported for the general US population in 2000. QFT-G was not better than TST at predicting abnormal CXRs consistent with TB.
doi:10.1155/2014/217969
PMCID: PMC3967820  PMID: 24738031
3.  Infective Endocarditis in Northeastern Thailand 
Emerging Infectious Diseases  2014;20(3):473-476.
Despite rigorous diagnostic testing, the cause of infective endocarditis was identified for just 60 (45.5%) of 132 patients admitted to hospitals in Khon Kaen, Thailand, during January 2010–July 2012. Most pathogens identified were Viridans streptococci and zoonotic bacteria species, as found in other resource-limited countries where underlying rheumatic heart disease is common.
doi:10.3201/eid2003.131059
PMCID: PMC3944839  PMID: 24572588
Infective endocarditis; congestive heart failure; Thailand; zoonoses; Bartonella; Q fever; Viridans streptococci; Coxiella burnetii; bacteria; antimicrobial drugs; rheumatic heart disease; heart valve
4.  Antisense Reduction of Tau in Adult Mice Protects against Seizures 
The Journal of Neuroscience  2013;33(31):12887-12897.
Tau, a microtubule-associated protein, is implicated in the pathogenesis of Alzheimer's Disease (AD) in regard to both neurofibrillary tangle formation and neuronal network hyperexcitability. The genetic ablation of tau substantially reduces hyperexcitability in AD mouse lines, induced seizure models, and genetic in vivo models of epilepsy. These data demonstrate that tau is an important regulator of network excitability. However, developmental compensation in the genetic tau knock-out line may account for the protective effect against seizures. To test the efficacy of a tau reducing therapy for disorders with a detrimental hyperexcitability profile in adult animals, we identified antisense oligonucleotides that selectively decrease endogenous tau expression throughout the entire mouse CNS—brain and spinal cord tissue, interstitial fluid, and CSF—while having no effect on baseline motor or cognitive behavior. In two chemically induced seizure models, mice with reduced tau protein had less severe seizures than control mice. Total tau protein levels and seizure severity were highly correlated, such that those mice with the most severe seizures also had the highest levels of tau. Our results demonstrate that endogenous tau is integral for regulating neuronal hyperexcitability in adult animals and suggest that an antisense oligonucleotide reduction of tau could benefit those with epilepsy and perhaps other disorders associated with tau-mediated neuronal hyperexcitability.
doi:10.1523/JNEUROSCI.2107-13.2013
PMCID: PMC3728694  PMID: 23904623
5.  Identifying Essential Cell Types and Circuits in Autism Spectrum Disorders 
Autism spectrum disorder (ASD) is highly genetic in its etiology, with potentially hundreds of genes contributing to risk. Despite this heterogeneity, these disparate genetic lesions may result in the disruption of a limited number of key cell types or circuits –information which could be leveraged for the design of therapeutic interventions. While hypotheses for cellular disruptions can be identified by postmortem anatomical analysis and expression studies of ASD risk genes, testing these hypotheses requires the use of animal models. In this review, we explore the existing evidence supporting the contribution of different cell types to ASD, specifically focusing on rodent studies disrupting serotonergic, GABAergic, cerebellar and striatal cell types, with particular attention to studies of the sufficiency of specific cellular disruptions to generate ASD-related behavioral abnormalities. This evidence suggests multiple cellular routes can create features of the disorder, though it is currently unclear if these cell types converge on a final common circuit. We hope that in the future, systematic studies of cellular sufficiency and genetic interaction will help to classify patients into groups by type of cellular disruptions which suggest tractable therapeutic targets.
doi:10.1016/B978-0-12-418700-9.00003-4
PMCID: PMC3897614  PMID: 24290383
autism; serotonin; GABA; cerebellum; striatum; rodent behavior; conditional deletion
6.  Tuberculosis Screening by Tuberculosis Skin Test or QuantiFERON®-TB Gold In-Tube Assay among an Immigrant Population with a High Prevalence of Tuberculosis and BCG Vaccination 
PLoS ONE  2013;8(12):e82727.
Rationale
Each year 1 million persons acquire permanent U.S. residency visas after tuberculosis (TB) screening. Most applicants undergo a 2-stage screening with tuberculin skin test (TST) followed by CXR only if TST-positive at > 5 mm. Due to cross reaction with bacillus Calmette-Guérin (BCG), TST may yield false positive results in BCG-vaccinated persons. Interferon gamma release assays exclude antigens found in BCG. In Vietnam, like most high TB-prevalence countries, there is universal BCG vaccination at birth.
Objectives
1. Compare the sensitivity of QuantiFERON ®-TB Gold In-Tube Assay (QFT) and TST for culture-positive pulmonary TB. 2. Compare the age-specific and overall prevalence of positive TST and QFT among applicants with normal and abnormal CXR.
Methods
We obtained TST and QFT results on 996 applicants with abnormal CXR, of whom 132 had TB, and 479 with normal CXR.
Results
The sensitivity for tuberculosis was 86.4% for QFT; 89.4%, 81.1%, and 52.3% for TST at 5, 10, and 15 mm. The estimated prevalence of positive results at age 15–19 years was 22% and 42% for QFT and TST at 10 mm, respectively. The prevalence increased thereafter by 0.7% year of age for TST and 2.1% for QFT, the latter being more consistent with the increase in TB among applicants.
Conclusions
During 2-stage screening, QFT is as sensitive as TST in detecting TB with fewer requiring CXR and being diagnosed with LTBI. These data support the use of QFT over TST in this population. 
doi:10.1371/journal.pone.0082727
PMCID: PMC3868593  PMID: 24367546
7.  The Disruption of Celf6, a Gene Identified by Translational Profiling of Serotonergic Neurons, Results in Autism-Related Behaviors 
The immense molecular diversity of neurons challenges our ability to understand the genetic and cellular etiology of neuropsychiatric disorders. Leveraging knowledge from neurobiology may help parse the genetic complexity: identifying genes important for a circuit that mediates a particular symptom of a disease may help identify polymorphisms that contribute to risk for the disease as a whole. The serotonergic system has long been suspected in disorders that have symptoms of repetitive behaviors and resistance to change, including autism. We generated a bacTRAP mouse line to permit translational profiling of serotonergic neurons. From this, we identified several thousand serotonergic-cell expressed transcripts, of which 174 were highly enriched, including all known markers of these cells. Analysis of common variants near the corresponding genes in the AGRE collection implicated the RNA binding protein CELF6 in autism risk. Screening for rare variants in CELF6 identified an inherited premature stop codon in one of the probands. Subsequent disruption of Celf6 in mice resulted in animals exhibiting resistance to change and decreased ultrasonic vocalization as well as abnormal levels of serotonin in the brain. This work provides a reproducible and accurate method to profile serotonergic neurons under a variety of conditions and suggests a novel paradigm for gaining information on the etiology of psychiatric disorders.
doi:10.1523/JNEUROSCI.4762-12.2013
PMCID: PMC3711589  PMID: 23407934
8.  Pneumococcal Bacteremia Requiring Hospitalization in Rural Thailand: An Update on Incidence, Clinical Characteristics, Serotype Distribution, and Antimicrobial Susceptibility, 2005–2010 
PLoS ONE  2013;8(6):e66038.
Background
Streptococcus pneumoniae is an important cause of morbidity and mortality in Southeast Asia, but regional data is limited. Updated burden estimates are critical as pneumococcal conjugate vaccine (PCV) is highly effective, but not yet included in the Expanded Program on Immunization of Thailand or neighboring countries.
Methods
We implemented automated blood culture systems in two rural Thailand provinces as part of population-based surveillance for bacteremia. Blood cultures were collected from hospitalized patients as clinically indicated.
Results
From May 2005– March 2010, 196 cases of pneumococcal bacteremia were confirmed in hospitalized patients. Of these, 57% had clinical pneumonia, 20% required mechanical ventilation, and 23% (n = 46) died. Antibiotic use before blood culture was confirmed in 25% of those with blood culture. Annual incidence of hospitalized pneumococcal bacteremia was 3.6 per 100,000 person-years; rates were higher among children aged <5 years at 11.7 and adults ≥65 years at 14.2, and highest among infants <1 year at 33.8. The median monthly case count was higher during December–March compared to the rest of the year 6.0 vs. 1.0 (p<0.001). The most common serotypes were 23F (16%) and 14 (14%); 61% (74% in patients <5 years) were serotypes in the 10-valent PCV (PCV 10) and 82% (92% in <5 years) in PCV 13. All isolates were sensitive to penicillin, but non-susceptibility was high for co-trimoxazole (57%), erythromycin (30%), and clindamycin (20%).
Conclusions
We demonstrated a high pneumococcal bacteremia burden, yet underestimated incidence because we captured only hospitalized cases, and because pre-culture antibiotics were frequently used. Our findings together with prior research indicate that PCV would likely have high serotype coverage in Thailand. These findings will complement ongoing cost effectiveness analyses and support vaccine policy evaluation in Thailand and the region.
doi:10.1371/journal.pone.0066038
PMCID: PMC3694083  PMID: 23840395
9.  Influenza A(H1N1)pdm09-Associated Pneumonia Deaths in Thailand 
PLoS ONE  2013;8(2):e54946.
Background
The first human infections with influenza A(H1N1)pdm09 virus were confirmed in April 2009. We describe the clinical and epidemiological characteristics of influenza A(H1N1)pdm09-associated pneumonia deaths in Thailand from May 2009-January 2010.
Methods
We identified influenza A(H1N1)pdm09-associated pneumonia deaths from a national influenza surveillance system and performed detailed reviews of a subset.
Results
Of 198 deaths reported, 49% were male and the median age was 37 years; 146 (73%) were 20–60 years. Among 90 deaths with records available for review, 46% had no identified risk factors for severe influenza. Eighty-eight patients (98%) received antiviral treatment, but only 16 (18%) initiated therapy within 48 hours of symptom onset.
Conclusions
Most influenza A(H1N1)pdm09 pneumonia fatalities in Thailand occurred in adults aged 20–60 years. Nearly half lacked high-risk conditions. Antiviral treatment recommendations may be especially important early in a pandemic before vaccine is available. Treatment should be considered as soon as influenza is suspected.
doi:10.1371/journal.pone.0054946
PMCID: PMC3563645  PMID: 23390508
10.  Incidence and Epidemiology of Hospitalized Influenza Cases in Rural Thailand during the Influenza A (H1N1)pdm09 Pandemic, 2009–2010 
PLoS ONE  2012;7(11):e48609.
Background
Data on the burden of the 2009 influenza pandemic in Asia are limited. Influenza A(H1N1)pdm09 was first reported in Thailand in May 2009. We assessed incidence and epidemiology of influenza-associated hospitalizations during 2009–2010.
Methods
We conducted active, population-based surveillance for hospitalized cases of acute lower respiratory infection (ALRI) in all 20 hospitals in two rural provinces. ALRI patients were sampled 1∶2 for participation in an etiology study in which nasopharyngeal swabs were collected for influenza virus testing by PCR.
Results
Of 7,207 patients tested, 902 (12.5%) were influenza-positive, including 190 (7.8%) of 2,436 children aged <5 years; 86% were influenza A virus (46% A(H1N1)pdm09, 30% H3N2, 6.5% H1N1, 3.5% not subtyped) and 13% were influenza B virus. Cases of influenza A(H1N1)pdm09 first peaked in August 2009 when 17% of tested patients were positive. Subsequent peaks during 2009 and 2010 represented a mix of influenza A(H1N1)pdm09, H3N2, and influenza B viruses. The estimated annual incidence of hospitalized influenza cases was 136 per 100,000, highest in ages <5 years (477 per 100,000) and >75 years (407 per 100,000). The incidence of influenza A(H1N1)pdm09 was 62 per 100,000 (214 per 100,000 in children <5 years). Eleven influenza-infected patients required mechanical ventilation, and four patients died, all adults with influenza A(H1N1)pdm09 (1) or H3N2 (3).
Conclusions
Influenza-associated hospitalization rates in Thailand during 2009–10 were substantial and exceeded rates described in western countries. Influenza A(H1N1)pdm09 predominated, but H3N2 also caused notable morbidity. Expanded influenza vaccination coverage could have considerable public health impact, especially in young children.
doi:10.1371/journal.pone.0048609
PMCID: PMC3490866  PMID: 23139802
11.  Adrenal Steroids Uniquely Influence Sexual Motivation Behavior in Male Rats 
Behavioral Sciences  2012;2(3):195-206.
The androgenic adrenal steroids dehydroepiandrosterone (DHEA) and 4α-androstenedione (4-A) have significant biological activity, but it is unclear if the behavioral effects are unique or only reflections of the effects of testosterone (TS). Gonadally intact male Long-Evans rats were assigned to groups to receive supplements of DHEA, 4-A, TS, corticosteroid (CORT), all at 400 µg steroid/kg of body weight, or vehicle only for 5 weeks. All males were tested in a paradigm for sexual motivation that measures time and urinary marks near an inaccessible receptive female. It was found that DHEA and 4-A supplements failed to influence time near the estrous female in the same way TS supplements did, and, indeed, 5 weeks of 4-A administration reduced the time similar to the suppressive effects of CORT after 3 weeks. Further, animals treated with DHEA or 4-A left fewer urinary marks near an estrous female than TS and control groups. These results suggest that DHEA and 4-A are not merely precursors of sex hormones, and provide support for these steroids influencing the brain and behavior in a unique fashion that is dissimilar from the effects of TS on male sexual behavior.
doi:10.3390/bs2030195
PMCID: PMC4217631  PMID: 25379221
DHEA; androstenedione; corticosteroids; motivation; mechanisms
12.  Incidence of Bacteremic Melioidosis in Eastern and Northeastern Thailand 
Burkholderia pseudomallei, the causative agent of melioidosis, is endemic in northeastern Thailand. Population-based disease burden estimates are lacking and limited data on melioidosis exist from other regions of the country. Using active, population-based surveillance, we measured the incidence of bacteremic melioidosis in the provinces of Sa Kaeo (eastern Thailand) and Nakhon Phanom (northeastern Thailand) during 2006–2008. The average annual incidence in Sa Kaeo and Nakhon Phanom per 100,000 persons was 4.9 (95% confidence interval [CI] = 3.9–6.1) and 14.9 (95% CI = 13.3–16.6). The respective population mortality rates were 1.9 (95% CI = 1.3–2.8) and 4.4 (95% CI = 3.6–5.3) per 100,000. The case-fatality proportion was 36% among those with known outcome. Our findings document a high incidence and case fatality proportion of bacteremic melioidosis in Thailand, including a region not traditionally considered highly endemic, and have potential implications for clinical management and health policy.
doi:10.4269/ajtmh.2011.11-0070
PMCID: PMC3122354  PMID: 21734135
13.  Lessons Learned from Influenza A(H1N1)pdm09 Pandemic Response in Thailand 
Emerging Infectious Diseases  2012;18(7):1058-1064.
The strengths and weaknesses of this response can inform planning for pandemics and other prolonged public health emergencies.
In 2009, Thailand experienced rapid spread of the pandemic influenza A(H1N1)pdm09 virus. The national response came under intense public scrutiny as the number of confirmed cases and associated deaths increased. Thus, during July–December 2009, the Ministry of Public Health and the World Health Organization jointly reviewed the response efforts. The review found that the actions taken were largely appropriate and proportionate to need. However, areas needing improvement were surveillance, laboratory capacity, hospital infection control and surge capacity, coordination and monitoring of guidelines for clinical management and nonpharmaceutical interventions, risk communications, and addressing vulnerabilities of non-Thai displaced and migrant populations. The experience in Thailand may be applicable to other countries and settings, and the lessons learned may help strengthen responses to other pandemics or comparable prolonged public health emergencies.
doi:10.3201/eid1807.110976
PMCID: PMC3376790  PMID: 22709628
national response; surveillance; in-bound screening; influenza-like illness; risk communications; vaccine; pandemic; influenza; Thailand; influenza A(H1N1)pdm09; pH1N1 virus; lessons learned; pandemic planning; viruses
14.  Bartonella vinsonii subsp. arupensis in Humans, Thailand 
Emerging Infectious Diseases  2012;18(6):989-991.
We identified Bartonella vinsonii subsp. arupensis in pre-enriched blood of 4 patients from Thailand. Nucleotide sequences for transfer-messenger RNA gene, citrate synthase gene, and the 16S–23S rRNA internal transcribed spacer were identical or closely related to those for the strain that has been considered pathogenic since initially isolated from a human in Wyoming, USA.
doi:10.3201/eid1806.111750
PMCID: PMC3358162  PMID: 22607728
Bartonella vinsonii subsp. arupensis; animal hosts; Thailand; undiagnosed diseases; bacteria; zoonoses
15.  The Pneumonia Etiology Research for Child Health Project: A 21st Century Childhood Pneumonia Etiology Study 
The Pneumonia Etiology Research for Child Health (PERCH) project is a 7-country, standardized, comprehensive evaluation of the etiologic agents causing severe pneumonia in children from developing countries. During previous etiology studies, between one-quarter and one-third of patients failed to yield an obvious etiology; PERCH will employ and evaluate previously unavailable innovative, more sensitive diagnostic techniques. Innovative and rigorous epidemiologic and analytic methods will be used to establish the causal association between presence of potential pathogens and pneumonia. By strategic selection of study sites that are broadly representative of regions with the greatest burden of childhood pneumonia, PERCH aims to provide data that reflect the epidemiologic situation in developing countries in 2015, using pneumococcal and Haemophilus influenzae type b vaccines. PERCH will also address differences in host, environmental, and/or geographic factors that might determine pneumonia etiology and, by preserving specimens, will generate a resource for future research and pathogen discovery.
doi:10.1093/cid/cir1052
PMCID: PMC3297546  PMID: 22403238
16.  Estimating the Impact of Newly Arrived Foreign-Born Persons on Tuberculosis in the United States 
PLoS ONE  2012;7(2):e32158.
Background
Among approximately 163.5 million foreign-born persons admitted to the United States annually, only 500,000 immigrants and refugees are required to undergo overseas tuberculosis (TB) screening. It is unclear what extent of the unscreened nonimmigrant visitors contributes to the burden of foreign-born TB in the United States.
Methodology/Principal Findings
We defined foreign-born persons within 1 year after arrival in the United States as “newly arrived”, and utilized data from U.S. Department of Homeland Security, U.S. Centers for Disease Control and Prevention, and World Health Organization to estimate the incidence of TB among newly arrived foreign-born persons in the United States. During 2001 through 2008, 11,500 TB incident cases, including 291 multidrug-resistant TB incident cases, were estimated to occur among 20,989,738 person-years for the 1,479,542,654 newly arrived foreign-born persons in the United States. Of the 11,500 estimated TB incident cases, 41.6% (4,783) occurred among immigrants and refugees, 36.6% (4,211) among students/exchange visitors and temporary workers, 13.8% (1,589) among tourists and business travelers, and 7.3% (834) among Canadian and Mexican nonimmigrant visitors without an I-94 form (e.g., arrival-departure record). The top 3 newly arrived foreign-born populations with the largest estimated TB incident cases per 100,000 admissions were immigrants and refugees from high-incidence countries (e.g., 2008 WHO-estimated TB incidence rate of ≥100 cases/100,000 population/year; 235.8 cases/100,000 admissions, 95% confidence interval [CI], 228.3 to 243.3), students/exchange visitors and temporary workers from high-incidence countries (60.9 cases/100,000 admissions, 95% CI, 58.5 to 63.3), and immigrants and refugees from medium-incidence countries (e.g., 2008 WHO-estimated TB incidence rate of 15–99 cases/100,000 population/year; 55.2 cases/100,000 admissions, 95% CI, 51.6 to 58.8).
Conclusions/Significance
Newly arrived nonimmigrant visitors contribute substantially to the burden of foreign-born TB in the United States. To achieve the goals of TB elimination, direct investment in global TB control and strategies to target nonimmigrant visitors should be considered.
doi:10.1371/journal.pone.0032158
PMCID: PMC3287989  PMID: 22384165
17.  Long-term Effects of Multiple Glucocorticoid Exposures in Neonatal Mice 
Behavioral sciences  2011;1(1):4-30.
Glucocorticoids (GCs) such as dexamethasone (DEX) or betamethasone are repeatedly administered for up to a month to prematurely born infants as a treatment for chronic lung dysfunction. Results of clinical trials have shown that the use of GCs in these infants induces long-term deficits in neuromotor function and cognition. We have previously shown that a single exposure to clinically relevant doses of DEX or other GCs in the mouse during a period corresponding to the human perinatal period produces a dramatic increase in apoptotic cell death of neural progenitor cells in the developing cerebellum. To provide a model approximating more chronic clinical dosing regimens, we evaluated possible behavioral effects resulting from repeated exposures to DEX and subsequent GC-induced neuronal loss where neonatal mouse pups were injected with 3.0 mg/kg DEX or saline on postnatal days 7, 9, and 11 (DEX3 treatment). Adult, DEX3-treated mice exhibited long-term, possibly permanent, neuromotor deficits on a complex activity wheel task, which requires higher-order motor co-ordination skills. DEX3 mice exhibited impaired performance on this task relative to saline controls in each of two independent studies involving separate cohorts of mice. Histopathology studies utilizing stereological neuronal counts conducted in behaviorally-tested mice showed that the DEX3 treatment resulted in a significant decrease in the number of neurons in the internal granule layer (IGL) of the cerebellum, although the number of neurons in the Purkinje cell layer were unchanged. The results suggest that multiple neonatal DEX exposures can produce chronic deficits in fine motor co-ordination that are associated with cerebellar IGL neuronal loss.
doi:10.3390/behavsci1010004
PMCID: PMC3286606  PMID: 22375274
glucocorticoid; dexamethasone; neuromotor deficits; motor co-ordination; complex activity wheel; cerebellum; internal granule layer; neuron loss; apoptotic cell death
18.  The first reported cases of Q fever endocarditis in Thailand 
We describe the first two reported cases of Q fever endocarditis in Thailand. Both patients were male, had pre-existing heart valve damage and had contact with cattle. Heightened awareness of Q fever could improve diagnosis and case management and stimulate efforts to identify risk factors and preventive measures.
doi:10.4081/idr.2012.e7
PMCID: PMC3892650  PMID: 24470937
Coxiella burnetii; endocarditis; Q fever; Thailand.
19.  Long-term Effects of Multiple Glucocorticoid Exposures in Neonatal Mice 
Behavioral Sciences  2011;1(1):4-30.
Glucocorticoids (GCs) such as dexamethasone (DEX) or betamethasone are repeatedly administered for up to a month to prematurely born infants as a treatment for chronic lung dysfunction. Results of clinical trials have shown that the use of GCs in these infants induces long-term deficits in neuromotor function and cognition. We have previously shown that a single exposure to clinically relevant doses of DEX or other GCs in the mouse during a period corresponding to the human perinatal period produces a dramatic increase in apoptotic cell death of neural progenitor cells in the developing cerebellum. To provide a model approximating more chronic clinical dosing regimens, we evaluated possible behavioral effects resulting from repeated exposures to DEX and subsequent GC-induced neuronal loss where neonatal mouse pups were injected with 3.0 mg/kg DEX or saline on postnatal days 7, 9, and 11 (DEX3 treatment). Adult, DEX3-treated mice exhibited long-term, possibly permanent, neuromotor deficits on a complex activity wheel task, which requires higher-order motor co-ordination skills. DEX3 mice exhibited impaired performance on this task relative to saline controls in each of two independent studies involving separate cohorts of mice. Histopathology studies utilizing stereological neuronal counts conducted in behaviorally-tested mice showed that the DEX3 treatment resulted in a significant decrease in the number of neurons in the internal granule layer (IGL) of the cerebellum, although the number of neurons in the Purkinje cell layer were unchanged. The results suggest that multiple neonatal DEX exposures can produce chronic deficits in fine motor co-ordination that are associated with cerebellar IGL neuronal loss.
doi:10.3390/behavsci1010004
PMCID: PMC3286606  PMID: 22375274
glucocorticoid; dexamethasone; neuromotor deficits; motor co-ordination; complex activity wheel; cerebellum; internal granule layer; neuron loss; apoptotic cell death
20.  A Ketogenic Diet Does Not Impair Rat Behavior or Long-term Potentiation 
Epilepsia  2010;51(8):1619-1623.
Summary
The effect of the ketogenic diet on behavior and cognition is unclear. We addressed this issue in rats behaviorally and electrophysiologically. We fed postnatal day 21 rats a standard (SD), ketogenic (KD), or calorie-restricted (CR) diet for 2–3 weeks. CR controlled for the slower weight gain experienced by KD fed rats. We assessed behavioral performance with a locomotor activity and a conditioned fear test. To evaluate possible parallel effects of diet on synaptic function, we examined paired-pulse modulation (PPM) and long-term potentiation (LTP) in the medial perforant path in vivo. KD fed rats performed similarly to SD fed rats on the behavioral tests and electrophysiological assays. These data suggest that the KD does not alter behavioral performance or synaptic plasticity.
doi:10.1111/j.1528-1167.2009.02515.x
PMCID: PMC2996229  PMID: 20132289
Calorie-restricted; conditioned fear test; locomotor activity; medial perforant path; paired-pulse modulation
21.  Rabies-Related Knowledge and Practices Among Persons At Risk of Bat Exposures in Thailand 
Background
Rabies is a fatal encephalitis caused by lyssaviruses. Evidence of lyssavirus circulation has recently emerged in Southeast Asian bats. A cross-sectional study was conducted in Thailand to assess rabies-related knowledge and practices among persons regularly exposed to bats and bat habitats. The objectives were to identify deficiencies in rabies awareness, describe the occurrence of bat exposures, and explore factors associated with transdermal bat exposures.
Methods
A survey was administered to a convenience sample of adult guano miners, bat hunters, game wardens, and residents/personnel at Buddhist temples where mass bat roosting occurs. The questionnaire elicited information on demographics, experience with bat exposures, and rabies knowledge. Participants were also asked to describe actions they would take in response to a bat bite as well as actions for a bite from a potentially rabid animal. Bivariate analysis was used to compare responses between groups and multivariable logistic regression was used to explore factors independently associated with being bitten or scratched by a bat.
Findings
Of 106 people interviewed, 11 (10%) identified bats as a potential source of rabies. A history of a bat bite or scratch was reported by 29 (27%), and 38 (36%) stated either that they would do nothing or that they did not know what they would do in response to a bat bite. Guano miners were less likely than other groups to indicate animal bites as a mechanism of rabies transmission (68% vs. 90%, p = 0.03) and were less likely to say they would respond appropriately to a bat bite or scratch (61% vs. 27%, p = 0.003). Guano mining, bat hunting, and being in a bat cave or roost area more than 5 times a year were associated with history of a bat bite or scratch.
Conclusions
These findings indicate the need for educational outreach to raise awareness of bat rabies, promote exposure prevention, and ensure appropriate health-seeking behaviors for bat-inflicted wounds, particularly among at-risk groups in Thailand.
Author Summary
Rabies is a fatal encephalitis caused by lyssaviruses. Evidence of lyssavirus circulation has recently emerged in Southeast Asian bats. We surveyed persons regularly exposed to bats and bat habitats in Thailand to assess rabies‐related knowledge and practices. Targeted groups included guano miners, bat hunters, game wardens, and residents/personnel at Buddhist temples where mass bat roosting occurs. Of the 106 people interviewed, 11 (10%) identified bats as a source of rabies. History of a bat bite/scratch was reported by 29 (27%), and 38 (36%) expressed either that they would do nothing or that they did not know what they would do in response to a bat bite. Guano miners were less likely than other groups to indicate animal bites as a mechanism of transmission (68% vs. 90%, p=0.03) and were less likely to say they would respond appropriately to a bat bite or scratch (61% vs. 27%, p=0.003). These findings indicate a need for educational outreach in Thailand to raise awareness of bat rabies, promote exposure prevention, and ensure health‐seeking behaviors for bat‐inflicted wounds, particularly among at‐risk groups.
doi:10.1371/journal.pntd.0001054
PMCID: PMC3125144  PMID: 21738801
22.  Identification of Bartonella Infections in Febrile Human Patients from Thailand and Their Potential Animal Reservoirs 
To determine the role of Bartonella species as causes of acute febrile illness in humans from Thailand, we used a novel strategy of co-cultivation of blood with eukaryotic cells and subsequent phylogenetic analysis of Bartonella-specific DNA products. Bartonella species were identified in 14 blood clots from febrile patients. Sequence analysis showed that more than one-half of the genotypes identified in human patients were similar or identical to homologous sequences identified in rodents from Asia and were closely related to B. elizabethae, B. rattimassiliensis, and B. tribocorum. The remaining genotypes belonged to B. henselae, B. vinsonii, and B. tamiae. Among the positive febrile patients, animal exposure was common: 36% reported owning either dogs or cats and 71% reported rat exposure during the 2 weeks before illness onset. The findings suggest that rodents are likely reservoirs for a substantial portion of cases of human Bartonella infections in Thailand.
doi:10.4269/ajtmh.2010.09-0778
PMCID: PMC2877425  PMID: 20519614
23.  The first reported case of Bartonella endocarditis in Thailand 
Bartonella species have been shown to cause acute, undifferentiated fever in Thailand. A study to identify causes of endocarditis that were blood culture-negative using routine methods led to the first reported case in Thailand of Bartonella endocarditis A 57 year-old male with underlying rheumatic heart disease presented with severe congestive heart failure and suspected infective endocarditis. The patient underwent aortic and mitral valve replacement. Routine hospital blood cultures were negative but B. henselae was identified by serology, PCR, immunohistochemistry and specific culture techniques.
doi:10.4081/idr.2011.e9
PMCID: PMC3892604  PMID: 24470907
bartonella; endocarditis; cat scratch disease; Thailand.
24.  Recurrent Moderate Hypoglycemia Ameliorates Brain Damage and Cognitive Dysfunction Induced by Severe Hypoglycemia 
Diabetes  2010;59(4):1055-1062.
OBJECTIVE
Although intensive glycemic control achieved with insulin therapy increases the incidence of both moderate and severe hypoglycemia, clinical reports of cognitive impairment due to severe hypoglycemia have been highly variable. It was hypothesized that recurrent moderate hypoglycemia preconditions the brain and protects against damage caused by severe hypoglycemia.
RESEARCH DESIGN AND METHODS
Nine-week-old male Sprague-Dawley rats were subjected to either 3 consecutive days of recurrent moderate (25–40 mg/dl) hypoglycemia (RH) or saline injections. On the fourth day, rats were subjected to a hyperinsulinemic (0.2 units · kg−1 · min−1) severe hypoglycemic (∼11 mg/dl) clamp for 60 or 90 min. Neuronal damage was subsequently assessed by hematoxylin-eosin and Fluoro-Jade B staining. The functional significance of severe hypoglycemia–induced brain damage was evaluated by motor and cognitive testing.
RESULTS
Severe hypoglycemia induced brain damage and striking deficits in spatial learning and memory. Rats subjected to recurrent moderate hypoglycemia had 62–74% less brain cell death and were protected from most of these cognitive disturbances.
CONCLUSIONS
Antecedent recurrent moderate hypoglycemia preconditioned the brain and markedly limited both the extent of severe hypoglycemia–induced neuronal damage and associated cognitive impairment. In conclusion, changes brought about by recurrent moderate hypoglycemia can be viewed, paradoxically, as providing a beneficial adaptive response in that there is mitigation against severe hypoglycemia–induced brain damage and cognitive dysfunction.
doi:10.2337/db09-1495
PMCID: PMC2844814  PMID: 20086229
25.  The Burden of Hospitalized Lower Respiratory Tract Infection due to Respiratory Syncytial Virus in Rural Thailand 
PLoS ONE  2010;5(11):e15098.
Background
We describe the epidemiology of hospitalized RSV infections for all age groups from population-based surveillance in two rural provinces in Thailand.
Methods
From September 1, 2003 through December 31, 2007, we enrolled hospitalized patients with acute lower respiratory tract illness, who had a chest radiograph ordered by the physician, from all hospitals in SaKaeo and Nakhom Phanom Provinces. We tested nasopharyngeal specimens for RSV with reverse transcriptase polymerase chain reaction (RT-PCR) assays and paired-sera from a subset of patients with IgG enzyme immunoassay. Rates were adjusted for enrollment.
Results
Among 11,097 enrolled patients, 987 (8.9%) had RSV infection. Rates of hospitalized RSV infection overall (and radiographically-confirmed pneumonia) were highest among children aged <1 year: 1,067/100,000 (534/100,000 radiographically-confirmed pneumonia) and 1–4 year: 403/100,000 (222/100,000), but low among enrolled adults aged ≥65 years: 42/100,000. Age <1 year (adjusted odds ratio [aOR]  = 13.2, 95% confidence interval [CI] 7.7, 22.5) and 1–4 year (aOR = 8.3, 95% CI 5.0, 13.9) were independent predictors of hospitalized RSV infection.
Conclusions
The incidence of hospitalized RSV lower respiratory tract illness among children <5 years was high in rural Thailand. Efforts to prevent RSV infection could substantially reduce the pneumonia burden in children aged <5 years.
doi:10.1371/journal.pone.0015098
PMCID: PMC2994907  PMID: 21152047

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