Raised temperatures over the Kericho Tea Estates: revisiting the climate in the East African highlands malaria debate: Supplemental Information

Supplemental information to a study examining a time series of quality controlled daily temperature and rainfall data from Kericho, in the Kenyan Highlands, for the 30-year period 1 January 1979 to 31 December 2009

Raised temperatures over the Kericho tea estates: revisiting the climate in the East African highlands malaria debate

<p>Abstract</p> <p>Background</p> <p>Whether or not observed increases in malaria incidence in the Kenyan Highlands during the last thirty years are associated with co-varying changes in local temperature, possibly connected to global changes in climate, has been debated for over a decade. Studies, using differing data sets and methodologies, produced conflicting results regarding the occurrence of temperature trends and their likelihood of being responsible, at least in part, for the increases in malaria incidence in the highlands of western Kenya. A time series of quality controlled daily temperature and rainfall data from Kericho, in the Kenyan Highlands, may help resolve the controversy. If significant temperature trends over the last three decades have occurred then climate should be included (along with other factors such as land use change and drug resistance) as a potential driver of the observed increases in malaria in the region.</p> <p>Methods</p> <p>Over 30 years (1 January 1979 to 31 December 2009) of quality controlled daily observations ( > 97% complete) of maximum, minimum and mean temperature were used in the analysis of trends at Kericho meteorological station, sited in a tea growing area of Kenya's western highlands. Inhomogeneities in all the time series were identified and corrected. Linear trends were identified via a least-squares regression analysis with statistical significance assessed using a two-tailed t-test. These 'gold standard' meteorological observations were compared with spatially interpolated temperature datasets that have been developed for regional or global applications. The relationship of local climate processes with larger climate variations, including tropical sea surface temperatures (SST), and El Niño-Southern Oscillation (ENSO) was also assessed.</p> <p>Results</p> <p>An upward trend of ≈0.2°C/decade was observed in all three temperature variables (P < 0.01). Mean temperature variations in Kericho were associated with large-scale climate variations including tropical SST (r = 0.50; p < 0.01). Local rainfall was found to have inverse effects on minimum and maximum temperature. Three versions of a spatially interpolated temperature data set showed markedly different trends when compared with each other and with the Kericho station observations.</p> <p>Conclusion</p> <p>This study presents evidence of a warming trend in observed maximum, minimum and mean temperatures at Kericho during the period 1979 to 2009 using gold standard meteorological observations. Although local factors may be contributing to these trends, the findings are consistent with variability and trends that have occurred in correlated global climate processes. Climate should therefore not be dismissed as a potential driver of observed increases in malaria seen in the region during recent decades, however its relative importance compared to other factors needs further elaboration. Climate services, pertinent to the achievement of development targets such as the Millennium Development Goals and the analysis of infectious disease in the context of climate variability and change are being developed and should increase the availability of relevant quality controlled climate data for improving development decisions. The malaria community should seize this opportunity to make their needs heard.</p

Disruption of the Zdhhc9 intellectual disability gene leads to behavioural abnormalities in a mouse

Protein S-acylation is a widespread post-translational modification that regulates the trafficking and function of a diverse array of proteins. This modification is catalysed by a family of twenty-three zDHHC enzymes that exhibit both specific and overlapping substrate interactions. Mutations in the gene encoding zDHHC9 cause mild-to-moderate intellectual disability, seizures, speech and language impairment, hypoplasia of the corpus callosum and reduced volume of sub-cortical structures. In this study, we have undertaken behavioural phenotyping, magnetic resonance imaging (MRI) and isolation of S-acylated proteins to investigate the effect of disruption of the Zdhhc9 gene in mice in a C57BL/6 genetic background. Zdhhc9 mutant male mice exhibit a range of abnormalities compared with their wild-type littermates: altered behaviour in the open-field test, elevated plus maze and acoustic startle test that is consistent with a reduced anxiety level; a reduced hang time in the hanging wire test that suggests underlying hypotonia but which may also be linked to reduced anxiety; deficits in the Morris water maze test of hippocampal-dependent spatial learning and memory; and a 36% reduction in corpus callosum volume revealed by MRI. Surprisingly, membrane association and S-acylation of H-Ras was not disrupted in either whole brain or hippocampus of Zdhhc9 mutant mice, suggesting that other substrates of this enzyme are linked to the observed changes. Overall, this study highlights a key role for zDHHC9 in brain development and behaviour, and supports the utility of the Zdhhc9 mutant mouse line to investigate molecular and cellular changes linked to intellectual disability and other deficits in the human population

Drug-responsive autism phenotypes in the 16p11.2 deletion mouse model: a central role for gene-environment interactions

There are no current treatments for autism, despite its high prevalence. Deletions of chromosome 16p11.2 dramatically increase risk for autism, suggesting that mice with an equivalent genetic rearrangement may offer a valuable model for the testing of novel classes of therapeutic drug. 16p11.2 deletion (16p11.2 DEL) mice and wild-type controls were assessed using an ethological approach, with 24 h monitoring of activity and social interaction of groups of mice in a home-cage environment. The ability of the excitation/inhibition modulator N-acetyl cysteine (NAC) and the 5-HT1B/1D/1F receptor agonist eletriptan to normalise the behavioural deficits observed was tested. 16p11.2 DEL mice exhibited largely normal behaviours, but, following the stress of an injection, showed hyperlocomotion, reduced sociability, and a strong anxiolytic phenotype. The hyperactivity and reduced sociability, but not the suppressed anxiety, were effectively attenuated by both NAC and eletriptan. The data suggest that 16p11.2 DEL mice show an autism-relevant phenotype that becomes overt after an acute stressor, emphasising the importance of gene-environmental interactions in phenotypic analysis. Further, they add to an emerging view that NAC, or 5-HT1B/1D/1F receptor agonist treatment, may be a promising strategy for further investigation as a future treatment

Health and Climate–Needs

This paper describes the needs for climate risk management and information services for the health sector to serve research, educational and operational needs of ministries of health and their partners, those agencies that support broader public health service provision as well as respond to epidemics and emergencies. While climate information is considered highly relevant to helping guide improvements in public health provision, to date this information is largely underutilized. We explore some of the gaps in satisfying these needs, and we make recommendations to help fill the identified gaps

Testing a multi-malaria-model ensemble against 30 years of data in the Kenyan highlands

Background: Multi-model ensembles could overcome challenges resulting from uncertainties in models’ initial conditions, parameterization and structural imperfections. They could also quantify in a probabilistic way uncertainties in future climatic conditions and their impacts. Methods: A four-malaria-model ensemble was implemented to assess the impact of long-term changes in climatic conditions on Plasmodium falciparum malaria morbidity observed in Kericho, in the highlands of Western Kenya, over the period 1979–2009. Input data included quality controlled temperature and rainfall records gathered at a nearby weather station over the historical periods 1979–2009 and 1980–2009, respectively. Simulations included models’ sensitivities to changes in sets of parameters and analysis of non-linear changes in the mean duration of host’s infectivity to vectors due to increased resistance to anti-malarial drugs. Results: The ensemble explained from 32 to 38% of the variance of the observed P. falciparum malaria incidence. Obtained R2-values were above the results achieved with individual model simulation outputs. Up to 18.6% of the variance of malaria incidence could be attributed to the +0.19 to +0.25°C per decade significant long-term linear trend in near-surface air temperatures. On top of this 18.6%, at least 6% of the variance of malaria incidence could be related to the increased resistance to anti-malarial drugs. Ensemble simulations also suggest that climatic conditions have likely been less favourable to malaria transmission in Kericho in recent years. Conclusions: Long-term changes in climatic conditions and non-linear changes in the mean duration of host’s infectivity are synergistically driving the increasing incidence of P. falciparum malaria in the Kenyan highlands. User-friendly, online-downloadable, open source mathematical tools, such as the one presented here, could improve decision-making processes of local and regional health authorities

Altered functional brain network connectivity and glutamate system function in transgenic mice expressing truncated Disrupted-in-Schizophrenia 1

Considerable evidence implicates DISC1 as a susceptibility gene for multiple psychiatric diseases. DISC1 has been intensively studied at the molecular, cellular and behavioral level, but its role in regulating brain connectivity and brain network function remains unknown. Here, we utilize a set of complementary approaches to assess the functional brain network abnormalities present in mice expressing a truncated Disc1 gene (Disc1tr Hemi mice). Disc1tr Hemi mice exhibited hypometabolism in the prefrontal cortex (PFC) and reticular thalamus along with a reorganization of functional brain network connectivity that included compromised hippocampal-PFC connectivity. Altered hippocampal-PFC connectivity in Disc1tr Hemi mice was confirmed by electrophysiological analysis, with Disc1tr Hemi mice showing a reduced probability of presynaptic neurotransmitter release in the monosynaptic glutamatergic hippocampal CA1-PFC projection. Glutamate system dysfunction in Disc1tr Hemi mice was further supported by the attenuated cerebral metabolic response to the NMDA receptor (NMDAR) antagonist ketamine and decreased hippocampal expression of NMDAR subunits 2A and 2B in these animals. These data show that the Disc1 truncation in Disc1tr Hemi mice induces a range of translationally relevant endophenotypes underpinned by glutamate system dysfunction and altered brain connectivity

Impaired working memory, cognitive flexibility and reward processing in mice genetically lacking Gpr88: evidence for a key role in Gpr88 in multiple cortico-striatal-thalamic circuits : GPR88 and cortico-striatal-thalamic circuits

The GPR88 orphan G protein-coupled receptor is expressed throughout the striatum, being preferentially localized in medium spiny neurons. It is also present in lower densities in frontal cortex and thalamus. Rare mutations in humans suggest a role in cognition and motor function, while common variants are associated with psychosis. Here we evaluate the influence of genetic deletion of GPR88 upon performance in translational tasks interrogating motivation, reward evaluation and cognitive function. In an automated radial arm maze ‘N-back’ working memory task, Gpr88 KO mice showed impaired correct responding, suggesting a role for GPR88 receptors in working memory circuitry. Associative learning performance was similar to wildtype controls in a touchscreen task but performance was impaired at the reversal learning stage, suggesting cognitive inflexibility. Gpr88 KO mice showed higher breakpoints, reduced latencies and lengthened session time in a progressive ratio task consistent with enhanced motivation. Simultaneously, locomotor hyperactivity was apparent in this task, supporting previous findings of actions of GPR88 in a cortico-striatal-thalamic motor loop. Evidence for a role of GPR88 in reward processing was demonstrated in a touchscreen-based equivalent of the Iowa gambling task. Although both Gpr88 KO and wildtype mice showed a preference for an optimum contingency choice, Gpr88 KO mice selected more risky choices at the expense of more advantageous lower risk options. Together these novel data suggest that striatal GPR88 receptors influence activity in a range of procedures integrated by prefrontal, orbitofrontal and anterior cingulate cortico-striatal- thalamic loops leading to altered cognitive, motivational and reward evaluation processes

Lifespan extension and the doctrine of double effect

Recent developments in biogerontology—the study of the biology of ageing—suggest that it may eventually be possible to intervene in the human ageing process. This, in turn, offers the prospect of significantly postponing the onset of age-related diseases. The biogerontological project, however, has met with strong resistance, especially by deontologists. They consider the act of intervening in the ageing process impermissible on the grounds that it would (most probably) bring about an extended maximum lifespan—a state of affairs that they deem intrinsically bad. In a bid to convince their deontological opponents of the permissibility of this act, proponents of biogerontology invoke an argument which is grounded in the doctrine of double effect. Surprisingly, their argument, which we refer to as the ‘double effect argument’, has gone unnoticed. This article exposes and critically evaluates this ‘double effect argument’. To this end, we first review a series of excerpts from the ethical debate on biogerontology in order to substantiate the presence of double effect reasoning. Next, we attempt to determine the role that the ‘double effect argument’ is meant to fulfil within this debate. Finally, we assess whether the act of intervening in ageing actually can be justified using double effect reasoning