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The most common form of malaria outside Africa, Plasmodium vivax, is more difficult to control than P. falciparum because of the latent liver hypnozoite stage, which causes multiple relapses and provides an infectious reservoir. The African (A−) G6PD (glucose-6-phosphate dehydrogenase) deficiency confers partial protection against severe P. falciparum. Recent evidence suggests that the deficiency also confers protection against P. vivax, which could explain its wide geographical distribution in human populations. The deficiency has a potentially serious interaction with antirelapse therapies (8-aminoquinolines such as primaquine). If the level of protection was sufficient, antirelapse therapy could become more widely available. We therefore tested the hypothesis that G6PD deficiency is protective against vivax malaria infection.
Methods and Findings
A case-control study design was used amongst Afghan refugees in Pakistan. The frequency of phenotypic and genotypic G6PD deficiency in individuals with vivax malaria was compared against controls who had not had malaria in the previous two years. Phenotypic G6PD deficiency was less common amongst cases than controls (cases: 4/372 [1.1%] versus controls 42/743 [5.7%]; adjusted odds ratio [AOR] 0.18 [95% confidence interval (CI) 0.06–0.52], p = 0.001). Genetic analysis demonstrated that the G6PD deficiency allele identified (Mediterranean type) was associated with protection in hemizygous deficient males (AOR = 0.12 [95% CI 0.02–0.92], p = 0.041). The deficiency was also protective in females carrying the deficiency gene as heterozygotes or homozygotes (pooled AOR = 0.37 [95% CI 0.15–0.94], p = 0.037).
G6PD deficiency (Mediterranean type) conferred significant protection against vivax malaria infection in this population whether measured by phenotype or genotype, indicating a possible evolutionary role for vivax malaria in the selective retention of the G6PD deficiency trait in human populations. Further work is required on the genotypic protection associated with other types of G6PD deficiency and on developing simple point-of-care technologies to detect it before administering antirelapse therapy.
Please see later in the article for the Editors' Summary
Citation: Leslie T, Briceño M, Mayan I, Mohammed N, Klinkenberg E, et al. (2010) The Impact of Phenotypic and Genotypic G6PD Deficiency on Risk of Plasmodium vivax Infection: A Case-Control Study amongst Afghan Refugees in Pakistan. PLoS Med 7(5): e1000283. doi:10.1371/journal.pmed.1000283
Academic Editor: Stephen John Rogerson, University of Melbourne, Australia
Received: September 22, 2009; Accepted: April 15, 2010; Published: May 25, 2010
Copyright: © 2010 Leslie et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: The study was funded in part by GlaxoSmithKline as an investigator-initiated study and was sponsored by the London School of Hygiene & Tropical Medicine. MR and CJMW were supported by the Gates Malaria Partnership, and TL is supported by the ACT Consortium. Neither the funder nor the sponsor played any role in design and conduct of the study, in the collection, analysis, and interpretation of the data, decision to publish, or in the preparation, review, or approval of the manuscript.
Competing interests: Other than the partial funding by GlaxoSmithKline of this investigator-initiated study, CJMW has received funding for investigator -initiated research from Pfizer. None of the other authors have conflicts of interest to declare.
Abbreviations: AOR, adjusted odds ratio
Editors' Summary
Malaria is a parasitic infection transmitted to people through the bite of an infected mosquito. Although Plasmodium falciparum is responsible for most malaria deaths, P. vivax is the commonest, most widespread cause of malaria outside sub-Saharan Africa. Like other malaria parasites, P. vivax has a complex life cycle. Infected mosquitoes inject a parasitic form known as sporozoites into people where they replicate inside liver cells without causing symptoms. About 8–9 days later, merozoites (another parasitic form) are released from the liver cells and invade red blood cells. Here, they replicate rapidly before bursting out and infecting more red blood cells. This increase in the parasitic burden causes malaria's characteristic symptoms (debilitating and recurring chills and fevers). P. vivax infections are usually treated with chloroquine (although resistance to this drug is now emerging) but patients must also take primaquine, a drug that kills hypnozoites, a form of P. vivax that hibernates in the liver. Hypnozoites can cause a relapse months after the initial bout of malaria and make P. vivax malaria harder to control than P. faciparum malaria.
Why Was This Study Done?
Some mutations (DNA changes) protect their human carriers against specific disease-causing organisms. These mutations occur at high frequencies in populations where these organisms are common. For example, the widespread distribution of mutations that cause a deficiency in an enzyme called glucose-6-phosphate dehydrogenase (G6PD) mirrors the distribution of malaria and the African (A−) form of G6PD deficiency, a type of G6PD deficiency that is common in people of African origin, is known to provide partial protection against severe P. falciparum malaria—P. falciparum does not thrive in G6PD-deficient red blood cells. In areas where P. vivax malaria is common, Mediterranean and Asian variants of G6PD deficiency are more widespread than A− G6PD, so the question is, do these variants protect against P. vivax malaria? In this case-control study (a study in which the characteristics of people with and without a specific condition are compared), the researchers investigate whether G6PD deficiency protects against P. vivax infection in a population of Afghan refugees living in Pakistan.
What Did the Researchers Do and Find?
The researchers enrolled 372 Afghan refugees who had had P. vivax malaria during the previous two years and 743 refugees who had not had malaria over the same period. They measured G6PD activity in the participants' blood to detect "phenotypic" G6PD deficiency (reduced enzyme activity) and looked for the Mediterranean variant of the G6PD gene in the participants ("genotypic" G6PD deficiency). 5.7% of the controls but only 1.1% of the cases had phenotypic G6PD deficiency. Statistical analyses indicated that participants with reduced G6PD levels were about one-fifth as likely to develop P. vivax malaria as those with normal G6PD levels after allowing for other factors that might affect their susceptibility to malaria, an adjusted odds ratio (AOR) of 0.18. The genetic analysis indicated that the Mediterranean G6PD gene variant provided protection against P. vivax infection in men (AOR 0.12) and in women carrying either one or two defective copies of the G6PD gene (AOR 0.37); because the G6PD gene is on the X chromosome, men have only one copy of the gene but women have two copies.
What Do These Findings Mean?
These findings indicate that Mediterranean-type G6PD deficiency protects against P. vivax malaria infection in this population of Afghan refugees. Although further studies are needed to determine whether other G6PD variants protect against P. vivax malaria, these findings suggest that P. vivax malaria might be responsible for the retention of the G6PD deficiency trait in some human populations. In addition, these findings may have implications for the treatment of P. vivax malaria. Currently, in most places where P. vivax malaria is common, primaquine is not given routinely because primaquine can trigger red blood cell death (hemolytic anemia) in G6PD-deficient people and tests for G6PD deficiency are rarely available. These findings suggest that the risk of exposure to primaquine among people infected with P. vivax might be lower than previously assumed, because G6PD deficiency is less common among P. vivax-infected patients than among the general population. Nevertheless, these findings are unlikely to increase the use of primaquine immediately. Such an increase, the researchers suggest, will only occur if a simple test for G6PD deficiency is developed.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000283.
- Information is available from the World Health Organization on malaria (in several languages)
- The US Centers for Disease Control and Prevention provides information on malaria (in English and Spanish)
- Information is available from the Wellcome Trust on all aspects of malaria, including a news item about G6PD deficiency protecting against severe P. falciparum malaria
- MedlinePlus provides links to additional information on malaria (in English and Spanish)
- The Malaria Vaccine Initiative has a fact sheet on Plasmodium vivax malaria
- Vivaxmalaria provides information about P. vivax
- More about G6PD deficiency can be found on KidsHealth from the Nemours Children's Health System
The majority of malaria outside sub-Saharan Africa is caused by Plasmodium vivax, which causes up to 390 million clinical cases a year amongst a population at risk of approximately 2.6 billion [1],[2]. Its wide geographical distribution is due, in part, to its ability to undergo development (sporogony) in mosquitoes at a lower temperature than P. falciparum and to its formation of a latent liver stage (the hypnozoite), which initiates secondary blood-stage infections [3]. These characteristics make vivax malaria significantly more difficult to control or eliminate than falciparum malaria.
Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common genetic enzymopathy in humans with more than 200 variants identified to date [4]. Because the trait is X-linked and recessive, expression of phenotypic deficiency occurs more frequently in males than females. G6PD deficiency is relatively rare in populations where malaria is rare but may exceed 10% in prevalence where malaria is common [5]. In patients with G6PD deficiency, treatment with 8-aminoquinoline drugs such as primaquine may cause methemoglinaemia [6] and precipitate haemolytic anaemia which, although often mild and subclinical, can be severe in some people with particular G6PD deficiency variants [7],[8]. The potentially life-threatening interaction between the enzyme deficiency and anti-hypnozoite drugs places a major constraint on the ability of endemic countries to control or eliminate vivax malaria, because G6PD testing is not available in most areas with vivax malaria, so safe treatment of hypnozoite infections with 8-aminoquinoline drugs is not deemed feasible [9].
The concordance of the distribution of G6PD deficiency with maps of historical malaria led to the hypothesis that the trait is protective against P. falciparum. This hypothesis was confirmed in endemic areas of Africa where the African (A−) variant of G6PD deficiency protected against severe disease [10]–[12]. Falciparum malaria is now thought to be the principal evolutionary driver for retention of the A− variant of G6PD deficiency [10]–[12]. Mediterranean and Asian variants of G6PD deficiency are, however, more common in areas where vivax malaria is endemic. Mediterranean variants tend to cause more significant haemolysis than the A− variant when challenged with antimalarial drugs, fava beans, or other environmental stressors. A recent study [13] demonstrated that one Asian variant (G6PD-Mahidol) was associated with lower levels of parasitaemia in Thai adults with vivax malaria, but not with P. vivax infection or with P. falciparum. Genetic evidence for an evolutionary interaction was also demonstrated. Vivax malaria, often incorrectly assumed to be benign [14],[15], seems likely to exert evolutionary pressure for retention of the G6PD trait in human populations. We therefore investigated whether G6PD deficiency is protective against vivax malaria infection in a South Asian population in Pakistan.
Using a case-control design, we examined the association of G6PD deficiency with vivax malaria, retrospectively, over 2 years of observation. The study was conducted in three Afghan refugee villages in North West Frontier Province, Pakistan (Adizai, Baghicha, and Kaghan). The refugee villages had populations ranging from 1,000 to 3,500 people. Malaria transmission was seasonal and hypoendemic [16],[17] with the majority (approximately 95%) of cases being due to vivax malaria and the remainder to P. falciparum. Ethnically, the population is Pashtun [18].
Selection of Cases and Controls
In November and December 2006, cases were selected from residents of the refugee villages who in earlier studies were diagnosed with vivax malaria [19],[20]. Cases were defined as individuals who had had at least one episode of vivax malaria in the previous 2 years based on research slides collected using standard methods and double read by two experienced microscopists. Discordant slides were read by a third microscopist. A cross-checking procedure was in place in all clinics and maintained accuracy at >98% [21] (HealthNet TPO, unpublished data, 2004–5). In addition, PCR was conducted on blood samples taken from cases during one of the studies [19] (n = 30), which confirmed that all tested cases were indeed infected with P. vivax.
Village health records were used to select community controls from the same population as cases. Controls had no known episodes of malaria during the same 2 years of observation. The record system contained information on every family, and each family had a health card on which every member was recorded by name. The registration was regularly updated for births and deaths during consultation in the village health clinics. If a malaria blood smear was taken, the slide result was recorded against the patient's record (even if it was negative). If the patient was parasitaemic, the treatment given was also recorded. The records are maintained by trained village health workers and clinic staff. This allowed the compilation of a list of all individuals in the villages who had not had malaria over the 2 years before the study. All residents from the same villages as cases who were more than 2 years old and had no history of malaria in their clinic record were therefore eligible for enrolment as controls.
Controls were selected at random from the complete list of eligible village residents. A bottle was spun outside the house of each case in order to select a random house and if it contained an eligible control (of the same sex and within 5 years of age of the case), then the control was enrolled. If no suitable control was available, the bottle was re-spun until a suitable control was found from a house in the vicinity of the case. The selection was therefore controlled for the likely confounding factors of age and village (associated with risk of infection) and sex (associated with risk of G6PD deficiency) to ensure that disease and exposure risk was broadly similar between cases and controls. Once informed consent was given, the control was assessed by microscopy for current malaria parasitaemia, and if positive the control was not included. Because no controls had parasitaemia at the time of the survey, none were excluded on the basis of this criterion. Information on treatment-seeking practice was collected to identify those individuals who had sought medical care outside the village in the last 2 years; a restricted analysis, in which such individuals were excluded, was conducted as a check against potential bias resulting from malaria that was not recorded in clinic records. Children under the age of 2 years were excluded since they would not have been born at the start of the observation period.
Blood samples were collected in EDTA tubes and immediately tested for phenotypic G6PD deficiency using a colorimetric test (Sigma Diagnostics, Poole, Dorset, UK) according to the manufacturer's instructions. Samples found to be deficient were tested a second time. Each participant gave a blood sample stored on filter paper for genetic analysis. The filter papers were allowed to dry, marked with the participant's identifier and stored in individual bags. The samples selected for analysis were sent to the Department of Genome Sciences at the University of Washington, Seattle, USA.
Ethics Statement
Ethical approval was obtained from the London School of Hygiene and Tropical Medicine Ethics Review Board and from the Pakistan Medical Research Council Committee on Bioethics. All participants gave written informed consent to participate. For the gene sequencing, ethical approval was given by the University of Washington Ethics Committee.
Statistical Analysis
The primary analysis examined the association between phenotypic G6PD deficiency and vivax malaria. A sample size was calculated for a 2:1 ratio of controls to cases. A sample of 500 cases and 1,000 controls gave 80% power to detect a frequency of phenotypic G6PD deficiency of 1% amongst cases and 3.5% amongst controls [19],[20] at the 95% confidence level.
We conducted univariate and multivariate analysis using unconditional logistic regression and adjusting for prespecified potential confounding factors between cases and controls; those factors included in the final unconditional multivariate logistic regression model for the primary outcome were age group, sex, tribe, and refugee village. In response to suggestions from the statistical referee we undertook an additional post-hoc analysis using conditional logistic regression, which was not part of the prespecified analytical plan. In this analysis each case was matched with the two controls identified in their village by bottle-spinning and was thus matched for village, sex, and age group. We included tribe as a potential confounding factor in the model.
G6PD deficiency is an X-linked mutation so the secondary analysis examined the association between the deficiency (both phenotypic and genotypic) and infection separately for males and females. This analysis took the same approach as before and applied unconditional logistic regression and a post-hoc conditional logistic regression. The genotyped samples were used to assess the level of protection conferred by confirmed hemizygous deficiency in males and heterozygous and homozygous deficiency in females. The study was not powered specifically for the secondary analyses. Data was analysed using STATA v8 (STATA Corp, College Station, TX, USA).
Genetic Analysis
Participant blood samples were examined for G6PD genotype in two phases. Initially, we selected half of the samples from males who were phenotypically deficient and the requisite number of male non-deficient samples (in an approximate 1:2 ratio). We then amplified a 5.2 kb fragment using the primers 13125F: 5′ GTT TAT GTC TTC TGG GTC AGG GAT GG 3′ and 18396R: 5′ AGT GTT GCT GGA AGT CAT CTT GGG T 3′ from Saunders et al, [22]. Forty-six out of 57 of the samples that we attempted to amplify gave good sequence across the majority of that fragment (up to exon 10) and showed that the predominant allele was the Mediterranean (Med) type.
In the second phase we conducted PCR amplification of Med allele fragments on the 40% sample of the participants whose samples were available, in equal proportion between cases and controls. These comprised the same 1:2 ratio of cases to controls and allowed examination of the frequency of the Med− allele between cases and controls. Med allele fragments were amplified in a 20 µl reaction volume containing: 1× PCR PreMix A, 0.2 µM each primer, 0.5 units FailSafe enzyme mix (Epicentre, Madison, WI), and 2 µL of template DNA. Cycling conditions were: 94°C for 3 min; 36 cycles of 94°C for 30 s, 55°C for 30 s, 62°C for 60 s; 62°C for 5 min, 15°C for 5 min. Sequencing was done in a 10 µl volume, using 1–3 µl of PCR product, 1.7 µl 5× sequencing buffer for Big Dye (400 mM Tris-HCl, 10 mM MgCl2, pH = 9.0), 0.8 µM primer, and 1 µl Big Dye (Applied Biosystems, Foster City, CA). Products of sequencing reactions were separated on an ABI 3130xl (Applied Biosystems, Foster City, CA) and analyzed using Sequencher (Gene Codes Corporation, Ann Arbor, MI). The following primers were used for the Med allele: Medf: 5′ ATGATGCAGCTGTGATCCTCACTC 3′ and Medr: 5′ ATGAGGTTCTGCACCATCTCCTTG 3′.
A total of 372 cases and 743 controls were enrolled into the study at a ratio of roughly 1:2. Table 1 shows enrolment data for cases and controls. There were no differences in the frequency of sex, village, or age group between cases and controls, although tribal group did differ. There was a lower than anticipated number of participants, because some of the cases (identified in the earlier studies [19],[20]; n = 125) had either repatriated to Afghanistan or had been enrolled more than once in the previous studies (but were included only once in the present survey). All participants were ethnic Pashtuns.
There was a lower frequency of phenotypic G6PD deficiency amongst cases (4/372 [1.1%]) than controls (42/743 [5.7%]), Chi2 = 13.1, p<0.001) (Table 2). Unconditional univariate analysis was conducted to identify prespecified potential confounding associations with G6PD deficiency. The prespecified variables entered into the unconditional logistic regression model were sex, age group, refugee village, and tribe (Table 2). The primary analysis demonstrated significant protection in those with phenotypic G6PD deficiency with adjusted odds ratio (AOR) 0.18 [95%CI 0.06–0.52], p = 0.001. Overall, tribe was associated with the deficiency, and there was some variation between individual tribal groups (Table 2). For the post-hoc matched analysis, the AOR (0.17 [95% CI 0.06–0.48], p = 0.001) was similar to the unmatched analysis (Table 2) although the association with tribe was not seen.
Because the G6PD gene is located on the X chromosome, sex-stratified analysis was also conducted. The frequency of deficiency in males (7.0%) was higher than for females (2.0%). Amongst males, G6PD deficiency was less likely in cases than in controls (AOR 0.12 [95%CI 0.03–0.49], p = 0.004). Amongst females we did not detect evidence of an effect (AOR 0.35 [95%CI 0.08–1.61], p = 0.2), the number of deficient females being too low to make a robust estimate (n = 2/215) (Table 3). For the post-hoc matched analysis, the AOR was again similar between the unmatched analysis (Table 3) and the matched analysis (AOR from matched analysis, amongst males: 0.11 [95% CI 0.03–0.51], p = 0.004 and amongst females: 0.35 [95% CI 0.07–1.67, p = 0.19).
A total of 418 samples were successfully sequenced to provide genotype data (Table 4). As expected, all of the hemizygous G6PD-deficient males (n = 16) and homozygous deficient females (n = 2) in the sample were phenotypically deficient, and all genotypically G6PD normal males and females were phenotypically nondeficient. Of the heterozygous females 24/32 (75%) were phenotypically normal and 25% were phenotypically deficient. All individuals identified as carrying the mutant allele had a C to T change at nucleotide 563, which is characteristic of the Mediterranean variant and similar to alleles found in India [23] and Iran [24]. Six samples (three male and three female) yielded discordant results showing phenotypic deficiency but a normal genotype. All of these were controls (Table 4). Attempts to examine other possible variants (Orissa, Chatham, and Cosenza) were unsuccessful.
The secondary analysis, conducted using G6PD genotype as the explanatory variable, showed that females carrying a single or double copy of the deficiency were partially protected against vivax malaria infection (pooled AOR: 0.37 [95% CI 0.15–0.94], p = 0.037) (Table 5). Amongst heterozygous females, there was weak evidence of protection although the sample size was small for this analysis (Table 5). Only three homozygous deficient females were found, and none of these were cases. In hemizygous deficient males the AOR was 0.12 (95% CI 0.02–0.92), p = 0.041.
The frequency of the allele for G6PD deficiency among male controls was 12.1% (15/124), and because males carry a single copy of the X-linked gene, this approximates the population frequency of the deficient allele (Table 5). Among the female controls, there were 16.9% (26/154) heterozygotes and 1.3% (2/154) homozygotes for G6PD deficiency. Therefore, if the frequency of the allele among controls approximates the population genotype frequencies, more than 90% (26/28) of G6PD deficiency alleles in females occur as heterozygotes and only 7.4% (2/28) as homozygotes; this is similar to the genotype frequencies in females predicted by the Hardy-Weinberg model (i.e., 1.5% homozygotes for deficiency, 21.3% heterozygotes, 77.3% G6PD normal) based on a G6PD deficient allele frequency of 12.1% (Chi2 = 1.03, p = 0.69). Among cases, the frequency of the allele among males (1.6%) and females (7.7%) was much lower, and being protective against malaria these will differ from the gene frequency in the general population.
To examine evidence of possible misclassification of cases as controls, several factors that could have led to misclassification were considered using a restricted analysis against the primary outcome, as follows. Less than one-third of the controls reported using health facilities outside the village as their source of consultation for minor illness or malaria treatment and diagnosis (30.0%, 13.2%, respectively). Also amongst controls, 26/743 (3.5%) had self-reported malaria, which was not recorded in clinic records over the period of observation and 5/743 (0.7%) had ambiguous clinic records. In addition, 202/727 (27.8%) of controls were family members of cases. The restricted analysis, in which all individuals who were in these categories were excluded, produced results that did not differ from the unrestricted analysis.
The study demonstrated that G6PD deficiency, whether measured by phenotype or genotype, is associated with substantial protection against vivax malaria infection. Among heterozygous females the deficiency was associated with protection less often than in hemizygous males. In populations where G6PD deficiency has been measured it rarely occurs at a frequency greater than 15% [4],[5],[9],[11]. Even at this upper limit of the frequency range, the majority of phenotypically G6PD deficient females will be heterozygous. Heterozygous females may be either phenotypically deficient or normal depending on the relative proportion of circulating deficient and nondeficient red cells, because females exhibit mosaicism in expression of G6PD [25]. In our sample, 75% of heterozygous females were phenotypically normal, despite which there was a trend towards protection in this group.
The discovery that G6PD deficiency is protective against P. vivax infection is supported by its geographical distribution and may explain why the more severe variants (Mediterranean and Asia) are seen in vivax-predominant areas. This study is supported by recently published findings [13] that the G6PD Mahidol deficiency, an Asian strain, is associated with reduced parasitaemia and had experienced strong selection pressure from about 2,500 years ago. We have demonstrated a stronger protection against infection by the Mediterranean variant. The relationship between the type of G6PD variant and level of protection requires further investigation but the contrary findings presented here and in Thailand suggest that it differs between variants. Too few cases had G6PD deficiency in our sample to reliably analyse its effect on parasite density amongst cases.
Malaria is considered by some to be the single greatest source of selection pressure acting on human populations originating from endemic areas [12],[26], and the geographical distribution of several genetic polymorphisms that are protective against malaria are consistent with this theory [26],[27]. The finding that G6PD deficiency is protective against severe P. falciparum malaria in African variant G6PD-deficient children [10]–[12] is one example of this evolutionary interaction. Our findings provide strong empirical evidence, and complement the evolutionary genetic findings of Louicharoen et al. [13], that P. vivax has exerted considerable selection pressure on human populations. This pressure could come either through mortality—severe vivax malaria being much more common than previously realised [14],[15]—or through an indirect socioeconomic effect on human fecundity [2],[27]. P. vivax is known to cause anaemia and low birthweight in pregnancy [28] and the effect of malaria in young children can lead to mental and physical retardation [2]. A recent evaluation of the clinical picture of vivax malaria has identified complications which had not been previously acknowledged as common, for example, severe anaemia, cerebral malaria, renal failure, hepatic dysfunction, acute respiratory distress syndrome, sepsis and shock [14],[15]. Most areas outside Africa that are endemic for vivax malaria also have falciparum malaria. Recent data describing the relative proportion of the two species is inconsistent with evolutionary time, and drawing conclusions as to the relative impact of these species on human evolution and the retention of the G6PD gene in coendemic areas requires caution. However, vivax malaria is thought to have originated in Asia [29] and to have existed for longer than falciparum [30],[31]. Furthermore, vivax malaria is known to have been endemic to Africa before the emergence between 30,000 and 10,000 years ago of the Duffy negative trait which confers almost complete immunity to P. vivax [27], providing indirect evidence that vivax has exerted evolutionary pressure on human populations. Vivax could certainly have contributed to the retention of the deficiency.
The discovered protection is biologically plausible. G6PD-deficient erythrocytes infected by P. falciparum are known to be more sensitive to the oxidative stress produced by the parasite [4]. The resulting cellular damage impairs parasite growth, causes lysis of infected cells, and stimulates early phagocytosis of erythrocytes. This is likely to be as relevant in vivax as falciparum malaria. Lysis of G6PD-deficient red cells challenged with oxidative stress is, in part, dependent on the age of the cell. The African deficiency variant generally causes significant lysis only in older erythrocytes, but the Mediterranean variant also causes damage and ultimately lysis of young erythrocytes (reticulocytes) in the presence of a variety of stressors such as drugs or infection. Vivax malaria preferentially infects reticulocytes whilst falciparum malaria infects erythrocytes of all ages [26]. The Mediterranean variant G6PD deficiency is one of the most common of the severe deficiencies and has potential adverse negative selective effects (such as favism). Its wide distribution across Asia may be explained if it confers greater protection against vivax than against falciparum malaria.
Potential shortcomings of the case-control design include misclassification of cases as controls at the selection stage. Misclassification will be limited because asymptomatic infections are rare (none were found in this study) and almost all treatment was given in village clinics. Any such misclassification is unlikely to explain the observed result because any dilution would underestimate the effect of G6PD deficiency on vivax infection. Similarly, misclassification due to patients with P. falciparum being wrongly diagnosed as having P. vivax is unlikely in the present study because the highly trained research microscopists were routinely subjected to quality control through slide re-examination [21]; secondly, all slides were double-read (or triple-read); thirdly, PCR was conducted on 30 samples from cases which confirmed the microscopic diagnosis; fourthly falciparum malaria, at the time of the study, was very rare in this area.
G6PD deficiency is heritable and therefore could be clustered at the household level and provide a source of sampling bias. However, when family members of cases were excluded from the analysis, the overall conclusions were unchanged; again, residual clustering would lead to an underestimate of the observed effect. Failure of laboratory determination of G6PD phenotypic deficiency is another potential source of error. The high concordance of genotypic and phenotypic deficiency suggests this is not a major factor in this study. It is probable that some controls with discordant results (i.e., normal for the Mediterranean variant but phenotypically deficient) were, in fact genuinely G6PD deficient for other variants that may exist at low levels in this population. The small proportion of discordant phenotypic and genotypic results makes this unlikely to be a significant source of bias in this study.
In case-control studies the association between two factors does not necessarily prove the direction of causality except in the case, as here, of innate genetic conditions. Measured potential confounding factors had little effect on the outcome. We conclude that it is unlikely the apparent substantial protective effect of G6PD deficiency arose by chance or from bias in the study design.
In public health terms, the current treatment practice in most settings where vivax malaria is common is not to use antirelapse therapy in proven cases of vivax malaria because of the risk of haemolysis when testing for phenotypic G6PD deficiency is not available. This restriction is one of the major barriers to effective control and eventual elimination because hypnozoites constitute the reservoir of infection. The findings presented here indicate that, assuming accurate diagnosis, the risk of exposure to primaquine amongst G6PD-deficient individuals with vivax malaria would be lower than previously assumed because the prevalence of G6PD in vivax-infected patients would be significantly lower than in the general population. It is important to examine the level of protection conferred by other types of G6PD variant occurring in other vivax-endemic areas. The risk of severe haemolysis among G6PD-deficient individuals administered with other regimens of primaquine is also unclear; literature on this topic is sparse. For example, in Mediterranean variant G6PD deficiency, haemolysis with primaquine can be severe and, on the basis of limited data, might be quite common if full 14-day courses are taken [32] whereas weekly primaquine for 8 weeks seems safe in Pashtun populations [20]. For a more informed risk analysis, additional data is required, plus modelling to assess the potential effects of G6PD variant, epidemiological background, sex, dose, or duration of treatment on the risk of haemolysis in deficient individuals.
Under prevailing conditions, however, G6PD testing is rarely available and G6PD deficiency goes largely undetected, so our finding is unlikely to increase access to antirelapse drugs in the near future because of the continuing risk of haemolysis. Hence the hypnozoite reservoir will remain unchallenged and will continue to contribute to morbidity through relapse and transmission. For effective control and treatment, either a simple test for G6PD deficiency or an antirelapse drug that can be safely given to patients with G6PD deficiency is required. This study, however, shows that the probability of individuals with vivax malaria being deficient for G6PD may be significantly lower than in the general population from which they are drawn.
The authors are grateful to HealthNet TPO for field assistance in conducting the study and to the people of Adizai, Baghicha, and Kaghan refugee villages for their participation. We are also grateful to Matthew Saunders for his help with the analysis of the gene sequence. The views expressed herein are solely those of the authors and do not necessarily reflect those of the funder or sponsor or any other associated agency.
Author Contributions
ICMJE criteria for authorship read and met: TL MB IM NM EK CHS CJMW MR. Agree with the manuscript's results and conclusions: TL MB IM NM EK CHS CJMW MR. Designed the experiments/the study: TL IM EK CJMW MR. Analyzed the data: TL MB EK CHS CJMW MR. Collected data/did experiments for the study: TL MB IM NM CHS. Enrolled patients: NM. Wrote the first draft of the paper: TL. Contributed to the writing of the paper: TL MB IM EK CHS CJMW MR. Planned and executed molecular analysis, analyzed molecular data, and edited final draft: CHS.
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- 8. World Health Organisation (1989) Working group Glucose-6-phosphate dehyrogenase deficiency. Bull WHO 67: 601–11.
- 9. Cappellini MD, Fiorelli G (2008) Glucose-6-phosphate dehydrogenase deficiency. Lancet 371: 64–74.
- 10. Guido A, Fairhurst RM, Doumbo OK, Wellems TE, Diallo DA (2007) X-linked G6PD deficiency protects hemizygous males but not heterozygous females against severe malaria. PLoS Med 4: e66. doi:10.1371/journal.pmed.0040066.
- 11. Gilles HM, Fletcher KA, Hendrickse RG, Lindner R, Reddy S (1967) Glucose-6-phosphate dehydrogenase and malaria. Deficiency, sickling, and malaria in African children in South West Nigeria. Lancet 1: 138–140.
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- 13. Louicharoen C, Patin E, Paul R, Nuchprayoon I, Witoonpanich B, et al. (2009) Positively selected G6PD-Mahidol mutation reduces Plasmodium vivax density in Southeast Asians. Science 326: 1546–9.
- 14. Anstey NM, Russell B, Yeo T, Price RN (2009) The pathophysiology of vivax malaria. Trends Parasitol 25: 220–227.
- 15. Price RN, Tjitra E, Guerra C, Yeung S, White NJ, et al. (2007) Vivax malaria: neglected but not benign. Am J Trop Med Hyg 77: Suppl 679–87.
- 16. Rowland M, Nosten F (2001) Malaria epidemiology and control in refugee camps and complex emergencies. Ann Trop Med Parasitol 95: 741–754.
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Caroe O (1984) The Pathans: 500 B.C.-A.D. 1957. Oxford in Asia Historical Reprints. Oxford University Press.
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- 20. Leslie T, Mayan I, Mohammed N, Erasmus P, Kolaczinski J, et al. (2008) Randomised trial of an eight-week, once weekly primaquine regimen to prevent relapse of plasmodium vivax in Northwest Frontier Province, Pakistan. PLoS ONE 3: e2861. doi:10.1371/journal.pone.0002861.
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- 25. Peters AL, Van Noorden CJF (2009) Glucose-6-phosphate dehydrogenase deficiency and malaria: cytochemical detection of heterozygous G6PD deficient women. J Histochem Cytochem 57: 1003–11.
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- 32. Hill DR, Baird JK, Parise ME, Lewis LS, Ryan ET, et al. (2006) Primaquine: report from CDC expert meeting on malaria chemoprophylaxis I. Am J Trop Med Hyg 75: 402–15.


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Sunday, July 12, 2009
London Rocked.
Our trip was a big success. If you had told me a couple years ago that we would be traveling internationally with a minimum of stress, I would have smiled politely and thought, "Not with these kids, we won't." Peanut was simply incapable dealing with that much change and transition and it wasn't worth the struggle to go anywhere when just getting through a routine day at home was so tough.
I won't pretend that this trip was all sweetness and light, because there were a couple rough episodes, the worst of which involved a weeping Peanut repeatedly banging his head on the fiberglass window of the tube train we were squashed into like sardines while I attempted to restrain him.
That was pretty ugly, a combination of heat and exhaustion and stress and ASD. All those people trying not to watch us as Peanut screamed for water and then screamed harder after spilling some on his shirt, as I tried to soothe him and keep him restrained while pressed up against strangers. Awful. But we pressed onward, stopped for breaks, got through it.
But for each one of those episodes there were entire afternoons of watching the kids discover everything there was to see all around them. Over the course of the week, we visited Big Ben and Parliament, rode a boat tour down the Thames to Greenwich and back, and spent a day at the Science Museum, where the kids were thrilled to find a "Wallace and Grommit" exhibit.
We spent another full day at the zoo, complete with a stroll through Regent's Park at the end of the day:
We made multiple visits to the British Museum, since it was right near our apartment:
At the end of the week, we rode the London Eye and saw the entire city laid out at our feet:
As if that weren't enough, we also rode around town on a double decker tour bus, visited London's largest toy store, and managed to cram as much time in with my sister and her family as possible.
Pepper astounded me with the kindness and patience she showed with her younger cousins and Peanut is such a little sponge for factual information that he was in heaven with all of the history and dates that filled our days. The place we stayed was terrific - it cost us less than a single hotel room at a nice hotel would have, and we ended up in a 2 bedroom 2 bathroom apartment with washer/dryer and kitchen. While the lack of air conditioning was a problem, the location turned out to be perfect for us. There was a children's park a block away, a shopping center 2 blocks away, and the British Museum was only 3 blocks away.
In fact, other than the occasional crazy ASD-style meltdown, the only downside of the trip was the heat - it was in the 80's the entire time, which means the non-air-conditioned buses and tube trains were a nightmare. The weather report before we left indicated 70 degrees and breezy, so I never got to wear those cute cardigans I brought. As I've detailed before, I really don't do well in sweaty situations. The only thing that made me feel better about the heat was coming home and finding that the weather on Cape Cod had been wet and cool, including one freaky July hailstorm.
Getting back into the swing of things has been tough for all of us, but I always think it takes twice as long as you are away on vacation to get back to normal after you get back. Unfortunately, this means we should be approaching normalcy right around the time I leave for BlogHer, which is going to throw everything out of whack again.
(But - YAY! BlogHer!)
6 comments:
A belated thank you for your lovely comments. We're really glad to see that you had such a great time. It's always nice to hear that international visitors enjoy our cities as much as we do. I was hoping that you might do us a small favour, and change the link in your blog to our new .com domain rather than .co.uk . These things are so important these days!
Feel free to get in touch with me directly if you decide to come back, we have apartments all across the UK, and there is so much more to see outside of London! I can highly recommend SACO Bath (bath.sacoapartments.com) or SACO Bristol (bristol.sacoapartments.com) for some good old fashioned culture! My email address is email@example.com. We'd love to hear from you again.
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text: I can't have children, so my period is absolutely useless, too! I always think to myself…"i have to do this hundreds of times over a span of 40 years or so? This is ***ing bullsh*t! My body wants to "build something" but it can't! Goddamn it. She was hysterical. :)


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Items where Department is "Faculty of Arts & Social Sciences > Politics & International Relations (Merged into PPR 2010-08-01)" and Year is 1989
Jump to: K Number of items: 2.
KKnott, Kim (1989) Hindu communities in Britain. In: Religion, State and Society in Modern Britain. Texts and studies in religion . Edwin Mellen Press, Lampeter, pp. 243-258. ISBN 9780889469761 Knott, Kim (1989) Mata Ki Jay! A Hindu pilgrimage to Ambaji in North Gujarat. In: World Religions in Education: An Anthology of Writings. Shap Working Party/BFSS RE Centre, Isleworth, pp. 43-46. |


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By Jeffrey Hodges B.Sc. M.Sc.(Hons) B.Ed. Previously I've mentioned that there are seven essential mental skills for shooting success, all of which are learnable and teachable :
All these skills of the SPORTS MIND can be learned and improved with some simple mental training techniques. I have already covered the first skill of Visualisation, noting that it is the most important mental skill for shooters, and that to direct your shooting performance effectively you want to use clear visual images with feeling, not words, and that visualisation works because it has a measurable, physiological effect on our body. I also noted the importance of getting into the right mental state to visualise, outlined six specific applications for visualisation for shooters, and gave some simple tips for getting the best out of your visualisation sessions.
I also introduced the important topic of motivation and said that motivation is an energy - an energy which is influenced by how you communicate with yourself. I noted that there are basically two simple motivation strategies : positive motivation and negative motivation. Negative motivation moves you away something you don't want to happen, while positive motivation moves you towards something you do want to happen.
This led in the last few issues to a discussion about goals and how to attain them, and I want to conclude my information about goals by talking about the role of your thinking.
What is thinking, and how do the processes of our thoughts influence our ability to achieve our goals?
On Thinking
If you had a chance to listen to, and really hear, the news conference given by Ian Thorpe announcing his retirement, you would have picked up some really valuable insights into just how important thinking is to all sportspeople - and not just champions.
Ian walked us through his thinking behind his decision, and it was interesting to note his mention of how he was "questioning himself" a lot prior to his ultimate decision.
This is important, because if you question anything enough, you will begin to doubt. Self doubt, lack of direction, unmotivation, loss of confidence, and so on, are often the result of continuous questioning, or of asking the wrong kinds of questions.
Questions such as : Why am I doing this? What's wrong with me? Why does this always happen to me? Why can't I .................. (whatever).
What I call why(n)ing thinking.
This is not to say that Ian made an incorrect decision, or that after ten years of extraordinary achievement in his sport, he doesn't deserve the right to move on and do other things in his life.
I simply wonder if he had enough psychological support over the past six to twelve months, to aid him in the process - because it's very easy to allow the 'why' questioning process to become self-sustaining - and ultimately destructive of an athlete's direction and motivation.
I think we've all been there at some time in our life - questioning "Why am I in this sport / job / role / relationship / whatever?"
Those who moved on obviously didn't find a satisfactory answer; while those who stayed found a way to answer the questions - and then got on with it.
If you keep asking 'why' questions of yourself, over and over again, the only result is going to be self doubt, and ultimately, giving up.
For this reason, I recommend to the athletes I work with, that they take some time to find really powerful answers to questions such as : "Why am I playing this sport?".
Answers that are personally meaningful for the athlete, and which they can have ready in their mind whenever those little doubts or questions surface - either from themselves, or from others.
It's important to recognise that every athlete will ask, or be asked, these 'why' questions at some point in their sporting careers, (and probably many times), and if they don't already have really strong, convincing answers, then the process will continue to build and feed on itself ........ until they decide to do something else.
Elite, competitive sport today is a tough business, and only those individuals who are really clear on why they are there - and fully satisfied with those answers - will have the mental and emotional energy to handle the challenges and setbacks they will inevitably face.
Having heartfelt, powerful reasons for why you're playing / competing in your sport provides the motivational fuel that will sustain you through the hours of arduous training; the constant, fickle media scrutiny; the niggling injuries; and all the other challenges on your way to success.
The bygone aspiration of many of our sporting champions in the past -"to represent Australia", is no longer enough any more ...... and really, why should it be?
When athletes see company directors sitting in $500,000 corporate boxes with government bureaucrats, politicians, and other parasites feeding off their athletic efforts like some emotional vampires unable or unwilling to engage their own spirit; why should they be satisfied with idealism?
So take some time today to think about it .... WHY are you playing your sport - or doing what you're doing in your life right now?
Find at least six really meaningful and heartfelt reasons; acknowledge them to yourself; and then get on with it!
For athletes to succeed consistently over a long period of time, these reasons must include a love of the actual playing of your sport - including the training. It's also helpful to see competition in a very personal way ....... to compete for yourself first; to test yourself and hone your skills and your spirit, rather than for the rewards or glory.
Once you've found these personally meaningful reasons, trust, and tell yourself that you HAVE made the right decisions - and commit to them. Of course, you may want to re-evaluate your life from time to time, (at the end the year, or at the end of the season for example), but excessive questioning is counter-productive.
The Structure of Thoughts
Having explained just how important questions are, it's useful to recognise that questions are just one aspect of the thinking processes which affect sports performance.
Think about thinking for a moment. What is thinking? What happens in your mind when you think - what actual processes happen?
Thinking comprises two processes: visualisation and verbalisation (or other internal auditory stimuli), and usually both simultaneously. We think visually, by imagining, or picturing, or dreaming - seeing things in our mind's eye. We also think auditorily by talking to ourselves, or by hearing music or other sounds in our head.
It's interesting to realise and appreciate that all of our performances and behaviours are directed by these two simple processes!
All that you have done and become - and will yet be - is a consequence of how you manipulate your thinking processes.
Further, in relation to the auditory aspect of thinking, it can be divided into self talk and other sounds. The self talk component includes the questions, which I have already discussed, and statements.
'Statements' are verbalisations of what you believe about your sport, the world, and life in general - and often relate to yourself. For example : "I'm not a morning person"; "It's hard to get to the top"; "I've got a strong forehand"; "Women are fickle"; "Men are bastards"; "No pain, no gain"; "I'm not a lucky person"; "People are cruel"; "I'm a good cook"; etc.
These statements are often very subtle and the individual is barely conscious of them. The trouble is, that these internal verbalisations -especially the ones that relate to you - influence your performance and behaviour. What you say about and of yourself, becomes true for you.
So, an important key to mental training for sportspeople is to assert some control over all these thinking processes - to take charge of the imagery, questions and statements that happen in their mind.
Recognise that you are the master of your mind. Your mind is your servant - not the other way around!
All mental discipline begins with the simple acknowledgement that you are not your mind! With this simple understanding, you can reassert your authority over the mind.
Too many people allow their mind to direct them, instead of them directing their mind!
A good example of this happened recently with a golf professional who came to me for some assistance with his mental game. He said he found his concentration wandering regularly, and often imagining negative things - which of course then happened.
I gave him a simple remedy : YOU ARE NOT YOUR MIND. I instructed him to write out the following phrase and say it often to himself throughout the day :
I am the master of my mind. I see myself playing well, now.


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Like us on Facebook for inter-esting movie poster-related stuff:
Idina Menzel
On this page you'll find links to movies starring or directed by Idina Menzel. This data is provided by Freebase, so if you see any incorrect information please change it on their site.
Frozen Fever 2015 |
Frozen 2013 |
Enchanted 2007 |
Ask The Dust 2006 |
"The Wonder Pets" 2006 |
Rent 2005 |
Just a Kiss 2002 |


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4 New Square Lincoln's Inn London, WC2A 3RJ
Tel: +44 20 7822 2000 DX: 1041 London Chancery Lane
Email us View location map
Date: 06/03/2012
Graeme Mew's decision on the appeal by the GB Rhythmic Gymnastics Group against the British Amateur Gymnastics Association's decision not to put the GB Group forward for nomination to participate in the London Olympics has been released by Sport Resolutions.
Sport Resolutions, the independent dispute resolution service for sport in the United Kingdom, appointed Four New Square's Graeme Mew as the sole arbitrator to hear the athletes' appeal. The hearing took place in London on 29 February 2012.
Graeme allowed the appeal and directed that the GB Group's Olympic nomination should now go forward.
To read the full written reasons for decision, released on 5 March, click here


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Play Away!
3 August 2006 by Karen
Green and mean.
Yesterday Dawn told you it was National Play Day 2006. There was plenty going on at World Museum Liverpool as part of the Liverpool Children's Festival as these pictures show. Hoardes of happy kids got stuck into face painting, dance sessions, dressing-up and making workshops, culminating in a parade along William Brown Street, accompanied by drummers, stiltwalkers and museum staff. Happy days!
Umbrella fun at the parade
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Brown's 2014-15 state budget leaked; Education to get $10B
UPDATED 11:09 PM PST Jan 08, 2014Gov. Jerry Brown is calling for nearly $10 billion more in education spending in his 2014-15 state budget, which was leaked to the media on Wednesday.
Video TranscriptFUND AND A RAISE FOR STATE WORKERS. NOW MORE ON WHAT THAT PROPOSED BUDGET WILL LOOK LIKE. THE GOVERNOR PLANNED TO RELEASE THE BUNLTS ON FRIDAY BUT BECAUSE OF THIS LEAK HE WILL FORMALLY ANNOUNCE IT TOMORROW. THE GOVERNOR'S PLANS FOR THE STATE BUDGET LEAKED TWO DAYS AHEAD OF THE EXPECTED FORMAL ANNOUNCEMENT. MY INITIAL THOUGHTS ARE THAT THE GOVERNOR KEPT HIS PROMISE IN TRYING TO REIGN IN TOO MUCH SPENDING. FORMER KCRA STATE CAPITOL REPORTER SPOKE WITH US ABOUT THE LEAKED DOCUMENT. MANY WILL SAY THE BIG WIN CERTIFICATE EDUCATION. EDUCATION COMES OUT WITH MORE MONEY THAN BEFORE. IT ALLOCATES AN ADDITIONAL $10 BILLION TO EDUCATION. HE INCREASED SPENDING FOR K THROUGH 1, THE UNIVERSITY OF CALIFORNIA. IT INCLUDES TRIGGER BASED PAY INCREASES FOR STATE WORKERS. IF THE TRIGGER IS PULLED, EMPLOYEES WILL SEE A SALARY INCREASE OF 2014-2015 F. THE TRIGGER IS NOT PULLED THEY WILL RECEIVE A 4.5% INCREASE IN 2015. THERE MAY BE PUSHBACK ON THE 4.5% PAY INCREASE FOR STATE EMPLOYEES SUGGESTING THAT THE GOVERNOR IS AWARDING ORGANIZED LABOR BUT HE IS DOLING OUT SOME OF THE SURPLUS TO VARIOUS GROUPS THAT HAVE BEEN HURT OVER THE PAST FEW YEARS.
The views expressed are not those of this site, this station or its affiliated companies. By posting your comments you agree to accept our terms of use.blog comments powered by Disqus


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60CSX vs Montana
I am looking to replace the 60csx as it is slowly dieing. I wanted to know if the sensitivity, ruggedness and other features that made the 60csx so good for off road had been carried over to the Montana.
I am looking for input from those that had both and their take on it. I use my GPS exclusively off road, I dont use it to punch in an address and then have it guide me from point to point so that is not a feature I need. Mostly making tracks, running off tracks/way-points and ease of readability is what is drawing me to the Montana. I have read through the other threads regarding the Montana but did not come across one looking for a direct comparison between the two from real world experience. :ear |
I sold my 60CSx and 76CSx to go to Oregon 550 units, and they were really good, but let down by a lousy power connector in the mini USB connector, and the 550's relatively smaller screen was a bit hard to see while riding. So I sold those when the Montana was released. But new gen Garmins are much better at map handling and track recording, and have wireless transfer between like units, so once you've used those features, you generally don't want to go back to the 60/76. |
Still run both
The Montana is really good & the screen is large & readable in most situations I also use them off-road most of the time The track size on the Montana is very useful but you'll need to figure out the storing & archiving of them If you'd do the changeover I don't think you'll be sorry, I know I'm not |
I did the switch from a 60cx to a Montana 600 a couple of months ago. The Montana works pretty much as advertised. The big push for me was the brighter screen and indeed I can read the screen in virtually all lighting conditions now.
It is nice having all the track memory I need. If you get one you, need to be really cautious about upgrading the firmware. It seems like about every other revision causes more problems than it fixes. I am about 4 revs behind and have no intention of upgrading until some feature comes along that I can't live without - like maybe not drawing a straight line between locations in the current track when you turn the unit off move to a new place and then turn it back on. I took the Montana on a very rugged ride in Utah last month with no problems. I also only use it for off hiway motorcycle riding. The Montana does not work as well with Mapsource as the 60. So I normally read and write to it from BaseCamp using files I created in Mapsource and transferring new files to Mapsource. The Montana has lots more "features" than the 60 and it takes a while to learn them especially as noted above about maintaining and archiving tracks. All in all it cost a little more than I would have liked to pay, but I am pretty happy with it. |
I use my GPS like you - not needing house to house, mostly offroad. I like the Montana although I still keep the 60 in my camelbac with waypoints and tracks JIC. Only thing I learned about the Montana is next time I will leave the square battery home and just use AA's. On my last 10 day trip I ran that battery dead and had no way to charge it so I put it in my pocket until I got home - would not take a charge,seems this type battery doesn't like being left discharged - so an expensive lesson. Probably won't replace it as I see no good reason to tie up my GPS to recharge a battery. Other than that I really like my Montana :wink:
Speaking of warranty claims, Garmin would probably send you another since yours failed. Give 'em a call. |
The Li-ion battery in mine gave me grief in that the unit kept rebooting while connected to the cradle
I removed the battery & fitted AA's but in the middle of the night without the little torx tool it was a bit of a job I was trying to follow a track to a camp & the unit jus kept rebooting & when I disconnected the power lead the vibration would keep switching off, since then I just run with the AA's |
I have one earplug in my battery compartment but some people stuff a bunch in all the open spaces. Mine does not have any issues with just the one - it never turns off. https://lh3.googleusercontent.com/-n...0/IMGP0320.JPG |
Nice to I am not the only genius out there. :eek1 |
Isn't the one big difference between the two, is the Montana is touch screen?
How does that work with gloves? |
One doesn't realize how often you routinely wipe dust, water, and mud from the sceen until you have a touch screen. |
The Montana is great for Adv bike and car but I think the 78 will replace the old 60/76 and the hard core dirt rider gps of choice. I promote DS rides and the 78 is what my customers are switching to. I have only seen a couple of montanas. |
I have the 60csx and it's been great. Very tough unit. Problem is, these eyes don't work like they used so, if I could find a 60CSX with a larger screen, I'd be sold.
Is there such a unit? |
The 60 series is a benchmark in handheld units.
I've had both the 60csx and the montana so i'm not guessing. Real buttons are nice. They are tactile and you know when you press it even without looking. The touch screen requires your attention much more. The 60 is very small and compact. It works well off the bike too. If you were doing allot of off bike work with a gps, the 60 is hard to beat. What i do like about the montana is the way it generally works. It is fast. Easy to input, big screen, and the ability to load many maps at the same time makes this a deal maker. Wiping dust from the screen is a pain. Setting those damn pins is annoying, but those annoyances make the tradeoff worth every pennny. I'm sticking to the montana. |
Times are GMT -7. It's 09:14 AM. |
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TRAVERSE CITY, Michigan — Saturday was a day of great personal accomplishment for me, but I couldn't help but think of other people who helped make it happen.
I ran the first marathon of my life, the Bayshore Marathon, hoping to at least run the standard of 3 hours, 30 minutes and 59 seconds that I needed to qualify for the Boston Marathon. My goal was to run maybe five minutes faster than that, just to be safe.Instead, I blew away all of my expectations by finishing in 3:11:38. I guess I'm in better shape than I thought.
Nobody accomplishes anything of value without a great support system.
In my case, I've been fortunate to run at least some of the time with some very experienced runners who were more than willing to prepare me physically and mentally for the task of running 26.2 miles.
Drew Williams of Grand Blanc did long runs with me almost every Saturday at Genesys Athletic Club during the winter, even if I was annoying to run with at times. Bill Robson of Grand Blanc and Jim Webb of Clio are long-time training partners who, while I didn't run as much with them this winter, have shown me what real training is like. Webb, in fact, won the men's 65-69 division at Bayshore for the third straight year.At various times, I got to run with excellent local runners like Leo Foley, Larry Gutierrez, Mike Scannell, Mark Egner ... I know I'm forgetting somebody. After feeling how beat up my body was after Saturday's race, I'm even more amazed that Gutierrez ran his fifth quality marathon since early April on Saturday.
The spinning classes at Genesys that I took from Harry Garrison, Lori Krimball and Leslie Braun helped my running immensely.
The coolest thing that happened to me Saturday had nothing to do with how I ran my race or my result.
I had gone up to Traverse City alone and wound up sharing a room with Dave Wolbert of Flint, who was the third masters runner in the half marathon, winning $100 for his effort. I was glad just to have some friends up there who could encourage me before and after the race.
As we entered the final stretch before the finish on the Traverse City Central High track, I noticed a sign someone was holding in the crowd that gathered on the left side of the road. It said "Way to go Bill" or something like that. I was in survival mode at this point because of cramps in my calves, so details are fuzzy.
I do remember seeing the sign, then wondering if that was really my sister holding it. As I got closer, sure enough, my sister, Cathy Rodd, and her son Mike were cheering me on. They drove three-plus hours all the way up from Fenton to surprise me at the finish.
My sister yelled, "You're going to Boston!" I lost it at that point, crying as I entered the track for the final 300 meters to the finish. It was one of those powerful moments I'll always remember, because she went all that way just to watch me run a short part of the race and support me at a time when I can use all the support I can get.
My sister has always been my biggest cheerleader. She called me two minutes after I finished my first half marathon to see how I did. She ran Bayshore a few years back herself for her only marathon — so far!
At the start of the race, I thought about my mom and dad. My dad died in his early 30s. My mom died in her mid-50s. My family history isn't conducive to marathons. I remembered them as I was lost in my thoughts before the race, which seemed to take forever to start (I was really nervous). Of course, I cried a little.
The race itself was amazing. I've been told that finishing a marathon is a life-changing experience, that you will come away with the belief that you can do anything.I ran much faster than I expected. Several times, I asked myself, "Bill, why are you running this fast?" I feared the common mistake among rookie marathoners, going too hard too soon and dying in the final miles. I came back with a positive response each time: "Because I can!"
The only problem I had were cramps in my calves after the 20-mile mark. They slowed me down, but never slower than a 7:55 mile.
After the race, the other participants from the Flint area couldn't have been nicer as they congratulated me.
I was the one who had to run the race Saturday, but I couldn't have done it without the support and inspiration of some people whom I can't thank enough.


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Bunny Dip Bowl
Our figural Bunny dip bowl is perfect for serving dips for your Easter table. Featuring an antiqued whitewash finish and an adorable bunny shape that's sure to be a hit this holiday. Coordinates perfectly with the Bunny Spreader and the rest of our exclusive Bunny dinnerware collection.
- Material: Earthenware
- Care: Dishwasher safe
- Dimensions: 6.5" x 4.25" x 4.75"
- Capacity: 12.5 oz.
- Made in China exclusively for Sur La Table


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Play this 3D accelerated football game by Midway. Featuring full season mode, updated rosters and 2 player action. Try coaching your players so that... He Can Go All the Way!Features
- Arcade pro-football game for Game Boy
- Teams are easily distinguished with improved graphics
- Computer players adapt to repetitive plays, providing greater challenge
- Print screens, rosters, stats, and passwords with separately sold Game Boy Printer
- Play accurate NFL schedules, and continue later with password
Recent threads
- haha Jan 11
- I can't find it! Jul 20
- Genre: Football (PSX)
- Developer: Midway
- Publisher: Midway
Released North America Sep 14, 2000


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It looks like Snooki is set to have a ball this New Year's Eve.
Nicole Polizzi of MTV's Jersey Shore will be placed inside a ball that will be dropped in Time Square as the click strikes midnight.
The other Jersey Shore castmembers, including Mike Sorrentino (A.K.A. "The Situation"), will lead the massive crowd in fist-pumping contest to try and break a Guinness world record.
The MTV New Year's Bash will be hosted by comedian Whitney Cummings and will feature a performance from Flo Rida.
Related articles
- 'Jersey Shore' Stars And Flo Rida Will Ring In New Year On MTV (mtv.com)
- Snooki to drop inside ball on New Year's Eve (cnn.com)


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Guidelines for Process Safety Fundamentals in General Plant Operations April, 1995 At last, a book that covers safety procedures and standards with information that is rarely available outside of proprietary materials. A comprehensive source for basic and essential operations and procedures in use in any facility, the book offers chemical operators and first line supervisors...
Guidelines for Chemical Reactivity Evaluation and Application to Process Design April, 1995 Drawn from international sources, this book provides principles and strategies for the evaluation of chemical reactions, and for using this information in process design and management. A useful resource for engineers who design, start-up, operate, and manage chemical and petrochemical plants, the...
Guidelines for Consequence Analysis of Chemical Releases March, 1995 This Guidelines book provides technical information on how to conduct a consequence analysis to satisfy your company's needs and the EPA rules. It covers quantifying the size of a release, dispersion of vapor clouds to an endpoint concentration, outcomes for various types of explosions and fires,...
Guidelines for Safe Automation of Chemical Processes October, 1993 Increased automation reduces the potential for operator error, but introduces the possibility of new types of errors in design and maintenance. This book provides designers and operators of chemical process facilities with a general philosophy and approach to safe automation, including independent...
Emergency Relief System Design Using DIERS Technology: The Design Institute for Emergency Relief Systems (DIERS) Project Manual April, 1993 OSHA (29 CFR 1910.119) has recognized AIChE/DIERS two-phase flow publications as examples of "good engineering practice" for process safety management of highly hazardous materials. The prediction of when two-phase flow venting will occur, and the applicability of various sizing methods for two-...
Guidelines for Process Equipment Reliability Data, with Data Tables February, 1989 The book supplements Guidelines for Chemical Process Quantitative Risk Analysis by providing the failure rate data needed to perform a chemical process quantitative risk analysis.
Improve Safety by Improving Human Performance August 2006 Safety Donald K. Lorenzo Follow these guidelines to identify situations in which human errors are likely to occur and to correct potential problems early enough to avoid adverse consequences.
Special Section: Energy - Expanding the Shale Gas Infrastructure August 2012 Special Section Jesse F. Goellner Development of U.S. shale gas resources will require expansion of infrastructure assets ranging from roads and rails to pipelines and seaports to power-generation plants and ethane crackers, and more.
CEP: Process Safety Beacon -Some Answers to the November 2012 Beacon Find-the-Problem Contest January 2013 Process Safety Beacon
CEP: Commentary - Working Together to Put CFATS Back on Track November 2012 Commentary Bill Allmond More than five years ago, Congress enacted the most robust and comprehensive chemical security regulatory program to date. The regulation — the Chemical Facility Anti-Terrorism Standards (CFATS) — protects facilities against attack without impairing...
Design an Inherently Safer Plant January 2012 Special Section Senem Surmeli, Kristin D. Norton, P.E., Steven T. Maher, P.E. Continue to search for ways to build safety into your process — from conceptual through detailed design, to procurement and construction, and even into operation.
Make Your Existing Plant Inherently Safer January 2012 Special Section Jack Chosnek, Victor H. Edwards, P.E. Don't overlook opportunities to build more safety into a process that is already in operation.
Managing Dust Explosion Hazards August 2009 Safety Vahid Ebadat Companies that handle powders or other particulate solids need to be aware of the potential for fire and explosions, and follow industry best practices, codes and standards to manage the risk.
Avoid Chemical Reactivity Incidents in Warehouses February 2008 Safety Peter Lodal, Scott Berger, J. Wayne Chastain, William W. Doerr, Scott Berger and Peter N. Lodal Use this approach for the initial evaluation of potential reactivity hazards in storage applications.
Is Your Dust Collection System An Explosion Hazard? October 2003 Safety Vahid Ebadat The prevalence of dust explosions in dust collection units may be due to the fact that the hazards posed by the powders handled are not fully understood or that explosion preventive and protective control measures are insufficient or absent. This...
CEP: Process Safety Beacon - Overflow + Ignition = Tank Farm Fire (Part 2) October 2009 Safety Process Safety Beacon
CEP: Process Safety Beacon - What If You Unload the Wrong Material into a Tank? April 2012 Process Safety Beacon
Size Depressurization and Relief Devices for Pressurized Segments Exposed to Fire September 2002 Safety Per Salater Piping and equipment must withstand fires without rupturing. This can be accomplished by properly designing relief and depressurization systems and using passive fire protection,when needed.
Addressing the Hazards of Data Omission from MSDSs April 2005 Safety James C. Mulligan If certain chemicals lack physical hazards data, suppliers must be proactive to keep workers safe. Here's how to determine dust flammability and reactivity data for inclusion on MSDSs.
CEP: YPOV - Engineering Cyber Security July 2012 YPOV Arjun Gopalratnam Between March and April 2010, a powerful but seemingly limited computer worm, now referred to as Stuxnet, infected computers around the world, beginning in Iran and spreading to Indonesia and India. A recently published book uncovers findings on the origin of the worm and raises concerns that are relevant to chemical engineers everywhere.
Managing Transportation Safety and Security Risks October 2009 Safety Brad A. Fuller Effective transportation risk management (TRM) balances safety and security with operational efficiency. When developing a TRM program, use this comprehensive framework and these practical techniques to identify and screen risks.
It's Time to Consider Human Factors in Alarm Management November 2002 Instrumentation Ian Nimmo Implement these procedures to consider human factors, not simply human error, in control-room architecture and reduce the chance for incidents in the plant.
CEP: Process Safety Beacon - Construction Damage Causes Pipeline Fire May 2008 Safety Process Safety Beacon
Designing Emergency Relief Devices for Reactive Systems September 2005 Safety Peter Howell , Georges Melhem This guidance applies to reactive systems subject to fire-induced runaway reactions, tanks that store reactive materials, and two-phase flow of reactive materials.
Will IST Stall CFATS Reauthorization? August 2010 News Feature Matthew McKeon-Slattery Debate over the Chemical Facility Anti-Terrorism Standards continues to revolve around whether manufacturers and processors will be required to incorporate inherently safer technology into their security plans.
Plant Security Remains a Moving Target May 2008 News Feature Cynthia F. Mascone While chemical companies work toward complying with existing standards, legislators are poised to revise those very rules — with changes ranging from minor tweaking to major overhaul on the table.
Tackling the Human Challenges of Facility Security February 2006 Safety Bill Effron, Dennis A. Attwood The increased complexity of security systems may come at the expense of the user. Thus, they must be designed to match their operators' capabilities and limitations.
CEP: Process Safety Beacon - The Great Boston Molasses Flood of 1919 May 2007 Safety Process Safety Beacon
What Pressure Relief Really Means September 2010 Back To Basics Brian D. Kelly Poor design, inadequate maintenance, and improper operation can all lead to mechanical failure. The basic concepts of pressure relief, when understood and applied properly, can help prevent this failure
Inherent Security: Protecting Process Plants Against Threats December 2003 Safety Paul Baybutt The best defense against deliberate acts, such as terrorism, sabotage, vandalism or theft, is the application of inherent security principles to facility design and operation.
Safe Automation Through Process Engineering December 2008 Safety Angela E. Summers Use this step-by-step procedure to apply safety instrumented systems (SISs) and continuously reduce risk.
Designing Resilient Engineered Systems April 2006 Safety Susan M. Mitchell By viewing resiliency as a property of complex systems, it may be possible to develop resilient systems that can withstand unanticipated failures without disastrous consequences.
Addressing Combustible Dust Hazards May 2011 Back To Basics Michelle Murphy, Molly R. Myers, Judy Perry Facilities that handle or generate dusts are at risk for explosions and flash fires. Follow this approach to understand and mitigate your combustible dust hazards.
Understanding Reactive Chemical Incidents March 2004 Safety John F. Murphy In order to avoid incidents involving reactive chemical hazards, it is useful to understand the types of chemicals and types of equipment involved, as well as the root causes of the incidents.
Conducting Process Hazard Analyses for Dust-Handling Operations February 2009 Safety Judy A. Perry Use this checklist-based technique of process-hazard analysis (PHA) to identify and assess potential dust hazards and to evaluate safeguards that can mitigate risks.
CEP: Process Safety Beacon - Static Electricity Discharge Causes Fire December 2008 Process Safety Beacon
Preventing Dust Explosions: Are You Doing Enough? March 2008 News Feature Issue Date: March 2008 Experts agree that greater vigilance is needed to snuff out the ever-present risk at facilities handling powdered materials.
Screening Reactive Chemical Hazards May 2006 Safety Yen-Shan Liu Use these tools to identify potentially reactive chemical hazards and avoid the expense of conducting numerous detailed hazard assessments.
CEP: Process Safety Beacon - Hose Repaired with Duct Tape Causes Fire July 2007 Process Safety Beacon
Classifying Reactive Chemicals March 2004 Safety William J. Rogers, Sanjeev R. Saraf, M. Sam Mannan This simple classification scheme can be used to characterize the thermal instability risks posed by reactive chemicals in a process.
CEP: Process Safety Beacon - More Lessons from Container-Filling Fire February 2009 Process Safety Beacon
Reduce VOC and HAP Emissions June 2002 Environmental Management Edward C. Moretti Follow this roadmap to understand the abatement technologies available for controlling emissions of volaitle organic compounds and hazardous air pollutants and the criteria for choosing among them.
Predesign with Safety in Mind July 2006 Safety Palligarnai T. Vasudevan, Gael D. Ulrich This article will help you develop strong safety instincts that will guide you in making critical decisions in the preliminary design phase.
CEP: Process Safety Beacon - Hazards of Temporary Confined Spaces August 2007 Safety Process Safety Beacon
Reliability for Safety Instrumented Systems September 2004 Instrumentation J. Patrick Williams This article offers a detailed reliability-based methodology for determining the safety integrity level of instrumented systems by providing overpressure protection where arrangements of multiple pressure-relief valves are impractical to implement.
Guidelines for the Management of Change for Process Safety March, 2008 Guidelines for the Management of Change for Process Safety provides guidance on the implementation of effective and efficient Management of Change (MOC) procedures, which can be applied to improve process safety. In addition to introducing MOC systems, the book describes how to design an initial...
Safe Design and Operation of Process Vents and Emission Control Systems March, 2006 Process vent header collection systems are subject to continually varying compositions and flow rates and thus present significant challenges for safe design. Due to increasingly demanding safety, health, environmental, and property protection requirements, today's industrial designers are faced...
19th Annual International Conference: Emergency Planning Preparedness, Prevention & Response April, 2005 Over 40 papers and posters that share the latest practices in emergency planning related to fixed chemical, pharmaceutical, LNG, and petroleum facilities, storage facilities, transportation, and security.
Guidelines for Analyzing and Managing the Security Vulnerabilities of Fixed Chemical Sites June, 2003 This new initiative demonstrates a process and tools for managing the security vulnerability of sites that produce and handle chemicals, petroleum products, pharmaceuticals, and related materials such as fertilizers and water treatment chemicals. Includes: enterprise screening; site screening;...
RELEASE: A Model with Data to Predict Aerosol Rainout in Accidental Releases March, 1998 This book documents CCPS's Aerosol Research Program to develop a model to predict liquid rainout from release of a pressurized, liquefied gas--and, hence the residual amount of material in a vapor cloud, which may be greater than the amount calculated from an enthalpy chart. RELEASE predicts the...
CEP: Process Safety Beacon - The Bhopal Tragedy - 25 Years Ago December 2009 Safety Process Safety Beacon
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CEP: Process Safety Beacon - Process Safety Beacon — Corrosion and Erosion January 2010 Safety Process Safety Beacon
CEP: Process Safety Beacon - Understanding the Reactivity of Your Heat-Transfer Fluid February 2011 Safety Process Safety Beacon
CEP: Process Safety Beacon - Facility Siting — It's All About Location March 2010 Safety Process Safety Beacon


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All Features in
Samplitude Music Studio 2015
Multitrack recordings & arrangements
Multitrack recordings
Multitrack recording in 24-bit/96 kHz studio quality on up to 16 mono tracks & eight stereo tracks at the same time.
With multitrack recording you can record, edit & mix band practices, demo tapes or complete albums in studio quality on multiple tracks at the same time.
The MR-128 is a virtual mixing console with up to 128 channels. Each individual track in every channel contains four effects slots for internal and VST effects.
In the MR-128 you have direct access to the master effects section and you can use up to 8 plug-ins in the master track itself. Each mixer channel contains four aux channels.
Correct vocal recordings
The feature range and usability of Vocal Tune 2 have been clearly optimized. The new pitch curves & wave forms help you keep track of everything and can be edited in detail with the pencil tool.
Pitch shifting
Great for making quick harmony changes in arrangements: You can easily adjust the pitch of samples or audio files without affecting the playback speed.
For impressive transitions
The first transition solutions to create a lasting effect: You can use the Cross-Fade editor to design your own transitions between different audio files.
Virtual Instruments
Analog Synths
Take the sounds of legendary synthesizers, add various effects options and top it all off with a bucketful of euphoria – and what you have is the new Analog Synths. This is where euphoric dream sequences meet hard-hitting bass lines, warm keys, organs, strings and aggressive leads. Includes Arpeggiator function.
World Flutes
Precious woods: The xiao, tambin and pan flutes provide an impressive traditional sound, as well as a multitude of effects parameters. Immerse yourself in a world
full of natural and exotic sounds.
FX Rack
The FX Rack offers a first-class overview of all relevant effects and makes working with the equalizer, hall, delay, pitch and tempo sections much easier. Make your music productions stand out.
For an excellent sound image: Mastering Suite 4
Professional tools for an even more professional sound. Here are some of the things you'll find in MAGIX Samplitude Music Studio: A StereoFX module, a multiband compressor, a 6-band equalizer, a limiter, and MultiMax.
6-Band Equalizer
The parametric 6-band equalizer provides your music productions with the optimal sound. So you can set different frequency range volumes in accordance with one another and avoid masked frequencies
when mixing down.
Sound analysis
Visual sound analysis
It's a good idea to use visual analysis tools for mixing and tidying up the frequency range or, for example, finding masked frequencies in the stereo field. A vectorscope, spectroscope & spectrogram, among other tools are included.
Hardware support
Samplitude Music Studio 2015 supports the Mackie control protocol and conventional hardware controllers. You can move the fader in the mixer or use an external controller to make live automatizations – levels are adjusted automatically to fit the progression.
VST & ReWire
Samplitude Music Studio 2015 offers VST and ReWire support for additional instruments and effects. VST 2 support for effects and instruments includes integration, automation and VST multi-output. Interfaces: VST 2, ASIO, ReWire, SMPTE, MTC, MC
MIDI support
In the MIDI editor you can easily edit patterns you've made with your mouse or recordings you've made with a MIDI device (e.g. a keyboard or drum pads). You can choose between the piano roll, score and drum editor views. MIDI data can be adjusted and created in various ways with mouse modes such as Velocity.


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Since 1918, the National Slag Association (NSA) has promoted the use of blast furnace and steel furnace slag. Blast furnace slag has been called the "all-purpose aggregate" as it can be used in all construction applications as either a normal weight or lightweight (expanded or pelletized) aggregate depending on how it was formed and processed.
Please contact with any association updates.


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Tue | ||
Start: 12:00 pm
Two years ago in Padilla v. Kentucky, the U.S. Supreme Court ruled that the Sixth Amendment requires that defense attorneys advise their noncitizen clients about the immigration consequences of a plea. The Court recognized what, for decades, the defense and immigration bars have known: competent defense counsel must advise about immigration consequences of a plea. Tim Arnold has represented José Padilla either as lead counsel or co-counsel through the Supreme Court, and he continues to represent Mr. Padilla on remand to the state court, where the case is now pending. During his career at DPA Tim Arnold has been awarded the Kentucky Association of Criminal Defense Lawyer's Juvenile Justice Award, the DPA's In Re Gault Award for excellence in juvenile representation, the DPA's Furman v. Georgia award for excellence in death penalty representation, and most recently the American Immigration Lawyers Association Jack Wasserman Memorial Award for Excellence in Litigation in the field of Immigration Law. He has served as DPA's Post-Trial Division Director since 2008. Join U of L's ACS chapter and Tim Arnold as we discuss the implications from the Padilla decision, applications moving forward, and how this decision will shape the role of criminal defense attorneys.Room 175, lunch will be provided from Jason's Deli. |


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Phase III Clinical Trial of Fentanyl Transdermal Matrix Patch, in the Management of Chronic Intractable Pain- Assessment of Effectiveness, Safety and Pharmacokinetics
- Full Text View
- Tabular View
- No Study Results Posted
- Disclaimer
- How to Read a Study Record
The purpose of this study is to verify the effectiveness, and safety in Japanese patients with chronic intractable pain after 4-week medication of fentanyl transdermal matrix patches containing either 12.5 mcg/hr, 25 mcg/hr, 50 mcg/hr, 75 mcg/hr, or 100 mcg/hr, who have been switched from existing formulations, such as codeine, morphine hydrochloride, or fentanyl injectable. Furthermore, the safety and effectiveness of long term treatment such as 48 weeks are to be assessed, if possible.
Condition | Intervention | Phase |
Pain, Intractable |
Drug: fentanyl |
Phase 3 |
Study Type: | Interventional |
Study Design: | Allocation: Non-Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Single Group Assignment Masking: Open Label Primary Purpose: Treatment |
Official Title: | An Open Label Study to Confirm the Effectiveness, and Safety of Fentanyl Transdermal Matrix Patch in Japanese Patients With Chronic Intractable Pain Who Has Prior Therapy of Codeine, Morphine Hydrochloride, or Fentanyl Injectable Preparations. |
- Patient's global assessments of pain on the completion day of Treatment period 1
- Physician's global assessments, pain intensity (Visual Analog Scale: VAS), pain intensity (categorical scale), total pain duration per day, and dose of rescue medication, Adverse events, laboratory values, and vital signs. Pharmacokinetics
Enrollment: | 139 |
Study Start Date: | May 2005 |
Study Completion Date: | September 2006 |
Fentanyl transdermal matrix patch is a narcotic analgesic agent. Compared with the existing reservoir-type Durotep® Patch, fentanyl transdermal matrix patch is not liable to leakage of drug solution and does not contain alcohol, which becomes a cause of skin irritation. Also this new formulation has become available in a smaller dose of 12.5mg/hr while the smallest Durotep® Patch is 25mg/hr. While Durotep® Patch is currently indicated only for cancer pain in Japan, this clinical trial was planned to assess effectiveness, and safety of fentanyl transdermal matrix patch in Japanese patients with chronic intractable pain receiving codeine, morphine hydrochloride, or fentanyl injectable formulations. After pre-treatment period for seven to fourteen days for evaluating the eligibility of the patients for the study, patients will be treated for 4 weeks as Treatment period 1 and 48 weeks as Treatment period 2 followed by 3-day post-treatment observation period. One patch can be used for 72 hours, which is the same as the existing Patch. Starting from the first day of treatment, fentanyl will be applied to the chest, the upper arm or other appropriate site, which will be replaced with a new patch every three days (ca. 72 hr). Starting dose should be between 12.5 mcg/hr and 75 mcg/hr, depending on the prior opioid dose.
Ages Eligible for Study: | 20 Years and older |
Genders Eligible for Study: | Both |
Accepts Healthy Volunteers: | No |
Inclusion Criteria:
- Patients with chronic intractable pain receiving any of the following treatments :(1)Codeine phosphate, (2)Morphine hydrochloride preparations equivalent to less than 315 mg/day of oral morphine, (3)Fentanyl citrate injectable solution equivalent to less than 0.3 mg/day
- Patients with chronic intractable pain in whom lesions causative of pain cannot be removed or treated, or in whom pain has been persisting for at least 12 weeks despite of the existing medication
- Patients may be hospitalized during application of the initial transdermal dose of fentanyl transdermal matrix patches (patients may be ambulatory when the study starts).
Exclusion Criteria:
- Patients with respiratory dysfunction such as chronic pulmonary disease
- Patients with asthma
- Patients with bradyarrhythmia
- Patients with concurrent liver and/or kidney dysfunction according to the latest laboratory test values within 14 days before the start of the pre-treatment observation period
- Patients with organic brain disorder such as elevated intracranial pressure, disturbance of consciousness/coma, or brain tumor
- Patients with any psychoneurologic complication and judged incapable of self assessment
- Patients with or with a history of drug dependency or narcotic abuse
- Patients with a history of hypersensitivity to fentanyl or any other opioid analgesic
Please refer to this study by its ClinicalTrials.gov identifier: NCT00216684
Study Director: | Janssen Pharmaceutical K.K. Clinical Trial | Janssen Pharmaceutical K.K. |
No publications provided
ClinicalTrials.gov Identifier: | NCT00216684 History of Changes |
Other Study ID Numbers: | CR004879 |
Study First Received: | September 13, 2005 |
Last Updated: | January 31, 2011 |
Health Authority: | Japan: Japan Pharmaceuticals And Medical Devices Evaluation Center |
Keywords provided by Janssen Pharmaceutical K.K.:
Fentanyl, Chronic intractable pain, Japanese patients |
Additional relevant MeSH terms:
Pain, Intractable Nervous System Diseases Neurologic Manifestations Pain Signs and Symptoms Fentanyl Adjuvants, Anesthesia Analgesics Analgesics, Opioid Anesthetics |
Anesthetics, General Anesthetics, Intravenous Central Nervous System Agents Central Nervous System Depressants Narcotics Peripheral Nervous System Agents Pharmacologic Actions Physiological Effects of Drugs Sensory System Agents Therapeutic Uses |
ClinicalTrials.gov processed this record on April 23, 2015


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Released: Apr 01st, 2006
Running Time: 110
Director: Tony Galda
Company: Galdavision
Loni, Daisy (I), Katie (I), Sierra (I)
Critical Rating: AAA
Genre: Pro-Am
Tony gets an OK quartet of fresh young talent for the latest installment of his amateur series.
Loni is a sexy young'un with fake boobs and a stripper's body. She seems primed for porn, and we'll likely be seeing more of this one in the future. She and Tony crank out a good scene on the floor.
Daisy is a big girl with big, implanted boobs and a generous booty that gets slammed in doggie. But the booty prize easily goes to Sierra. That girl packs a wallop in her caboose. She's definitely worth watching in a POV reverse cow.
Retailing: Add this to the rest of Tony's series.


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1. Do something fun you used to do as a kid. Think about when you WERE happy during the holidays and recreate it. Maybe it was ice-skating as a kid or watching a favorite holiday movie. Just do it again and try to recapture the magic.
2. Do something selfish. You deserve "you-time" during the holidays, just like the rest of the year. So take a nap, or schedule a massage or some spa treatments. Don't waste time on guilt, just call and schedule the appointment.
3. Go outside. It's probably cold out, but that's actually great for your health. Keeping warm exerts energy, and you need fresh air when you've been stuck in malls.
4. Volunteer. Helping other people is actually a great way for YOU to feel better. But don't force it by doing something you hate. Volunteer to do something you love.
5. Honor people who've passed. You can get depressed during the holidays if you think about someone you've lost. So honor them by making their favorite food, their favorite drink, doing the things they loved, and ENJOYING it. They'd want you to.
6. Forgive your family. They may be annoying, or worse, but they probably love you. So do yourself a favor and let go of any anger and resentment.
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