Search tips
Search criteria

Results 1-9 (9)

Clipboard (0)

Select a Filter Below

Year of Publication
Document Types
1.  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
2.  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
3.  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.
4.  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
5.  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
6.  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
7.  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
8.  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
9.  World Health Organization Global Conference on Severe Acute Respiratory Syndrome 
Emerging Infectious Diseases  2003;9(9):1191-1192.
PMCID: PMC3016766  PMID: 14531385

Results 1-9 (9)