Environmental, dietary and case-control study of Nodding Syndrome in Uganda: A post-measles brain disorder triggered by malnutrition?

AbstractNodding Syndrome (NS) is an epileptic encephalopathy characterized by involuntary vertical head nodding, other types of seizures, and progressive neurological deficits. The etiology of the east African NS epidemic is unknown. In March 2014, we conducted a case-control study of medical, nutritional and other risk factors associated with NS among children (aged 5–18years) of Kitgum District, northern Uganda (Acholiland). Data on food availability, rainfall, and prevalent disease temporally related to the NS epidemic were also analyzed. In NS Cases, the mean age of reported head nodding onset was 7.6years (range 1–17years). The epidemiologic curve of NS incidence spanned 2000–2013, with peaks in 2003 and 2008. Month of onset of head nodding was non-uniform, with all-year-aggregated peaks in April and June when food availability was low. Families with one or more NS Cases had been significantly more dependent on emergency food and, immediately prior to head nodding onset in the child, subsistence on moldy plant materials, specifically moldy maize. Medical history revealed a single significant association with NS, namely prior measles infection. NS is compared with the post-measles disorder subacute sclerosing panencephalitis, with clinical expression triggered by factors associated with poor nutrition

Stochastic resonance between dissipative structures in a bistable noise-sustained dynamics

We study an extended system that without noise shows a monostable dynamics, but when submitted to an adequate multiplicative noise, an effective bistable dynamics arise. The stochastic resonance between the attractors of the \textit{noise-sustained dynamics} is investigated theoretically in terms of a two-state approximation. The knowledge of the exact nonequilibrium potential allows us to obtain the output signal-to-noise ratio. Its maximum is predicted in the symmetric case for which both attractors have the same nonequilibrium potential value.Comment: RevTex, 13 pages, 6 figures, accepted in Physical Review

Targeting serine hydroxymethyltransferases 1 and 2 for T-cell acute lymphoblastic leukemia therapy

Despite progress in the treatment of acute lymphoblastic leukemia (ALL), T-cell ALL (T-ALL) has limited treatment options, particularly in the setting of relapsed/refractory disease. Using an unbiased genome-scale CRISPR-Cas9 screen we sought to identify pathway dependencies for T-ALL which could be harnessed for therapy development. Disruption of the one-carbon folate, purine and pyrimidine pathways scored as the top metabolic pathways required for T-ALL proliferation. We used a recently developed inhibitor of SHMT1 and SHMT2, RZ-2994, to characterize the effect of inhibiting these enzymes of the one-carbon folate pathway in T-ALL and found that T-ALL cell lines were differentially sensitive to RZ-2994, with the drug inducing a S/G2 cell cycle arrest. The effects of SHMT1/2 inhibition were rescued by formate supplementation. Loss of both SHMT1 and SHMT2 was necessary for impaired growth and cell cycle arrest, with suppression of both SHMT1 and SHMT2 inhibiting leukemia progression in vivo. RZ-2994 also decreased leukemia burden in vivo and remained effective in the setting of methotrexate resistance in vitro. This study highlights the significance of the one-carbon folate pathway in T-ALL and supports further development of SHMT inhibitors for treatment of T-ALL and other cancers

Short Message Service (SMS)-Based Intervention to Improve Treatment Adherence among HIV-Positive Youth in Uganda: Focus Group Findings

This paper presents one of the first qualitative studies to discuss programmatic barriers to SMS-based interventions for HIV-positive youth and discusses pathways through which youth perceive them to work. We conducted six focus groups with 20 male and 19 female HIV-positive youths in two clinics in Kampala, Uganda. We find that youth commonly use SMS as over 90% of this study’s youths knew how to read, write and send messages and almost three-fourths of them had phones. Youth strongly felt that the success of this intervention hinged on ensuring confidentiality about their HIV-positive status. Key programmatic challenges discussed where restrictions on phone use and phone sharing that could exclude some youth. Participants felt that the intervention would improve their adherence by providing them with needed reminders and social support. Youths’ suggestions about intervention logistics related to content, frequency, timing and two-way messages will be helpful to practitioners in the field

Nodding syndrome is unlikely to be an autoimmune reaction to leiomodin-1 after infection by Onchocerca volvulus

Nodding syndrome is a neurological disease of children in northern Uganda. Infection with the nematode parasite Onchocerca volvulus has been epidemiologically implicated as the cause of the disease. It has been proposed that an autoantibody directed against the human protein leiomodin-1 cross reacts with a tropomyosin-like nematode protein, thus suggesting that nodding syndrome is an autoimmune brain disease due to extra-cerebral parasitism. This hypothesis is dependent on constitutive neuronal expression of leiomodin-1. We tested this hypothesis by studying the distribution of leiomodin-1 in the normal human brain and other human tissues using immunohistochemistry. We found that immunostaining for leiomodin-1 follows a smooth muscle cell specific pattern. In the brain, it is confined to the smooth muscle cells of cerebral blood vessels and is not generally present in neurons or glia. However, immunoreactivity was identified in human Purkinje cell membrane and the body wall of C. elegans (as a proxy for Onchocerca volvulus) but only when immunostained with an antibody recognizing the N-terminal of leiomodin-1. Homology between leiomodin-1 and tropomodulin, specifically at the N-terminus, could explain why leiomodin-1 antibody cross reactivity between human Purkinje cells and C. elegans. However, we cannot provide proof confirming that the immunoreactivity in the membranes of Purkinje cells is specifically caused by the expression of tropomodulin. To overcome this limitation, further investigations using additional immunohistochemical and biochemical studies are required to corroborate our findings and provide more comprehensive evidence. Nevertheless, our findings do not support to the autoimmunity hypothesis involving Onchocerca volvulus and leiomodin-1. To gain a more comprehensive understanding of the cause and pathogenesis of NS, it is essential to explore alternative hypotheses

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A real-time medical cartography of epidemic disease (Nodding syndrome) using village-based lay mHealth reporters - Fig 2

<p><b>A, B</b>) Geo-localized visualization of the Acholiland surveillance area. <b>C</b>) Close-up of a surveillance area section. <b>D, E</b>) Real-time electronic map of child health, injury and illness relating to NS in Paikat Akidi village (Angole parish, Awere sub-county, Pader district) and Bolo Lapeta village (Bolo parish, Awere sub-county, Pader district) at week 6 of data collection. Color coding: <i>Red</i>- Households with at least 1 child with NS; <i>Green</i>- Households with at least 1 child with NS who did not have medication (E1); was injured (E2); or died (E3) that week.</p

Pie charts, one for each village of study, displaying different NS health-related data across the 12-week study period.

<p>Color coding: <i>Red-</i> Proportion of children with NS; <i>Black-</i> Proportion of children with nodding spells reported for the first time; <i>Yellow</i>- Proportion of children with NS who were injured; <i>Green-</i> Proportion of children with NS who died; <i>Blue-</i> Proportion of children with NS who did not have anti-seizure medication. For comparison purposes, the number of children with NS monitored per village was normalized to 100%. Percentages above 100% are indicative of repeated outcomes. The pie chart corresponding to Ludok and Olam villages (bottom right) should be taken only for reader orientation because values summarize data collected for only 4 weeks (<a href="http://www.plosntds.org/article/info:doi/10.1371/journal.pntd.0006588#pntd.0006588.s001" target="_blank">S1 Tables</a>).</p

Data collected in Paikat Akidi village (Angole parish, Awere sub-county, Pader district) throughout the 12-week study period.

<p>Data collected in Paikat Akidi village (Angole parish, Awere sub-county, Pader district) throughout the 12-week study period.</p