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1.  Developing an Assessment Process for a Master’s of Science Degree in a Pharmaceutical Sciences Program 
Objective. To develop a program-level assessment process for a master’s of science degree in a pharmaceutical sciences (MSPS) program.
Design. Program-level goals were created and mapped to course learning objectives. Embedded assessment tools were created by each course director and used to gather information related to program-level goals. Initial assessment iterations involved a subset of offered courses, and course directors met with the department assessment committee to review the quality of the assessment tools as well as the data collected with them. Insights from these discussions were used to improve the process. When all courses were used for collecting program-level assessment data, a modified system of guided reflection was used to reduce demands on committee members.
Assessment. The first two iterations of collecting program-level assessment revealed problems with both the assessment tools and the program goals themselves. Course directors were inconsistent in the Bloom’s Taxonomy level at which they assessed student achievement of program goals. Moreover, inappropriate mapping of program goals to course learning objectives were identified. These issues led to unreliable measures of how well students were doing with regard to program-level goals. Peer discussions between course directors and the assessment committee led to modification of program goals as well as improved assessment data collection tools.
Conclusion. By starting with a subset of courses and using course-embedded assessment tools, a program-level assessment process was created with little difficulty. Involving all faculty members and avoiding comparisons between courses made obtaining faculty buy-in easier. Peer discussion often resulted in consensus on how to improve assessment tools.
PMCID: PMC5066928  PMID: 27756933
program assessment; graduate education; pharmaceutical sciences
2.  Dual Proteolytic Pathways Govern Glycolysis and Immune Competence 
Cell  2014;159(7):1578-1590.
Proteasomes and lysosomes constitute the major cellular systems that catabolize proteins to recycle free amino acids for energy and new protein synthesis. Tripeptidyl peptidase II (TPPII) is a large cytosolic proteolytic complex that functions in tandem with the proteasome-ubiquitin protein degradation pathway. We found that autosomal recessive TPP2 mutations cause recurrent infections, autoimmunity, and neurodevelopmental delay in humans. We show that a major function of TPPII in mammalian cells is to maintain amino acid levels, and that TPPII-deficient cells compensate by increasing lysosome number and proteolytic activity. However, the overabundant lysosomes derange cellular metabolism by consuming the key glycolytic enzyme hexokinase-2 through chaperone-mediated autophagy. This reduces glycolysis and impairs the production of effector cytokines including IFN-γ and IL-1β. Thus, TPPII controls the balance between intracellular amino acid availability, lysosome number, and glycolysis, which is vital for adaptive and innate immunity and neurodevelopmental health.
PMCID: PMC4297473  PMID: 25525876
3.  Is my drinking a problem? A community-based alcohol intervention programme post-Haiyan in Tacloban City 
Evidence on alcohol use following disasters is scarce. After Typhoon Haiyan in the Philippines we wanted to determine whether there were alcohol-related problems among the disaster survivors and to strengthen the appropriate local health service support in Tacloban City.
Tacloban City is a highly urbanized city that was one of the areas worst hit by Typhoon Haiyan. Prior to Haiyan there was very little support for people with alcohol problems, and the rehabilitation facility was located about 40 km away.
A pilot community-based alcohol intervention programme was conducted that included: assessment of the extent of alcohol problems in the community and health-care workers baseline knowledge and skills; training of health-care workers on primary care alcohol intervention provision; and community outreach with post-training supervision.
The alcohol screening found 26 (22%) of those attending health care facilities would benefit from some form of alcohol intervention. Health-care workers knowledge on basic alcohol intervention was low. This was strengthened during the training, and at outreach clinics the trained health-care workers were able to identify people with alcohol problems and provide them with treatment plans.
Lessons learnt
We learnt that there was a problem with alcohol in Tacloban City and that it was possible to run an alcohol intervention programme in the community using minimal resources. Addressing alcohol-related issues in the community is an important public health intervention. While there is a need for policies and guidelines at the national level, a community-based intervention is possible to establish with referral mechanism to specialized care. Training modules for such programs can be further developed and institutionalized.
PMCID: PMC4710064  PMID: 26767145
4.  The prevention and control of dengue after Typhoon Haiyan 
Many of the areas in the Philippines affected by Typhoon Haiyan are endemic for dengue; therefore, dengue prevention was a priority in the initial post-disaster risk assessment. We describe the dengue prevention and response strategies applied after Haiyan.
The dengue response was implemented by a wide range of national and international stakeholders. Priorities included the rapid re-establishment of an effective surveillance system to quickly identify new dengue cases, monitor trends and determine the geographical distribution of cases. Dengue rapid diagnostic tests (RDTs) were distributed to sentinel health facilities, and comprehensive vector control activities and entomological surveys were implemented. Several training sessions for key stakeholders and awareness campaigns for communities were organized.
There were RDT-positive dengue cases reported from urban and semi-urban areas where entomological surveys also confirmed a high density of Aedes aegypti mosquitoes. Although there was an increase in dengue cases in January 2014, the number of cases remained below the epidemic threshold throughout the remaining months of 2014.
There was no large outbreak of dengue after Haiyan, possibly due to the targeted, multifaceted and rapid response for dengue after Haiyan. However, surveillance differed after Typhoon Haiyan, making comparisons with previous years difficult. Multiple players contributed to the response that was also facilitated by close communication and coordination within the Health Cluster.
PMCID: PMC4710066  PMID: 26767138
5.  Responding to the health and rehabilitation needs of people with disabilities post-Haiyan 
It is estimated that 15% of the world’s population has a disability, and disasters increase their risk and vulnerability. Rehabilitation services were limited in the area of the Philippines that was affected by Typhoon Haiyan. This study describes the initial rehabilitation needs assessment and activities to increase rehabilitation services conducted in Leyte province of Region 8 after Haiyan.
A rehabilitation needs assessment for people with disabilities and injuries needing physical and functional rehabilitation care and assistive devices was conducted in health facilities, evacuation centres and selected municipalities in Leyte province between 9 November 2013 and 30 April 2014 by a consortium of agencies. Improvements to service delivery and referrals were documented.
Rehabilitation services were reduced immediately after Haiyan, but they increased in the following months and peaked four months after Haiyan. There were 2998 individuals needing medicine and rehabilitation management, functional care and assistive devices. These included persons with pre-existing disabilities whose situations had worsened and people who had sustained injuries in the typhoon. Additional improvements included rehabilitation services with provision of assistive devices at the regional hospital, development of a directory of disability services in the region and advocacy through community-based rehabilitation.
Information services and community knowledge for people with disabilities improved in Region 8 after Typhoon Haiyan, demonstrating that strengthening rehabilitation systems is a realistic goal after disasters.
PMCID: PMC4710068  PMID: 26767137
6.  Responding to Typhoon Haiyan in the Philippines 
PMCID: PMC4710071  PMID: 26767125
10.  Restarting the tuberculosis programme post-Haiyan 
Typhoon Haiyan damaged or destroyed health infrastructure, equipment and services essential to the Philippine National Tuberculosis Programme (NTP), and it had to be re-established in the affected areas in Regions 6, 7 and 8. Continuing treatment and restoring diagnostic capacity were also challenging.
The Philippines has one of the highest tuberculosis (TB) burdens in the world. At the time of Typhoon Haiyan, there were an estimated 26 600 TB cases on treatment at directly observed treatment, short-course (DOTS) centres and 356 multidrug-resistant TB cases registered at programmatic management of drug-resistant TB (PMDT) sites. As TB was not included in the Philippines early-warning post-disaster surveillance system, tracking TB patients was difficult after Haiyan.
Actions and outcomes
Immediately following Haiyan, each aspect of the NTP was assessed to determine the extent of damage. TB patients were traced and services restored. We created maps showing the location of temporary TB diagnostic and treatment services, which hastened referrals. We provided new laboratory equipment, training and rapid testing capabilities in the affected regions. All TB services in the affected areas (473 DOTS, 490 TB microscopy and six PMDT facilities) were restored just two months after Haiyan.
Lessons learnt
Key lessons learnt from the NTP experience following Tyhoon Haiyan were: (1) the importance of having an electronic TB registry (database); (2) the need to include TB in the post-disaster surveillance system; (3) clear guidelines for TB control in disasters; and (4) the importance of coordination with all partners.
PMCID: PMC4710080  PMID: 26767144
11.  Social media as a risk communication tool following Typhoon Haiyan 
In the aftermath of Typhoon Haiyan, the World Health Organization (WHO) Representative Office in the Philippines had no social media presence to share timely, relevant public health information.
Risk communication is essential to emergency management for public health message dissemination. As social media sites, such as Facebook, are popular in the Philippines, these were adopted for risk communication during the response to Haiyan.
Action and outcome
The WHO Representative Office in the Philippines established Facebook, Twitter and Instagram accounts. Thirty days after these social medial channels were established, a gradual increase in followers was observed. Facebook saw the largest increase in followers which occurred as posted content gradually evolved from general public health information to more pro-active public health intervention and preparedness messaging. This included information on key health interventions encouraging followers to adopt protective behaviours to mitigate public health threats that frequently occur after a disaster.
Lessons learnt
During the response to Haiyan, creating a social media presence, raising a follower base and developing meaningful messages and content was possible. This event underscored the importance of building a social media strategy in non-emergency times and supported the value of developing public health messages and content that both educates and interests the general public.
PMCID: PMC4710081  PMID: 26767143
12.  A snapshot of catastrophic post-disaster health expenses after Typhoon Haiyan 
This paper provides a snapshot of the health-care costs, out-of-pocket expenditures and available safety nets post-Typhoon Haiyan.
This descriptive study used a survey and document review to report direct and indirect health-care costs and existing financial protection mechanisms used by households in two municipalities in the Philippines at one week and at seven months post-Haiyan.
Reported out-of-pocket health-care expenses were high immediately after the disaster and increased after seven months. The mean reported out-of-pocket expenses were higher than the reported average household income (US$ 24 to US$ 59).
The existing local and national mechanisms for health financing were promising and should be strengthened to reduce out-of-pocket expenses and protect people from catastrophic expenditures. Longer-term mechanisms are needed to ensure financial protection, especially among the poorest, beyond three months when most free services and medicines have ended. Preparedness should include prior registration of households that would ensure protection when a disaster comes.
PMCID: PMC4710082  PMID: 26767141
13.  Exposure to cold weather during a mass gathering in the Philippines 
The visit of Pope Francis to the Philippines in January 2015 coincided with a tropical storm. For security reasons, the only road in and out of the area was closed 14.5 hours before the Pope’s arrival. This meant that people had to wait for many hours with little shelter at the site. Medical teams in the field reported high numbers of people with cold stress during the mass gathering.
To review the event from a public health perspective, we examined the consultations made by medical teams in the field and interviewed key stakeholders, focusing on cold stress as a public health risk.
Local setting
The key reason for the Pope’s visit to Palo and Tacloban was the devastation caused in these cities by typhoon Haiyan in 2013. We estimated that the visit attracted 300 000 people. The medical teams were advised to consider cold stress risks two days before the event but no other measures were taken.
Relevant changes
Of the 1051 people seeking medical care, 231 people were experiencing symptoms of cold stress. People with cold stress ranged from 2 to 89 years of age and were more likely to be female than male, 173 (75%) versus 57 (25%).
Lessons learnt
Planning for mass gatherings should consider a wide range of public health risks, including cold stress. Improved data collection from the field is necessary to maximize the benefits of post-event evaluations and improve public health preparedness. Security measures to ensure the safety of key figures must be balanced with public health risks.
PMCID: PMC4622163  PMID: 26549910
14.  LRPPRC mutations cause early-onset multisystem mitochondrial disease outside of the French-Canadian population 
Brain  2015;138(12):3503-3519.
The French-Canadian variant of COX-deficient Leigh syndrome (LSFC) is unique to Québec and caused by a founder mutation in the LRPPRC gene. Using whole exome sequencing, Oláhová et al. identify mutations in this gene associated with multisystem mitochondrial disease and early-onset neurodevelopmental problems in ten patients from different ethnic backgrounds.
The French-Canadian variant of COX-deficient Leigh syndrome (LSFC) is unique to Québec and caused by a founder mutation in the LRPPRC gene. Using whole exome sequencing, Oláhová et al. identify mutations in this gene associated with multisystem mitochondrial disease and early-onset neurodevelopmental problems in ten patients from different ethnic backgrounds.
Mitochondrial Complex IV [cytochrome c oxidase (COX)] deficiency is one of the most common respiratory chain defects in humans. The clinical phenotypes associated with COX deficiency include liver disease, cardiomyopathy and Leigh syndrome, a neurodegenerative disorder characterized by bilateral high signal lesions in the brainstem and basal ganglia. COX deficiency can result from mutations affecting many different mitochondrial proteins. The French-Canadian variant of COX-deficient Leigh syndrome is unique to the Saguenay-Lac-Saint-Jean region of Québec and is caused by a founder mutation in the LRPPRC gene. This encodes the leucine-rich pentatricopeptide repeat domain protein (LRPPRC), which is involved in post-transcriptional regulation of mitochondrial gene expression. Here, we present the clinical and molecular characterization of novel, recessive LRPPRC gene mutations, identified using whole exome and candidate gene sequencing. The 10 patients come from seven unrelated families of UK-Caucasian, UK-Pakistani, UK-Indian, Turkish and Iraqi origin. They resemble the French-Canadian Leigh syndrome patients in having intermittent severe lactic acidosis and early-onset neurodevelopmental problems with episodes of deterioration. In addition, many of our patients have had neonatal cardiomyopathy or congenital malformations, most commonly affecting the heart and the brain. All patients who were tested had isolated COX deficiency in skeletal muscle. Functional characterization of patients’ fibroblasts and skeletal muscle homogenates showed decreased levels of mutant LRPPRC protein and impaired Complex IV enzyme activity, associated with abnormal COX assembly and reduced steady-state levels of numerous oxidative phosphorylation subunits. We also identified a Complex I assembly defect in skeletal muscle, indicating different roles for LRPPRC in post-transcriptional regulation of mitochondrial mRNAs between tissues. Patient fibroblasts showed decreased steady-state levels of mitochondrial mRNAs, although the length of poly(A) tails of mitochondrial transcripts were unaffected. Our study identifies LRPPRC as an important disease-causing gene in an early-onset, multisystem and neurological mitochondrial disease, which should be considered as a cause of COX deficiency even in patients originating outside of the French-Canadian population.
PMCID: PMC4655343  PMID: 26510951
LRPPRC; COX deficiency; mitochondrial disease; Leigh syndrome; malformations
15.  Outcome after surgical or conservative management of cerebral cavernous malformations 
Neurology  2014;83(7):582-589.
There have been few comparative studies of microsurgical excision vs conservative management of cerebral cavernous malformations (CCM) and none of them has reliably demonstrated a statistically and clinically significant difference.
We conducted a prospective, population-based study to identify and independently validate definite CCM diagnoses first made in 1999–2003 in Scottish adult residents. We used multiple sources of prospective follow-up to assess adults' dependence and to identify and independently validate outcome events. We used univariate and multivariable survival analyses to test the influence of CCM excision on outcome, adjusted for prognostic factors and baseline imbalances.
Of 134 adults, 25 underwent CCM excision; these adults were younger (34 vs 43 years at diagnosis, p = 0.004) and more likely to present with symptomatic intracranial hemorrhage or focal neurologic deficit than adults managed conservatively (48% vs 26%; odds ratio 2.7, 95% confidence interval [CI] 1.1–6.5). During 5 years of follow-up, CCM excision was associated with a deterioration to an Oxford Handicap Scale score 2–6 sustained over at least 2 successive years (adjusted hazard ratio [HR] 2.2, 95% CI 1.1–4.3) and the occurrence of symptomatic intracranial hemorrhage or new focal neurologic deficit (adjusted HR 3.6, 95% CI 1.3–10.0).
CCM excision was associated with worse outcomes over 5 years compared to conservative management. Long-term follow-up will determine whether this difference is sustained over patients' lifetimes. Meanwhile, a randomized controlled trial appears justified.
Classification of evidence:
This study provides Class III evidence that CCM excision worsens short-term disability scores and increases the risk of symptomatic intracranial hemorrhage and new focal neurologic deficits.
PMCID: PMC4141991  PMID: 24994841
16.  Hospital preparedness for Ebola virus disease: a training course in the Philippines 
To develop, teach and evaluate a training workshop that could rapidly prepare large numbers of health professionals working in hospitals in the Philippines to detect and safely manage Ebola virus disease (EVD). The strategy was to train teams (each usually with five members) of key health professionals from public, private and local government hospitals across the Philippines who could then guide Ebola preparedness in their hospitals.
The workshop was developed collaboratively by the Philippine Department of Health and the country office of the World Health Organization. It was evaluated using a pre- and post-workshop test and two evaluation forms. χ2 tests and linear regression analyses were conducted comparing pre- and post-workshop test results.
A three-day workshop was developed and used to train 364 doctors, nurses and medical technologists from 78 hospitals across the Philippines in three initial batches. Knowledge about EVD increased significantly (P < 0.009) although knowledge on transmission remained suboptimal. Confidence in managing EVD increased significantly (P = 0.018) with 96% of participants feeling more prepared to safely manage EVD cases.
Discussion: The three-day workshop to prepare hospital staff for EVD was effective at increasing the level of knowledge about EVD and the level of confidence in managing EVD safely. This workshop could be adapted for use as baseline training in EVD in other developing countries to prepare large numbers of hospital staff to rapidly detect, isolate and safely manage EVD cases.
PMCID: PMC4410102  PMID: 25960920
17.  Endocrine Disrupting Chemicals Promote the Growth of Ovarian Cancer Cells via the ER-CXCL12-CXCR4 Signaling Axis 
Molecular carcinogenesis  2012;52(9):715-725.
The majority of ovarian cancers over-express the estrogen receptor (ERα) and grow in response to estrogens. We previously demonstrated that ER induction of the chemokine CXCL12 (stromal cell-derived facor-1) is required for estradiol (E2)-stimulated proliferation of human ovarian carcinoma cells. In the current study we report that known ‘endocrine disrupting chemicals’ (EDCs) display mitogenic activities in ovarian cancer cells via their ability to activate the ER and upregulate CXCL12 expression. Notably, the EDCs genistein, bisphenol A and HPTE stimulated both cell proliferation and induction of CXCL12 mRNA and protein in a manner comparable to estradiol. The effects were completely attenuated by the ER antagonist ICI 182,780, revealing that observed activities of these agents were receptor-mediated. In cell proliferation assays the mitogenic effects of estradiol and EDCs were obviated by siRNAs targeting CXCL12 and restored upon addition of exogenous CXCL12. Furthermore, an inhibitor to the CXCL12 receptor CXCR4 completely attenuated growth-stimulatory effects of E2 and EDCs. These studies highlight a potential role of EDCs possessing estrogenic activities in the etiology of ovarian cancer. Moreover, they suggest that the ER-CXCL12-CXCR4 signaling axis may represent a promising target for development of therapeutics for ER+ ovarian cancers.
PMCID: PMC4287997  PMID: 22549810
endocrine disrupting chemicals (EDCs); ovarian cancer; estrogen receptor; cell proliferation; CXCL12; CXCR4
18.  Role of MTL-1, MTL-2, and CDR-1 in Mediating CadmiumSensitivity in Caenorhabditis elegans  
Toxicological Sciences  2012;128(2):418-426.
Cadmium is an environmental toxicant whose exposure is associated with multiple human pathologies. To prevent cadmium-induced toxicity, organisms produce a variety of detoxification molecules. In response to cadmium, the nematode Caenorhabditis elegans increases the steady-state levels of several hundred genes, including two metallothioneins, mtl-1 and mtl-2, and the cadmium-specific response gene, cdr-1. Despite the presumed importance in metal detoxification of mtl-1 and mtl-2, knockdown of their expression does not increase cadmium hypersensitivity, which suggests that these genes are not required for resistance to metal toxicity in C. elegans. To determine whether cdr-1 is critical in metal detoxification and compensates for the loss of mtl-1 and/or mtl-2, C. elegans strains were generated in which one, two, and all three genes were deleted, and the effects of cadmium on brood size, embryonic lethality, the Bag phenotype, and growth were determined. Growth at low cadmium concentrations was the only endpoint in which the triple mutant displayed more sensitivity than the single and double mutants. A lack of hypersensitivity in these strains suggests that other factors may be involved in the response to cadmium. Caenorhabditis elegans produces phytochelatins (PCs) that are critical in the defense against cadmium toxicity. PC levels in wild type, cdr-1 single, mtl-1, mtl-2 double, and triple mutants were measured. PC levels were constitutively higher in the mtl-1, mtl-2 double, and triple mutants compared with wild type. Following cadmium exposure, PC levels increased. The lack of cadmium hypersensitivity when these genes are deleted may be attributed to the compensatory effects of increases in PCs.
PMCID: PMC3493192  PMID: 22552775
Caenorhabditis elegans; metallothionein; cadmium; phytochelatin.
19.  Untreated clinical course of cerebral cavernous malformations: a prospective, population-based cohort study 
Lancet Neurology  2012;11(3):150-156.
Cerebral cavernous malformations (CCMs) are prone to bleeding but the risk of intracranial haemorrhage and focal neurological deficits, and the factors that might predict their occurrence, are unclear. We aimed to quantify these risks and investigate whether they are affected by sex and CCM location.
We undertook a population-based study using multiple overlapping sources of case ascertainment (including a Scotland-wide collaboration of neurologists, neurosurgeons, stroke physicians, radiologists, and pathologists, as well as searches of registers of hospital discharges and death certificates) to identify definite CCM diagnoses first made in Scottish residents between 1999 and 2003, which study neuroradiologists independently validated. We used multiple sources of prospective follow-up both to identify outcome events (which were assessed by use of brain imaging, by investigators masked to potential predictive factors) and to assess adults' dependence. The primary outcome was a composite of intracranial haemorrhage or focal neurological deficits (not including epileptic seizure) that were definitely or possibly related to CCM.
139 adults had at least one definite CCM and 134 were alive at initial presentation. During 1177 person-years of follow-up (completeness 97%), for intracranial haemorrhage alone the 5-year risk of a first haemorrhage was lower than the risk of recurrent haemorrhage (2·4%, 95% CI 0·0–5·7 vs 29·5%, 4·1–55·0; p<0·0001). For the primary outcome, the 5-year risk of a first event was lower than the risk of recurrence (9·3%, 3·1–15·4 vs 42·4%, 26·8–58·0; p<0·0001). The annual risk of recurrence of the primary outcome declined from 19·8% (95% CI 6·1–33·4) in year 1 to 5·0% (0·0–14·8) in year 5 and was higher for women than men (p=0·01) but not for adults with brainstem CCMs versus CCMs in other locations (p=0·17).
The risk of recurrent intracranial haemorrhage or focal neurological deficit from a CCM is greater than the risk of a first event, is greater for women than for men, and declines over 5 years. This information can be used in clinical practice, but further work is needed to quantify risks precisely in the long term and to understand why women are at greater risk of recurrence than men.
UK Medical Research Council, Chief Scientist Office of the Scottish Government, and UK Stroke Association.
PMCID: PMC3282211
20.  A developmental neuroimaging investigation of the change paradigm 
Developmental science  2011;14(1):148-161.
This neuroimaging study examines the development of cognitive flexibility using the Change task in a sample of youths and adults. The Change task requires subjects to inhibit a prepotent response and substitute an alternate response, and the task incorporates an algorithm that adjusts task difficulty in response to subject performance. Data from both groups combined show a network of prefrontal and parietal areas that are active during the task. For adults vs. youths, a distributed network was more active for successful change trials versus go, baseline, or unsuccessful change trials. This network included areas involved in rule representation, retrieval (lateral PFC), and switching (medial PFC and parietal regions). These results are consistent with data from previous task-switching experiments and inform developmental understandings of cognitive flexibility.
PMCID: PMC3036172  PMID: 21159096
change task; development; strategy; executive function; cognitive control
21.  The Caenorhabditis elegans Homolog of Gen1/Yen1 Resolvases Links DNA Damage Signaling to DNA Double-Strand Break Repair 
PLoS Genetics  2010;6(7):e1001025.
DNA double-strand breaks (DSBs) can be repaired by homologous recombination (HR), which can involve Holliday junction (HJ) intermediates that are ultimately resolved by nucleolytic enzymes. An N-terminal fragment of human GEN1 has recently been shown to act as a Holliday junction resolvase, but little is known about the role of GEN-1 in vivo. Holliday junction resolution signifies the completion of DNA repair, a step that may be coupled to signaling proteins that regulate cell cycle progression in response to DNA damage. Using forward genetic approaches, we identified a Caenorhabditis elegans dual function DNA double-strand break repair and DNA damage signaling protein orthologous to the human GEN1 Holliday junction resolving enzyme. GEN-1 has biochemical activities related to the human enzyme and facilitates repair of DNA double-strand breaks, but is not essential for DNA double-strand break repair during meiotic recombination. Mutational analysis reveals that the DNA damage-signaling function of GEN-1 is separable from its role in DNA repair. GEN-1 promotes germ cell cycle arrest and apoptosis via a pathway that acts in parallel to the canonical DNA damage response pathway mediated by RPA loading, CHK1 activation, and CEP-1/p53–mediated apoptosis induction. Furthermore, GEN-1 acts redundantly with the 9-1-1 complex to ensure genome stability. Our study suggests that GEN-1 might act as a dual function Holliday junction resolvase that may coordinate DNA damage signaling with a late step in DNA double-strand break repair.
Author Summary
Coordination of DNA repair with cell cycle progression and apoptosis is a central task of the DNA damage response machinery. A key intermediate of recombinational repair and meiotic recombination, first proposed in 1964, involves four-stranded DNA structures. These intermediates have to be resolved upon completion of DNA repair to allow for proper chromosome segregation. Using forward genetics, we identified a Caenorhabditis elegans dual function DNA double-strand break repair and DNA damage signaling protein orthologous to the human GEN1 Holliday junction resolving enzyme. GEN-1 facilitates repair of DNA double-strand breaks, but is not essential for DNA double-strand break repair during meiotic recombination. The DNA damage signaling function of GEN-1 is separable from its role in DNA repair. Unexpectedly, GEN-1 defines a DNA damage-signaling pathway that acts in parallel to the canonical pathway mediated by CHK-1 phosphorylation and CEP-1/p53. Thus, an enzyme that can resolve Holliday junctions may directly couple a late step in DNA repair to a pathway that regulates cell cycle progression in response to DNA damage.
PMCID: PMC2908289  PMID: 20661466
22.  Low Salinity and High-Level UV-B Radiation Reduce Single-Cell Activity in Antarctic Sea Ice Bacteria▿  
Applied and Environmental Microbiology  2009;75(23):7570-7573.
Experiments simulating the sea ice cycle were conducted by exposing microbes from Antarctic fast ice to saline and irradiance regimens associated with the freeze-thaw process. In contrast to hypersaline conditions (ice formation), the simulated release of bacteria into hyposaline seawater combined with rapid exposure to increased UV-B radiation significantly reduced metabolic activity.
PMCID: PMC2786431  PMID: 19801462
23.  Leptospirosis in the Asia Pacific region 
Leptospirosis is a worldwide zoonotic infection that has been recognized for decades, but the problem of the disease has not been fully addressed, particularly in resource-poor, developing countries, where the major burden of the disease occurs. This paper presents an overview of the current situation of leptospirosis in the region. It describes the current trends in the epidemiology of leptospirosis, the existing surveillance systems, and presents the existing prevention and control programs in the Asia Pacific region.
Data on leptospirosis in each member country were sought from official national organizations, international public health organizations, online articles and the scientific literature. Papers were reviewed and relevant data were extracted.
Leptospirosis is highly prevalent in the Asia Pacific region. Infections in developed countries arise mainly from occupational exposure, travel to endemic areas, recreational activities, or importation of domestic and wild animals, whereas outbreaks in developing countries are most frequently related to normal daily activities, over-crowding, poor sanitation and climatic conditions.
In the Asia Pacific region, predominantly in developing countries, leptospirosis is largely a water-borne disease. Unless interventions to minimize exposure are aggressively implemented, the current global climate change will further aggravate the extent of the disease problem. Although trends indicate successful control of leptospirosis in some areas, there is no clear evidence that the disease has decreased in the last decade. The efficiency of surveillance systems and data collection varies significantly among the countries and areas within the region, leading to incomplete information in some instances. Thus, an accurate reflection of the true burden of the disease remains unknown.
PMCID: PMC2749047  PMID: 19732423
24.  World Health Organization Global Conference on Severe Acute Respiratory Syndrome 
Emerging Infectious Diseases  2003;9(9):1191-1192.
PMCID: PMC3016766  PMID: 14531385

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