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2.  Safety and pharmacokinetics of aciclovir in women following release from a silicone elastomer vaginal ring 
Objectives
Systemic aciclovir and its prodrug valaciclovir are effective in treating and reducing recurrences of genital herpes simplex virus (HSV) and reducing transmission. Local aciclovir delivery, if it can achieve and maintain comparable intracellular genital tract levels, may be equally effective in the treatment and suppression of genital HSV. Intravaginal ring (IVR) delivery of aciclovir may provide pre-exposure prophylaxis against HSV acquisition.
Methods
Tolerability and pharmacokinetics were evaluated in six HIV-negative women with recurrent genital HSV who switched their daily oral valaciclovir suppression to an aciclovir IVR for 7 days (n = 3) or 14 days (n = 3). Blood and cervicovaginal lavage (CVL) were collected after oral and IVR dosing to measure aciclovir concentrations and genital swabs were obtained to quantify HSV shedding by PCR.
Results
The rings were well tolerated. Median plasma aciclovir concentrations were 110.2 ng/mL (IQR, 85.9–233.5) 12–18 h after oral valaciclovir. Little or no drug was detected in plasma following IVR dosing. Median (IQR) CVL aciclovir levels were 127.3 ng/mL (21–660.8) 2 h after oral valaciclovir, 154.4 ng/mL (60.7–327.5) 12–18 h after oral valaciclovir and 438 ng/mL (178.5–618.5) after 7 days and 393 ng/mL (31.6–1615) after 14 days of aciclovir ring use. Median CVL aciclovir levels 2 h after oral dosing were similar to levels observed 7 (P = 0.99) and 14 (P = 0.75) days after ring use. HSV DNA was not detected in genital swabs and there was no significant change in inflammatory mediators.
Conclusions
This first-in-human study demonstrated that an IVR could safely deliver mucosal levels of aciclovir similar to oral valaciclovir without systemic absorption. More intensive site-specific pharmacokinetic studies are needed to determine whether higher local concentrations are needed to achieve optimal drug distribution within the genital tract.
doi:10.1093/jac/dks151
PMCID: PMC3394441  PMID: 22556381
herpes simplex virus; vaginal microbicides; genital herpes
3.  The Effect of Intermittent Antenatal Iron Supplementation on Maternal and Infant Outcomes in Rural Viet Nam: A Cluster Randomised Trial 
PLoS Medicine  2013;10(6):e1001470.
Beverley-Anne Biggs and colleagues conduct a community-based cluster randomized trial in rural Viet Nam to compare the effect of antenatal iron-folic acid supplementation taken daily or twice weekly on maternal and infant outcomes.
Please see later in the article for the Editors' Summary
Background
Anemia affects over 500 million women, and in pregnancy is associated with impaired maternal and infant outcomes. Intermittent antenatal iron supplementation is an attractive alternative to daily dosing; however, the impact of this strategy on infant outcomes remains unclear. We compared the effect of intermittent antenatal iron supplementation with daily iron supplementation on maternal and infant outcomes in rural Viet Nam.
Methods and Findings
This cluster randomised trial was conducted in Ha Nam province, Viet Nam. 1,258 pregnant women (<16 wk gestation) in 104 communes were assigned to daily iron–folic acid (IFA), twice weekly IFA, or twice weekly multiple micronutrient (MMN) supplementation. Primary outcome was birth weight. Mean birth weight was 3,148 g (standard deviation 416). There was no difference in the birth weights of infants of women receiving twice weekly IFA compared to daily IFA (mean difference [MD] 28 g; 95% CI −22 to 78), or twice weekly MMN compared to daily IFA (MD −36.8 g; 95% CI −82 to 8.2). At 32 wk gestation, maternal ferritin was lower in women receiving twice weekly IFA compared to daily IFA (geometric mean ratio 0.73; 95% CI 0.67 to 0.80), and in women receiving twice weekly MMN compared to daily IFA (geometric mean ratio 0.62; 95% CI 0.57 to 0.68), but there was no difference in hemoglobin levels. Infants of mothers who received twice weekly IFA had higher cognitive scores at 6 mo of age compared to those who received daily IFA (MD 1.89; 95% CI 0.23 to 3.56).
Conclusions
Twice weekly antenatal IFA or MMN did not produce a clinically important difference in birth weight, when compared to daily IFA supplementation. The significant improvement in infant cognitive outcomes at 6 mo of age following twice weekly antenatal IFA requires further exploration, and provides additional support for the use of intermittent, rather than daily, antenatal IFA in populations with low rates of iron deficiency.
Trial registration
Australia New Zealand Clinical Trials Registry 12610000944033
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Anemia is a common condition in which the blood does not supply the body with enough oxygen because of a low number of red blood cells or low levels of hemoglobin—the iron-containing pigment that enables red blood cells to carry oxygen. Iron deficiency is the most common cause of anemia worldwide and, according to the World Health Organization, affects over 2 billion people: half of all pregnant women and 40% of preschool children in low- and middle-income countries are thought to be anemic. Anemia contributes to 20% of all maternal deaths and is also linked to increased maternal morbidity, higher rates of preterm birth and low birth weight, and reduced infant survival, with potential long-term consequences for child growth and development. Identifying and treating iron deficiency anemia is therefore a global health priority.
Why Was This Study Done?
Daily iron–folic acid supplementation given from early in pregnancy is the standard recommended approach to prevent and treat anemia in pregnant women, but recently the World Health Organization recommended intermittent use because of poor compliance with daily regimes (because of side effects) and poor bowel absorption. However, the evidence from many of the studies used to support this recommendation was of poor quality, and so it remains unclear whether intermittent supplementation is as, or more, effective than daily supplementation, especially in lower income settings where antenatal testing for anemia is not readily available. So in this study, the researchers conducted a community-based cluster randomized trial (where groups of people are randomized, rather than individuals) in rural Viet Nam to compare the effect of antenatal iron–folic acid supplementation taken twice weekly (either alone, or in combination with other micronutrients) with daily iron–folic acid supplementation, on maternal and infant outcomes during the first six months of life.
What Did the Researchers Do and Find?
The researchers randomized 104 communes in Ha Nam Province, Viet Nam, and enrolled 1,258 women who were less than 16 weeks pregnant into the study between September and November 2010. Although the researchers intended to register the trial before the study started, registration was delayed by a month because the supplements arrived earlier than the researchers anticipated, and they thought it best to start recruiting at that time to avoid the Vietnamese New Year, when women might be travelling. Each woman was interviewed and had blood taken for hemoglobin and iron indices (ferritin) before receiving daily iron–folic acid supplementation (426 women), twice weekly iron–folic acid supplementation (425 women), or twice weekly iron–folic acid supplementation plus micronutrients (407 women). The women had follow-up assessments at 32 weeks gestation, delivery, and at six months postpartum: their infants were assessed at birth and at six months old.
The researchers found that at enrollment, the women's average hemoglobin concentration was 123 g/l, and 12.6% of the women were anemic. At 32 weeks gestation, 10.8% of the women were anemic, but there was no difference in hemoglobin levels between the three supplement groups. The average ferritin level was 75.6 µg/l at enrollment, with 2.2% of women iron deficient. Ferritin levels decreased from enrollment to 32 weeks gestation in all supplement groups but were lower in women who took twice weekly supplements. The researchers also found that birth weight (the primary outcome) was similar in all supplement groups, and there were also no differences in gestational age or in the risk of prematurity, stillbirth, or early neonatal death. At six months, there were also no differences in the levels of infant hemoglobin, prevalence of anemia, or growth rates. However, infants born to mothers in the twice weekly iron–folic acid group had improved cognitive development compared to infants born to mothers in the daily supplement group. Finally, the researchers found that adherence rates were significantly higher in the twice weekly iron–folic acid supplement group compared to the once daily regime.
What Do These Findings Mean?
These findings suggest that in an area of Southeast Asia with low anemia prevalence, once daily antenatal supplementation with iron–folic acid did not provide any benefits in birth weight or improved infant growth over twice weekly supplementation. Furthermore, twice weekly supplementation with iron–folic acid was associated with improved maternal adherence rates and also improved cognitive development in infants aged six months—a finding that requires further study and provides added support for the use of intermittent iron–folic acid supplementation over daily supplementation.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001470.
The World Health Organization website has comprehensive information on anemia, including a report of global estimates and the guideline Intermittent Iron and Folic Acid Supplementation in Non-Anaemic Pregnant Women
Wikipedia provides information on iron supplementation (note: Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
doi:10.1371/journal.pmed.1001470
PMCID: PMC3708703  PMID: 23853552
4.  Responder and nonresponder patients exhibit different peripheral transcriptional signatures during major depressive episode 
Translational Psychiatry  2012;2(11):e185-.
To date, it remains impossible to guarantee that short-term treatment given to a patient suffering from a major depressive episode (MDE) will improve long-term efficacy. Objective biological measurements and biomarkers that could help in predicting the clinical evolution of MDE are still warranted. To better understand the reason nearly half of MDE patients respond poorly to current antidepressive treatments, we examined the gene expression profile of peripheral blood samples collected from 16 severe MDE patients and 13 matched controls. Using a naturalistic and longitudinal design, we ascertained mRNA and microRNA (miRNA) expression at baseline, 2 and 8 weeks later. On a genome-wide scale, we detected transcripts with roles in various biological processes as significantly dysregulated between MDE patients and controls, notably those involved in nucleotide binding and chromatin assembly. We also established putative interactions between dysregulated mRNAs and miRNAs that may contribute to MDE physiopathology. We selected a set of mRNA candidates for quantitative reverse transcriptase PCR (RT-qPCR) to validate that the transcriptional signatures observed in responders is different from nonresponders. Furthermore, we identified a combination of four mRNAs (PPT1, TNF, IL1B and HIST1H1E) that could be predictive of treatment response. Altogether, these results highlight the importance of studies investigating the tight relationship between peripheral transcriptional changes and the dynamic clinical progression of MDE patients to provide biomarkers of MDE evolution and prognosis.
doi:10.1038/tp.2012.112
PMCID: PMC3565773  PMID: 23149449
antidepressant; biomarker; miRNA; mood disorder; PBMC; transcriptome
5.  Responder and nonresponder patients exhibit different peripheral transcriptional signatures during major depressive episode 
Translational Psychiatry  2012;2(10):e185-.
To date, it remains impossible to guarantee that short-term treatment given to a patient suffering from a major depressive episode (MDE) will improve long-term efficacy. Objective biological measurements and biomarkers that could help in predicting the clinical evolution of MDE are still warranted. To better understand the reason nearly half of MDE patients respond poorly to current antidepressive treatments, we examined the gene expression profile of peripheral blood samples collected from 16 severe MDE patients and 13 matched controls. Using a naturalistic and longitudinal design, we ascertained mRNA and microRNA (miRNA) expression at baseline, 2 and 8 weeks later. On a genome-wide scale, we detected transcripts with roles in various biological processes as significantly dysregulated between MDE patients and controls, notably those involved in nucleotide binding and chromatin assembly. We also established putative interactions between dysregulated mRNAs and miRNAs that may contribute to MDE physiopathology. We selected a set of mRNA candidates for quantitative reverse transcriptase PCR (RT-qPCR) to validate that the transcriptional signatures observed in responders is different from nonresponders. Furthermore, we identified a combination of four mRNAs (PPT1, TNF, IL1B and HIST1H1E) that could be predictive of treatment response. Altogether, these results highlight the importance of studies investigating the tight relationship between peripheral transcriptional changes and the dynamic clinical progression of MDE patients to provide biomarkers of MDE evolution and prognosis.
doi:10.1038/tp.2012.112
PMCID: PMC3565819
antidepressant; biomarker; miRNA; mood disorder; PBMC; transcriptome
6.  Expression of Interleukin-22 in Sjögren’s Syndrome: Significant Correlation with Disease Parameters 
Sjögren’s syndrome (SS) is an autoimmune disease targeting the exocrine glands resulting in xerostomia/keratoconjunctivitis sicca. Presently, we examined the levels and clinical correlations of IL-22 in SS. Patients with SS together with normal controls were randomly selected. IL-22 was detected at significantly higher levels in sera of patients with SS. The levels of IL-22 present in sera showed statistically significant direct correlations with hyposalivation, anti-SSB, anti-SSA/SSB combined, hypergammaglobulinemia and rheumatoid factor. IL-22 showed a direct correlation with major clinical parameters. The data suggest that IL-22 plays a critical role in the development of SS, and further study is needed to examine its function in human SS.
doi:10.1111/j.1365-3083.2011.02583.x
PMCID: PMC3250060  PMID: 21645026
7.  Variability of neural activation during walking in humans: short heels and big calves 
Biology Letters  2011;7(4):539-542.
People come in different shapes and sizes. In particular, calf muscle size in humans varies considerably. One possible cause for the different shapes of calf muscles is the inherent difference in neural signals sent to these muscles during walking. In sedentary adults, the variability in neural control of the calf muscles was examined with muscle size, walking kinematics and limb morphometrics. Half the subjects walked while activating their medial gastrocnemius (MG) muscles more strongly than their lateral gastrocnemius (LG) muscles during most walking speeds (‘MG-biased’). The other subjects walked while activating their MG and LG muscles nearly equally (‘unbiased’). Those who walked with an MG-biased recruitment pattern also had thicker MG muscles and shorter heel lengths, or MG muscle moment arms, than unbiased walkers, but were similar in height, weight, lower limb length, foot length, and exhibited similar walking kinematics. The relatively less plastic skeletal system may drive calf muscle size and motor recruitment patterns of walking in humans.
doi:10.1098/rsbl.2010.1169
PMCID: PMC3130218  PMID: 21288939
neural control; walking; heel length; medial gastrocnemius; humans
8.  Decreased Parasite Load and Improved Cognitive Outcomes Caused by Deworming and Consumption of Multi-Micronutrient Fortified Biscuits in Rural Vietnamese Schoolchildren 
Micronutrient deficiencies are associated with impaired growth and cognitive function. A school-based fortification program might benefit schoolchildren but a high prevalence of parasite infestation might affect effectiveness. A randomized, double-blind, placebo-controlled 2 × 2 factorial trial was conducted to assess the efficacy of multi-micronutrient fortified biscuits with or without de-worming on growth, cognitive function, and parasite load in Vietnamese schoolchildren. Schoolchildren (n = 510), 6–8 years of age were randomly allocated to receive albendazole or placebo at baseline and four months of multi-micronutrient fortified biscuits (FB) or non-fortified biscuits. Children receiving FB for four months scored higher on two cognitive tests: Raven's Colored Progressive Matrices and the Digit Span Forward test. Children receiving albendazole plus FB had the lowest parasite load after four months. In children receiving FB, mid-upper arm circumference was slightly improved (+0.082 cm) but there were no differences in other indexes of anthropometry. Combining multi-micronutrient fortified biscuits with de-worming is an effective strategy.
doi:10.4269/ajtmh.2011.10-0651
PMCID: PMC3144834  PMID: 21813856
9.  Circulating fibrocytes are increased in children and young adults with pulmonary hypertension 
The European Respiratory Journal  2011;39(1):104-111.
Chronic inflammation is an important component of the fibroproliferative changes that characterise pulmonary hypertensive vasculopathy. Fibrocytes contribute to tissue remodelling in settings of chronic inflammation, including animal models of pulmonary hypertension (PH). We sought to determine whether circulating fibrocytes were increased in children and young adults with PH.
26 individuals with PH and 10 with normal cardiac anatomy were studied. Fresh blood was analysed by flow cytometry for fibrocytes expressing CD45 and procollagen. Fibrocyte numbers were correlated to clinical and haemodynamic parameters, and circulating CC chemokine ligand (CCL)2 and CXC chemokine ligand (CXCL)12 levels.
We found an enrichment of circulating fibrocytes among those with PH. No differences in fibrocytes were observed among those with idiopathic versus secondary PH. Higher fibrocytes correlated to increasing mean pulmonary artery pressure and age, but not to length or type of treatment. Immunofluorescence analysis confirmed flow sorting specificity. Differences in plasma levels of CCL2 or CXCL12, which could mobilise fibrocytes from the bone marrow, were not found.
We conclude that circulating fibrocytes are significantly increased in individuals with PH compared with controls. We speculate that these cells might play important roles in vascular remodelling in children and young adults with pulmonary hypertension.
doi:10.1183/09031936.00072311
PMCID: PMC3319160  PMID: 21700605
Fluorescence-activated cell sorting; inflammation; mononuclear phagocyte; progenitor cells; vascular remodelling
10.  Nationwide shifts in the double burden of overweight and underweight in Vietnamese adults in 2000 and 2005: two national nutrition surveys 
BMC Public Health  2011;11:62.
Background
In developing countries, overweight prevalence is increasing while underweight prevalence is still high. This situation is known as the double nutrition burden. Both underweight and overweight are related to increased risk of chronic non-communicable diseases, reduced well-being and quality of life. This study aims to compare the prevalence of overweight and underweight among Vietnamese adults in 2000 and 2005.
Methods
The study was based on two nationally representative surveys, the National Nutrition Survey 2000 (14,452 subjects) and the National Adult Obesity Survey 2005 (17,213 subjects). Adults aged 25-64 years were sampled to be nationally representative. Multiple multinomial logistic regression analysis was used to investigate the association of underweight and overweight with socio-economic indicators.
Results
The distribution of BMI across the population and population groups indicated a shift towards higher BMI levels in 2005 as compared to 2000. The nationwide prevalence of overweight (BMI ≥ 25 kg/m2) and obesity (BMI ≥ 30 kg/m2) was 6.6% and 0.4% respectively in 2005, almost twice the rates of 2000 (3.5% and 0.2%). Using the Asian BMI cut-off of 23 kg/m2 the overweight prevalence was 16.3% in 2005 and 11.7% in 2000. In contrast, the underweight prevalence (BMI < 18.5 kg/m2) of 20.9% in 2005 was lower than the rate of 25.0% in 2000. Women were more likely to be both underweight and overweight as compared to men in both 2000 and 2005. Urban residents were more likely to be overweight and less likely to be underweight as compared to rural residents in both years. The shifts from underweight to overweight were clearer among the higher food expenditure levels.
Conclusions
The double nutrition burden was clearly present in Vietnam. The distribution of BMI across the population groups generally indicated a shift towards higher BMI levels in 2005 as compared to 2000. The prevalence of overweight was increased while the declined level of undernutrition was still high in 2005. The shifts of underweight to overweight were most obvious among population groups with higher food expenditure levels.
doi:10.1186/1471-2458-11-62
PMCID: PMC3041660  PMID: 21276266
11.  Genetic profiling of chromosome 1 in breast cancer: mapping of regions of gains and losses and identification of candidate genes on 1q 
British Journal of Cancer  2006;95(10):1439-1447.
Chromosome 1 is involved in quantitative anomalies in 50–60% of breast tumours. However, the structure of these anomalies and the identity of the affected genes remain to be determined. To characterise these anomalies and define their consequences on gene expression, we undertook a study combining array-CGH analysis and expression profiling using specialised arrays. Array-CGH data showed that 1p was predominantly involved in losses and 1q almost exclusively in gains. Noticeably, high magnitude amplification was infrequent. In an attempt to fine map regions of copy number changes, we defined 19 shortest regions of overlap (SROs) for gains (one at 1p and 18 at 1q) and of 20 SROs for losses (all at 1p). These SROs, whose sizes ranged from 170 kb to 3.2 Mb, represented the smallest genomic intervals possible based on the resolution of our array. The elevated incidence of gains at 1q, added to the well-established concordance between DNA copy increase and augmented RNA expression, made us focus on gene expression changes at this chromosomal arm. To identify candidate oncogenes, we studied the RNA expression profiles of 307 genes located at 1q using a home-made built cDNA array. We identified 30 candidate genes showing significant overexpression correlated to copy number increase. In order to substantiate their involvement, RNA expression levels of these candidate genes were measured by quantitative (Q)-RT–PCR in a panel of 25 breast cancer cell lines previously typed by array-CGH. Q–PCR showed that 11 genes were significantly overexpressed in the presence of a genomic gain in these cell lines, and 20 overexpressed when compared to normal breast.
doi:10.1038/sj.bjc.6603433
PMCID: PMC2360604  PMID: 17060936
array-CGH; amplicon; oncogene; profiling
12.  Novel Mitogen-Activated Protein Kinase MpkC of Aspergillus fumigatus Is Required for Utilization of Polyalcohol Sugars▿  
Eukaryotic Cell  2006;5(11):1934-1940.
The genome of Aspergillus fumigatus has four genes that encode mitogen-activated protein kinases (MAPKs), sakA/hogA, mpkA, mpkB, and mpkC. The functions of the MpkB and MpkC MAPKs are unknown for A. fumigatus and the closely related and genetically amenable species Aspergillus nidulans. mpkC deletion mutants of A. fumigatus were made and their phenotypes characterized. The mpkC deletion mutants were viable and had normal conidial germination and hyphal growth on minimal or complete media. This is in contrast to deletion mutants with deletions in the closely related MAPK gene sakA/hogA that we previously reported had a nitrogen source-dependent germination phenotype. Similarly, the growth of the mpkC deletion mutants was wild type on high-osmolarity medium. Consistent with these two MAP kinase genes regulating different cellular responses, we determined that the mpkC deletion mutants were unable to grow on minimal medium with sorbitol or mannitol as the sole carbon source. This result implicates MpkC signaling in carbon source utilization. Changes in mRNA levels for sakA and mpkC were measured in response to hypertonic stress, oxidative stress, and a shift from glucose to sorbitol to determine if there was overlap in the SakA and MpkC signaling pathways. These studies demonstrated that SakA- and MpkC-dependent patterns of change in mRNA levels are distinct and have minimal overlap in response to these environmental stresses.
doi:10.1128/EC.00178-06
PMCID: PMC1694801  PMID: 16998074
13.  Comparative study between deep sclerectomy with and without collagen implant: long term follow up 
Aim: To identify the value of using collagen implant in deep sclerectomy.
Methods: A prospective randomised trial of 104 eyes (104 patients) with medically uncontrolled primary and secondary open angle glaucoma. All patients had deep sclerectomy (DS), half of them with and the other half without a collagen implant (CI) sutured in the scleral bed. The main outcome measures were intraocular pressure (IOP), visual acuity, number of treatments preoperative and postoperative, and Nd:YAG goniopunctures.
Results: Mean follow up period was 44.5 (SD 21) months for the DS group and 43.9 (SD 14) months for the deep sclerectomy with a collagen implant (DSCI) group. The mean preoperative IOP was 23.3 (SD 7.2) mm Hg for the DS group and 25.6 (SD 4.9) mm Hg for the DSCI group. The mean IOP at the first postoperative day was 6.1 (SD 4.21) mm Hg for the DS group and 5.1 (SD 3.3) mm Hg for the DSCI group. At 48 months IOP was reduced by 40% (14 versus 23.3 mm Hg) for the DS group and by 50% (12.7 versus 25.6 mm Hg) for the DSCI group. Complete success rate, defined as IOP lower than 21 mm Hg without medication, was 34.6% (18/52 patients) at 48 months for the DS group, and 63.4% (33/52 patients) for the DSCI group. Qualified success rate; patients who achieved IOP below 21 mm Hg with or without medication, was 78.8% (41/52 patients) at 48 months and 94% (49/52 patients) for the DSCI group. The mean number of medications was reduced from 2.1 (SD 0.8) to 1.0 (SD 1) after DS, and was reduced from 2.2 (SD 0.7) to 0.4 (SD 0.6) in the DSCI group (p = 0.001)
Conclusion: The use of a collagen implant in DS enhances the success rates and lowers the need for postoperative medication.
PMCID: PMC1771937  PMID: 14693783
deep sclerectomy; collagen; glaucoma; surgery
14.  Five year results of viscocanalostomy 
Aim: To prospectively study the success rate and complications of viscocanalostomy, a non-penetrating glaucoma surgery.
Methods: Prospective non-randomised consecutive case series of 57 eyes (57 patients) with medically uncontrolled primary and secondary open angle glaucoma. Viscocanalostomy was performed on all participants with injection of viscoelastic in the surgically created ostia of Schlemm’s canal as well as in the scleral bed, the superficial scleral flap was loosely sutured. Intraocular pressure, visual acuity, and number of goniopunctures were measured.
Results: The mean follow up period was 34.1 months. The mean preoperative intraocular pressure (IOP) was 24.6 mm Hg; while the mean postoperative IOP was 5.6 mm Hg at day 1 and 13.9 mm Hg at 36 month. Patients who achieved IOP below 21 mm Hg with or without medication were 90% at 60 months, complete success rate (IOP<21 mm Hg without medication) was 60% at 60 months. 21 patients (37%) needed Nd:YAG goniopuncture postoperatively to control raised IOP, mean time for goniopuncture application was 9.4 months, mean pre-goniopuncture IOP was 20.4 mm Hg and mean postgoniopuncture IOP was 12.6 mm Hg (p <0.0001).
Conclusion: Viscocanalostomy appears to be a promising modification of filtering surgery.
PMCID: PMC1771626  PMID: 12642307
viscocanalostomy
15.  A Mitogen-Activated Protein Kinase That Senses Nitrogen Regulates Conidial Germination and Growth in Aspergillus fumigatus 
Eukaryotic Cell  2004;3(2):557-560.
We show that the mitogen-activated protein (MAP) kinase pathway that responds to osmotic stress in Aspergillus fumigatus is also involved in nutritional sensing. This MAP kinase regulates conidial germination in response to the nitrogen source and is activated upon starvation for either carbon or nitrogen during vegetative growth.
doi:10.1128/EC.3.2.557-560.2004
PMCID: PMC387654  PMID: 15075285
16.  Biological cages 
European Spine Journal  2000;9(Suppl 1):S102-S109.
Restoring a stable anterior column is essential to achieve normal spinal biomechanics. A variety of mechanical spacers have been developed and advocated for both anterior and posterior approaches. The ability to radiographically assess the “biology” of bone incorporation in these mechanical (metal) spacers is an inherent limitation. The femoral ring allograft (FRA) and posterior lumbar interbody fusion (PLIF) spacers have been developed as biological cages that permit restoration of the anterior column with a machined allograft bone (biological cage). Test results demonstrate that the FRA and PLIF Spacers have a compressive strength over 25,000 N. The pyramid shaped teeth on the surfaces and the geometry of the implant increase the resistance to expulsion at clinically relevant loads (1053 and 1236 N). The technique of anterior column reconstruction with both the FRA and the PLIF biological cages are discussed. Clinical experience with the PLIF biological cage (10 patients) and the FRA biological cage (90 patients) has not revealed any graft migration, infection, or subsidence. Additional posterior instrumentation may increase the stability of the motion segment, but the degree of stability necessary to achieve a biological union remains unclear. The incorporation of these biological cages can be monitored by conventional radiographic techniques. The method of insertion preserves the vertebral end-plates and can be performed by a minimally invasive or standard open procedure.
doi:10.1007/PL00008315
PMCID: PMC3611444  PMID: 10766065
Key words Biological cages; FRA spacer; PLIF spacer; Interbody ¶lumbar fusion; Arthrodesis
17.  'LABNOTE', a laboratory notebook system designed for academic genomics groups. 
Nucleic Acids Research  1999;27(2):601-607.
We have developed a relational laboratory database system, adapted to the daily book-keeping needs of laboratories that must keep track of information acquired on hundreds or thousands of clones in an effective and user-friendly fashion. Data, whether final or related to experiments in progress, can be accessed in many different ways, e.g. by clone name, by gene, by experiment or through DNA sequence. Updating, import and export of results is made easier by specially developed tools. This system, in network version, serves several groups in our Institute and (over the Internet) elsewhere, and is instrumental in collaborative studies based on expression profiling. It can be used in many similar situations involving progressiveaccumulation of information on sets of clones or related objects.
PMCID: PMC148221  PMID: 9862986
18.  Triple helices formed at oligopyrimidine*oligopurine sequences with base pair inversions: effect of a triplex-specific ligand on stability and selectivity. 
Nucleic Acids Research  1998;26(9):2179-2183.
Oligonucleotide-directed triple helix formation is mostly restricted to oligopyrimidine*oligopurine sequences of double helical DNA. An interruption of one or two pyrimidines in the oligopurine target strand leads to a strong triplex destabilisation. We have investigated the effect of nucleotide analogues introduced in the third strand at the site opposite the base pair inversion(s). We show that a 3-nitropyrrole derivative (M) discriminates G*C from C*G, A*T and T*A in the presence of a triplex-specific ligand (a benzo[e]pyridoindole derivative, BePI). N6-methoxy-2,6-diaminopurine (K) binds to an A*T base pair better than a T*A, G*C or C*G base pair. Some discrimination is still observed in the presence of BePI and triplex stability is markedly increased. These findings should help in designing BePI-oligonucleotide conjugates to extend the range of DNA sequences available for triplex formation.
PMCID: PMC147530  PMID: 9547278
19.  Nationwide telecare for diabetics: a pilot implementation of the HOLON architecture. 
This paper presents results from a demonstration project of nationwide exchange of health data for the home care of diabetic patients. A consortium of industry, academic, and health care partners has developed reusable middleware components integrated using the HOLON architecture. Engineering approaches for multi-organization systems development, lessons learned in developing layered object-oriented systems, security and confidentiality considerations, and functionality for nationwide telemedicine applications are discussed.
PMCID: PMC2232089  PMID: 9929239
20.  Tumor necrosis factor alpha-induced apoptosis in cardiac myocytes. Involvement of the sphingolipid signaling cascade in cardiac cell death. 
Journal of Clinical Investigation  1996;98(12):2854-2865.
In the present study, it was shown that physiologically relevant levels of the proinflammatory cytokine TNFalpha induced apoptosis in rat cardiomyocytes in vitro, as quantified by single cell microgel electrophoresis of nuclei ("cardiac comets") as well as by morphological and biochemical criteria. It was also shown that TNFalpha stimulated production of the endogenous second messenger, sphingosine, suggesting sphingolipid involvement in TNFalpha-mediated cardiomyocyte apoptosis. Consistent with this hypothesis, sphingosine strongly induced cardiomyocyte apoptosis. The ability of the appropriate stimulus to drive cardiomyocytes into apoptosis indicated that these cells were primed for apoptosis and were susceptible to clinically relevant apoptotic triggers, such as TNFalpha. These findings suggest that the elevated TNFalpha levels seen in a variety of clinical conditions, including sepsis and ischemic myocardial disorders, may contribute to TNFalpha-induced cardiac cell death. Cardiomyocyte apoptosis is also discussed in terms of its potential beneficial role in limiting the area of cardiac cell involvement as a consequence of myocardial infarction, viral infection, and primary cardiac tumors.
PMCID: PMC507753  PMID: 8981934
21.  Multiplex messenger assay: simultaneous, quantitative measurement of expression of many genes in the context of T cell activation. 
Nucleic Acids Research  1996;24(8):1435-1442.
The hybridization signature approach, using colony filters and labeled complex probes, can provide high throughput measurement of gene activity. We describe here the implementation of this method to follow the expression levels of 47 genes in resting and activated T cells, as well as in epithelial cells. Using 4-fold spotting of colonies, imaging plate detection and various correction and normalization procedures, the technique is sensitive enough to quantify expression levels for sequences present at 0.005% abundance in the probe. Comparison with Northern blotting shows good consistency between the two methods. Upon activation of a T cell clone by an anti-CD3 antibody variations ranging from 2- to 20-fold are measured, some of which had not been reported previously. This 'multiplex messenger assay' method, performed using available commercial apparatus, can be used in many cases where simultaneous assessment of mRNA levels for many genes is of interest.
PMCID: PMC145825  PMID: 8628675
22.  Characterization of a cell-type-restricted negative regulatory activity of the human granulocyte-macrophage colony-stimulating factor gene. 
Molecular and Cellular Biology  1994;14(3):2213-2221.
Human granulocyte-macrophage colony-stimulating factor (GM-CSF) stimulates the proliferation and maturation of normal myeloid progenitor cells and can also stimulate the growth of acute myelogenous leukemia (AML) blasts. GM-CSF is not normally produced by resting cells but is expressed by a variety of activated cells including T lymphocytes, macrophages, and certain cytokine-stimulated fibroblasts and endothelial cells. Production of GM-CSF by cultured AML cells has been demonstrated, and GM-CSF expression by normal myeloid progenitors has been postulated to play a role in myelopoiesis. We have investigated the regulation of expression of GM-CSF in AML cell lines, and our results demonstrate the presence of a strong constitutive promoter element contained within 53 bp upstream of the cap site. We have also identified a negative regulatory element located immediately upstream of the positive regulatory element (within 69 bp of the cap site) that is active in AML cell lines but not T cells or K562 CML cells. Competition transfection and mobility shift studies demonstrate that this activity correlates with binding of a 45-kDa protein.
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PMCID: PMC358581  PMID: 8114751
23.  Risk of occupational exposure to Herpesvirus simiae (B virus) in Quebec. 
Herpesvirus simiae (B virus) causes a mild infection in macaques. Transmission to humans may result in life-threatening encephalomyelitis. To evaluate the risk of occupational exposure to B virus we surveyed the directors of 11 biomedical laboratories in Quebec that use monkeys. Information was obtained on the monkey population and on the use of infection control measures recommended by the US Centers for Disease Control (CDC), Atlanta. Of the 519 monkeys belonging to susceptible species the serologic status was positive in 264 (51%), all captured in the wilds, and it was unknown in 24 (5%). All of the monkeys were caged individually, and newly acquired ones were quarantined for 2 to 8 weeks. Of the 84 workers 52 (62%) handled monkeys whose serologic status was either positive or unknown. Only five laboratories (representing 61% of the workers) complied fully with the CDC guidelines. Nine of the laboratories had a wound management protocol, but only six had a designated specialist for consultation and prophylaxis. Although no cases of B virus infection have been reported from Quebec the severity of human illness necessitates strict adherence to infection control measures and expert management of occupational exposure to susceptible monkeys.
PMCID: PMC1452871  PMID: 2171742

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