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1.  Mortality in Levodopa-Treated Parkinson's Disease 
Parkinson's Disease  2014;2014:426976.
Parkinson's disease (PD) is associated with increased mortality despite many advances in treatment. Following the introduction of levodopa in the late 1960's, many studies reported improved or normalized mortality rates in PD. Despite the remarkable symptomatic benefits provided by levodopa, multiple recent studies have demonstrated that PD patients continue to die at a rate in excess of their peers. We undertook this retrospective study of 211 deceased PD patients to determine the factors associated with mortality in levodopa-treated PD. Our findings confirm that PD is associated with increased mortality in both men and women. Unlike the majority of other mortality studies, we found that women have a greater reduction in lifespan compared to men. We also found that patients with early onset PD (onset at the age of 50 or before) have reduced survival relative to PD patients with later ages of onset. A final important finding is that survival is equal in PD patients treated with levodopa early (within 2 years or less of PD onset) versus later.
PMCID: PMC3927757  PMID: 24616821
2.  Validation of an Ambulatory Capacity Measure in Parkinson Disease: A Construct Derived from the Unified Parkinson’s Disease Rating Scale 
A construct calculated as the sum of items 13, 14, 15, 29, 30 of the Unified Parkinson’s Disease Rating Scale (UPDRS) has been used as an “Ambulatory Capacity Measure” (ACM in Parkinson disease (PD). Its construct validity has never been examined. A similar construct, consisting of the mean value of the same UPDRS items has been used under the acronym PIGD as a measure of postural instability and gait disorder in PD.
To examine the construct validity of the ACM and PIGD in PD.
We analyzed data in an existing database of 340 PD patients, Hoehn and Yahr stages (HYS) 1–5 who participated in a study of falls. Number of falls (NOF) was recorded over 4 weeks, and UPDRS (mental, ADL, and motor subscales), HYS, Activities Based Confidence Scale (ABC), Freezing of Gait Questionnaire (FOG), Five Times Sit-to-Stand (FTSS), Timed Up-and Go (TUG), Gait Velocity (GV), and Berg Balance Scale (BBS) evaluations were performed. Internal consistency was assessed by Cronbach’s alpha. Construct validity was assessed through correlations of the ACM and PIGD to these measures and to their summed-ranks. A coefficient of determination was calculated through linear regression.
Mean age was 71.4, mean age at diagnosis 61.4 years; 46% were women; mean UPDRS subscale scores were: mental 3.7; ADL 15.7; motor: 27.1; mean ACM was 6.51, and mean PIGD 1.30. Cronbach’s alpha was 0.78 for both ACM and PIGD. Spearman correlation coefficients between the ACM/PIGD and ABC, FOG, TUG, GV and BBS were 0.69, 0.72, 0.67, 0.58, and 0.70 respectively. Correlation between the ACM/PIGD and summed-ranks of HYS, NOF, ABC, FOG, FTSS, TUG, GV and BBS was high (Spearman r=0.823, p <0.0001); 68% of the variability in the summed-ranks was explained by ACM/PIGD.
The ACM and the PIGD are valid global measures and accurately reflect the combined effects of the various components of ambulatory capacity in PD patients with HY stages 1–4.
PMCID: PMC4478048  PMID: 25311202
Idiopathic Parkinson Disease; Ambulation; Scales; Balance; Falls; PIGD; Ambulatory Capacity
3.  When a discriminating dose assay is not enough: measuring the intensity of insecticide resistance in malaria vectors 
Malaria Journal  2015;14:210.
Guidelines from the World Health Organization for monitoring insecticide resistance in disease vectors recommend exposing insects to a predetermined discriminating dose of insecticide and recording the percentage mortality in the population. This standardized methodology has been widely adopted for malaria vectors and has provided valuable data on the spread and prevalence of resistance. However, understanding the potential impact of this resistance on malaria control requires a more quantitative measure of the strength or intensity of this resistance.
Bioassays were adapted to quantify the level of resistance to permethrin in laboratory colonies and field populations of Anopheles gambiae sensu lato. WHO susceptibility tube assays were used to produce data on mortality versus exposure time and CDC bottle bioassays were used to generate dose response data sets. A modified version of the CDC bottle bioassay, known as the Resistance Intensity Rapid Diagnostic Test (I-RDT), was also used to measure the knockdown and mortality after exposure to different multipliers of the diagnostic dose. Finally cone bioassays were used to assess mortality after exposure to insecticide treated nets.
The time response assays were simple to perform but not suitable for highly resistant populations. After initial problems with stability of insecticide and bottle washing were resolved, the CDC bottle bioassay provided a reproducible, quantitative measure of resistance but there were challenges performing this under field conditions. The I-RDT was simple to perform and interpret although the end point selected (immediate knockdown versus 24 h mortality) could dramatically affect the interpretation of the data. The utility of the cone bioassays was dependent on net type and thus appropriate controls are needed to interpret the operational significance of these data sets.
Incorporating quantitative measures of resistance strength, and utilizing bioassays with field doses of insecticides, will help interpret the possible impact of resistance on vector control activities. Each method tested had different benefits and challenges and agreement on a common methodology would be beneficial so that data are generated in a standardized format. This type of quantitative data are an important prerequisite to linking resistance strength to epidemiological outcomes.
PMCID: PMC4455279  PMID: 25985896
4.  Evaluating the feasibility of using insecticide quantification kits (IQK) for estimating cyanopyrethroid levels for indoor residual spraying in Vanuatu 
Malaria Journal  2014;13:178.
The quality of routine indoor residual spraying (IRS) operations is rarely assessed because of the limited choice of methods available for quantifying insecticide content in the field. This study, therefore, evaluated a user-friendly, rapid colorimetric assay for detecting insecticide content after routine IRS operations were conducted.
This study was conducted in Tafea Province, Vanuatu. Routine IRS was conducted with lambda cyhalothrin. Two methods were used to quantify the IRS activities: 1) pre-spray application of small felt pads and 2) post-spray removal of insecticide with adhesive. The insecticide content was quantified using a colorimetric assay (Insecticide Quantification Kit [IQK]), which involved exposing each sample to the test reagents for 15 mins. The concentration of insecticide was indicated by the depth of red colour.
The IQK proved simple to perform in the field and results could be immediately interpreted by the programme staff. The insecticide content was successfully sampled by attaching felt pads to the house walls prior to spraying. The IRS operation was well conducted, with 83% of houses being sprayed at the target dose (20 – 30 mg AI/m2). The average reading across all houses was 24.4 ± 1.5 mg AI/m2. The results from the felt pads applied pre-spray were used as a base to compare methods for sampling insecticide from walls post-spray. The adhesive of Sellotape did not collect adequate samples. However, the adhesive of the felt pads provided accurate samples of the insecticide content on walls.
The IQK colorimetric assay proved to be a useful tool that was simple to use under realistic field conditions. The assay provided rapid information on IRS spray dynamics and spray team performance, facilitating timely decision making and reporting for programme managers. The IQK colorimetric assay will have direct applications for routine quality control in malaria control programmes globally and has the potential to improve the efficacy of vector control operations.
PMCID: PMC4020589  PMID: 24885084
Colorimetric assay; Insecticide residual spray (IRS); Vanuatu; Insecticide quantification kit
5.  Rivastigmine for the treatment of dementia associated with Parkinson’s disease 
Parkinson’s disease (PD) afflicts millions of people worldwide and leads to cognitive impairment or dementia in the majority of patients over time. Parkinson’s disease dementia (PDD) is characterized by deficits in attention, executive and visuospatial function, and memory. The clinical diagnostic criteria and neuropathology surrounding PDD remain controversial with evidence of overlap among PDD, dementia with Lewy bodies (DLB) and Alzheimer’s disease (AD). Cortical cholinergic deficits are greater in PDD than in AD, and are well-correlated with the cognitive and neuropsychiatric dysfunction that occurs in PDD. Inhibition of acetylcholine metabolism is therefore a practical therapeutic strategy in PDD.
This review examines current evidence for rivastigmine (a cholinesterase/butyrylcholinesterase inhibitor) treatment in PDD. In addition to its efficacy, we examine the safety profile, side effects, and cost effectiveness of rivastigmine in PDD. Rivastigmine provides modest benefit in PDD and further long-term studies are needed to determine the effectiveness and safety of rivastigmine over time. Tolerability is a problem for many PDD patients treated with rivastigmine. Future studies of rivastigmine in PDD should focus on pragmatic outcomes such as time to need for nursing home placement, pharmacoeconomic outcomes and simultaneous patient/caregiver quality of life assessments.
PMCID: PMC2656320  PMID: 19300613
Parkinson’s disease; dementia; rivastigmine; cholinesterase inhibitor
6.  Identification and distribution of a GABA receptor mutation conferring dieldrin resistance in the malaria vector Anopheles funestus in Africa 
Growing problems of pyrethroid resistance in Anopheles funestus have intensified efforts to identify alternative insecticides. Many agrochemicals target the GABA receptors, but cross-resistance from dieldrin resistance may preclude their introduction.
Dieldrin resistance was detected in An. funestus populations from West (Burkina Faso) and central (Cameroon) Africa, but populations from East (Uganda) and Southern Africa (Mozambique and Malawi) were fully susceptible to this insecticide. Partial sequencing of the dieldrin target site, the γ-aminobutyric acid (GABA) receptor, identified two amino acid substitutions, A296S and V327I. The A296S mutation has been associated with dieldrin resistance in other species. The V327I mutations was detected in the resistant sample from Burkina Faso and Cameroon and consistently associated with the A296S substitution. The full-length of the An. funestus GABA-receptor gene, amplified by RT-PCR, generated a sequence of 1674 bp encoding 557 amino acid of the protein in An. funestus with 98% similarity to that of Anopheles gambiae. Two diagnostic assays were developed to genotype the A296S mutation (pyrosequencing and PCR-RFLP), and use of these assays revealed high frequency of the resistant allele in Burkina Faso (60%) and Cameroon (82%), moderate level in Benin (16%) while low frequency or absence of the mutation was observed respectively in Uganda (7.5%) or 0% in Malawi and Mozambique.
The distribution of the RdlR mutation in An. funestus populations in Africa suggests extensive barriers to gene flow between populations from different regions.
Graphical abstract
► Dieldrin resistance detected in An. funestus from West and Central Africa. ► Identification of the A296S conferring dieldrin resistance after sequencing. ► V327I mutation detected in resistant samples and associated with the A296S mutation. ► Two diagnostic assays were developed to genotype the A296S mutation. ► High frequency of RdlR in West Africa but complete absence in southern Africa.
PMCID: PMC3579012  PMID: 21501685
Insecticide resistance; Anopheles funestus; Dieldrin resistance; GABA receptor; Malaria
7.  Association Mapping of Insecticide Resistance in Wild Anopheles gambiae Populations: Major Variants Identified in a Low-Linkage Disequilbrium Genome 
PLoS ONE  2010;5(10):e13140.
Association studies are a promising way to uncover the genetic basis of complex traits in wild populations. Data on population stratification, linkage disequilibrium and distribution of variant effect-sizes for different trait-types are required to predict study success but are lacking for most taxa. We quantified and investigated the impacts of these key variables in a large-scale association study of a strongly selected trait of medical importance: pyrethroid resistance in the African malaria vector Anopheles gambiae.
Methodology/Principal Findings
We genotyped ≈1500 resistance-phenotyped wild mosquitoes from Ghana and Cameroon using a 1536-SNP array enriched for candidate insecticide resistance gene SNPs. Three factors greatly impacted study power. (1) Population stratification, which was attributable to co-occurrence of molecular forms (M and S), and cryptic within-form stratification necessitating both a partitioned analysis and genomic control. (2) All SNPs of substantial effect (odds ratio, OR>2) were rare (minor allele frequency, MAF<0.05). (3) Linkage disequilibrium (LD) was very low throughout most of the genome. Nevertheless, locally high LD, consistent with a recent selective sweep, and uniformly high ORs in each subsample facilitated significant direct and indirect detection of the known insecticide target site mutation kdr L1014F (OR≈6; P<10−6), but with resistance level modified by local haplotypic background.
Primarily as a result of very low LD in wild A. Gambiae, LD-based association mapping is challenging, but is feasible at least for major effect variants, especially where LD is enhanced by selective sweeps. Such variants will be of greatest importance for predictive diagnostic screening.
PMCID: PMC2956759  PMID: 20976111
8.  Pyrethroid Resistance in an Anopheles funestus Population from Uganda 
PLoS ONE  2010;5(7):e11872.
The susceptibility status of Anopheles funestus to insecticides remains largely unknown in most parts of Africa because of the difficulty in rearing field-caught mosquitoes of this malaria vector. Here we report the susceptibility status of the An. funestus population from Tororo district in Uganda and a preliminary characterisation of the putative resistance mechanisms involved.
Methodology/Principal Findings
A new forced egg laying technique used in this study significantly increased the numbers of field-caught females laying eggs and generated more than 4000 F1 adults. WHO bioassays indicated that An. funestus in Tororo is resistant to pyrethroids (62% mortality after 1 h exposure to 0.75% permethrin and 28% mortality to 0.05% deltamethrin). Suspected DDT resistance was also observed with 82% mortality. However this population is fully susceptible to bendiocarb (carbamate), malathion (organophosphate) and dieldrin with 100% mortality observed after exposure to each of these insecticides. Sequencing of a fragment of the sodium channel gene containing the 1014 codon conferring pyrethroid/DDT resistance in An. gambiae did not detect the L1014F kdr mutation but a correlation between haplotypes and resistance phenotype was observed indicating that mutations in other exons may be conferring the knockdown resistance in this species. Biochemical assays suggest that resistance in this population is mediated by metabolic resistance with elevated level of GSTs, P450s and pNPA compared to a susceptible strain of Anopheles gambiae. RT-PCR further confirmed the involvement of P450s with a 12-fold over-expression of CYP6P9b in the Tororo population compared to the fully susceptible laboratory colony FANG.
This study represents the first report of pyrethroid/DDT resistance in An. funestus from East Africa. With resistance already reported in southern and West Africa, this indicates that resistance in An. funestus may be more widespread than previously assumed and therefore this should be taken into account for the implementation and management of vector control programs in Africa.
PMCID: PMC2912372  PMID: 20686697
9.  High Level of Pyrethroid Resistance in an Anopheles funestus Population of the Chokwe District in Mozambique 
PLoS ONE  2010;5(6):e11010.
Although Anopheles funestus is difficult to rear, it is crucial to analyse field populations of this malaria vector in order to successfully characterise mechanisms of insecticide resistance observed in this species in Africa. In this study we carried out a large-scale field collection and rearing of An. funestus from Mozambique in order to analyse its susceptibility status to insecticides and to broadly characterise the main resistance mechanisms involved in natural populations.
Methodology/Principal Findings
3,000 F1 adults were obtained through larval rearing. WHO susceptibility assays indicated a very high resistance to pyrethroids with no mortality recorded after 1h30min exposure and less than 50% mortality at 3h30min. Resistance to the carbamate, bendiocarb was also noted, with 70% mortality after 1h exposure. In contrast, no DDT resistance was observed, indicating that no kdr-type resistance was involved. The sequencing of the acetylcholinesterase gene indicated the absence of the G119S and F455W mutations associated with carbamate and organophosphate resistance. This could explain the absence of malathion resistance in this population. Both biochemical assays and quantitative PCR implicated up-regulated P450 genes in pyrethroid resistance, with GSTs playing a secondary role. The carbamate resistance observed in this population is probably conferred by the observed altered AChE with esterases also involved.
The high level of pyrethroid resistance in this population despite the cessation of pyrethroid use for IRS in 1999 is a serious concern for resistance management strategies such as rotational use of insecticides. As DDT has now been re-introduced for IRS, susceptibility to DDT needs to be closely monitored to prevent the appearance and spread of resistance to this insecticide.
PMCID: PMC2882342  PMID: 20544036
10.  Field-Caught Permethrin-Resistant Anopheles gambiae Overexpress CYP6P3, a P450 That Metabolises Pyrethroids 
PLoS Genetics  2008;4(11):e1000286.
Insects exposed to pesticides undergo strong natural selection and have developed various adaptive mechanisms to survive. Resistance to pyrethroid insecticides in the malaria vector Anopheles gambiae is receiving increasing attention because it threatens the sustainability of malaria vector control programs in sub-Saharan Africa. An understanding of the molecular mechanisms conferring pyrethroid resistance gives insight into the processes of evolution of adaptive traits and facilitates the development of simple monitoring tools and novel strategies to restore the efficacy of insecticides. For this purpose, it is essential to understand which mechanisms are important in wild mosquitoes. Here, our aim was to identify enzymes that may be important in metabolic resistance to pyrethroids by measuring gene expression for over 250 genes potentially involved in metabolic resistance in phenotyped individuals from a highly resistant, wild A. gambiae population from Ghana. A cytochrome P450, CYP6P3, was significantly overexpressed in the survivors, and we show that the translated enzyme metabolises both alpha-cyano and non–alpha-cyano pyrethroids. This is the first study to demonstrate the capacity of a P450 identified in wild A. gambiae to metabolise insecticides. The findings add to the understanding of the genetic basis of insecticide resistance in wild mosquito populations.
Author Summary
Malaria, a disease spread by anopheline mosquitoes, is a global health problem with an enormous economic and social impact. Pyrethroid insecticides are critical in reducing malaria transmission, and resistance to these insecticides threatens current control efforts. With a limited number of public health insecticides available for the foreseeable future, it is vital to monitor levels of resistance to facilitate decisions on when new strategies should be implemented before control fails. For monitoring, simple molecular assays are highly desirable, because they can detect resistance at very low frequencies and should identify the presence of single recessive alleles well before bioassays. An understanding of the mechanisms conferring resistance facilitates the development of such tools and may also lead to novel strategies to restore the efficacy of the insecticide, or the development of new compounds. We set out to identify enzymes that may confer metabolic pyrethroid resistance by comparing levels of messenger RNA between insecticide-selected versus unselected mosquitoes. We caught members of the major malaria vector, A. gambiae s.s. from a highly pyrethroid resistant field population. We found increased transcript levels for a cytochrome P450, CYP6P3, and demonstrate that it encodes for an enzyme that metabolises pyrethroids.
PMCID: PMC2583951  PMID: 19043575

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