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Background Undernutrition and infectious diseases form a vicious cycle that poses a dual threat to vulnerable children in low- and middle-income countries. Integrating small-quantity lipid-based nutrient supplements (SQ-LNS) distribution into routine immunization services in children 6–23 months may act as both a nutritional intervention and as an incentive for increased vaccine uptake. Methods We will conduct a two-arm superiority pragmatic parallel cluster-randomized controlled trial with baseline measures in 20 wards of Nguru and Karasuwa Local Government Areas, Yobe State, Northeast Nigeria. Wards will be randomly allocated 1:1 to either the standard National Program on Immunization (NPI) arm or the NutriVax arm, which combines NPI with SQ-LNS distribution. After up to 12 months of implementation, measles immunization coverage will be assessed at two levels: population-level coverage in children aged 12–23 months (primary outcome, endline cross-sectional survey) and individual-level coverage in children aged 6–12 months (key secondary outcome, longitudinal survey). Each cross-sectional survey (baseline and endline) will include 1560 participants. The longitudinal survey will enroll 600 participants. Sampling will use a multi-stage design with probability proportional to size and systematic random household selection. All outcomes will be analyzed by intention-to-treat. Qualitative interviews will assess feasibility and acceptability. Cost-efficiency differences between arms will be estimated using an incremental cost-efficiency ratio. Discussion To our knowledge, this is the first trial to evaluate whether a preventive nutrition supplement can also serve as an incentive to increase vaccination coverage. Findings will provide evidence to guide governments and donors in settings where high rates of undernutrition and low immunization coverage persist as major public health challenges. Trial registration Protocol Number NCT06387511 (clinicaltrials.gov).

Children with moderate acute malnutrition (MAM) are treated based on low weight-for-length z-score (WLZ), low mid-upper arm circumference (MUAC) or both. This study aimed to assess associations of admission criteria and body composition (BC), to improve treatment of MAM. We undertook a cross-sectional study among 6–23 months old Burkinabe children with MAM. Fat-free (FFM) and fat mass (FM) were determined by deuterium dilution and expressed as FFM (FFMI) and FM index (FMI). Of 1,489 children, 439 (29.5%) were recruited by low MUAC only (MUAC-O), 734 (49.3%) by low WLZ and low MUAC (WLZ-MUAC) and 316 (21.2%) by low WLZ only (WLZ-O). Thus, 1,173 (78.8%) were recruited by low MUAC, with or without low WLZ (ALL-MUAC). After adjustments, WLZ-O had 89 g (95% confidence interval (CI) 5; 172) lower FFM compared to MUAC-O. Similarly, WLZ-O had 0.89 kg/m 2 (95% CI 0.77; 1.01) lower FFMI compared to MUAC-O, whereas there was no difference for FMI. However, boys included by WLZ-O compared to MUAC-O had 0.21 kg/m 2 (95% CI 0.05; 0.38) higher FMI. In contrast, girls included by WLZ-O had 0.17 (95% CI 0.01; 0.33) kg/m 2 lower FMI compared to MUAC-O (interaction, p = 0.002). We found that different criteria for admission into MAM treatment programmes select children with differences in BC, especially FFMI. Trial registration : ISRCTN42569496.

Canonical transient receptor potential channel 3 (TRPC3) is the most abundant TRPC channel in the brain and is highly expressed in all subfields of the hippocampus. Previous studies have suggested that TRPC3 channels may be involved in the hyperexcitability of hippocampal pyramidal neurons and seizures. Genetic ablation of TRPC3 channel expression reduced the intensity of pilocarpine-induced status epilepticus (SE). However, the underlying cellular mechanisms remain unexplored and the contribution of TRPC3 channels to SE-induced neurodegeneration is not determined. In this study, we investigated the contribution of TRPC3 channels to the electrophysiological properties of hippocampal pyramidal neurons and hippocampal synaptic plasticity, and the contribution of TRPC3 channels to seizure-induced neuronal cell death. We found that genetic ablation of TRPC3 expression did not alter basic electrophysiological properties of hippocampal pyramidal neurons and had a complex impact on epileptiform bursting in CA3. However, TRPC3 channels contribute significantly to long-term potentiation in CA1 and SE-induced neurodegeneration. Our results provided further support for therapeutic potential of TRPC3 inhibitors and raised new questions that need to be answered by future studies.

Background Community health workers (CHWs) are recommended to screen for acute malnutrition in the community by assessing mid-upper arm circumference (MUAC) on children between 6 and 59 months of age. MUAC is a simple screening tool that has been shown to be a better predictor of mortality in acutely malnourished children than other practicable anthropometric indicators. This study compared, under program conditions, mothers and CHWs in screening for severe acute malnutrition (SAM) by color-banded MUAC tapes. Methods This pragmatic interventional, non-randomized efficacy study took place in two health zones of Niger’s Mirriah District from May 2013 to April 2014. Mothers in Dogo (Mothers Zone) and CHWs in Takieta (CHWs Zone) were trained to screen for malnutrition by MUAC color-coded class and check for edema. Exhaustive coverage surveys were conducted quarterly, and relevant data collected routinely in the health and nutrition program. An efficacy and cost analysis of each screening strategy was performed. Results A total of 12,893 mothers and caretakers were trained in the Mothers Zone and 36 CHWs in the CHWs Zone, and point coverage was similar in both zones at the end of the study (35.14 % Mothers Zone vs 32.35 % CHWs Zone, p  = 0.9484). In the Mothers Zone, there was a higher rate of MUAC agreement (75.4 % vs 40.1 %, p <0.0001) and earlier detection of cases, with median MUAC at admission for those enrolled by MUAC <115 mm estimated to be 1.6 mm higher using a smoothed bootstrap procedure. Children in the Mothers Zone were much less likely to require inpatient care, both at admission and during treatment, with the most pronounced difference at admission for those enrolled by MUAC < 115 mm (risk ratio = 0.09 [95 % CI 0.03; 0.25], p  < 0.0001). Training mothers required higher up-front costs, but overall costs for the year were much lower ($8,600 USD vs $21,980 USD.) Conclusions Mothers were not inferior to CHWs in screening for malnutrition at a substantially lower cost. Children in the Mothers Zone were admitted at an earlier stage of SAM and required fewer hospitalizations. Making mothers the focal point of screening strategies should be included in malnutrition treatment programs. Trial registration The trial is registered with clinicaltrials.gov (Trial number NCT01863394 ).

Given the unique expression patterns and revelations of its critical involvement in a host of neurological disorders, the TRPC1/4/5 subgroup has become an intense target of drug development, and some compounds are now in clinical trials. However, little is known about the exact subunit composition of this subfamily of TRPC channels in various native tissues, and whether it has functional and pharmacological implications. In this study, we investigated the effects of two TRPC4 modulators located in the lateral septum, in which a metabotropic glutamate receptor (mGluR) agonist-induced plateau potential is mediated by TRPC channels composed of TRPC1 and TRPC4. Lateral septal neurons were recorded intracellularly in brain slices using sharp electrodes. Drugs were applied via bath superfusion. We showed that the plateau potential in mice lacking TRPC1 is modulated by ML204 and La3+ in a manner that is like homomeric TRPC4 channels in artificial expression systems. However, the plateau potential that is primarily mediated by heteromeric TRPC1/4 channels in lateral septal neurons in wildtype mice was modulated differently by ML204 and La3+. Our data suggest that native homomeric TRPC4 channels and heteromeric TRPC1/4 channels are pharmacologically distinct, and the current drug development strategy regarding TRPC1/4/5 may need to be reevaluated.

One feature of high-fat diet-induced neurodegeneration in the hypothalamus is an increased level of palmitate, which is associated with endoplasmic reticulum (ER) stress, loss of CoxIV, mitochondrial fragmentation, and decreased abundance of MC4R. To determine whether antidiabetic drugs protect against ER and/or mitochondrial dysfunction by lipid stress, hypothalamic neurons derived from pre-adult mice and neuronal Neuro2A cells were exposed to elevated palmitate. In the hypothalamic neurons, palmitate exposure increased expression of ER resident proteins, including that of SERCA2, indicating ER stress. Liraglutide reverted such altered ER proteostasis, while metformin only normalized SERCA2 expression. In Neuro2A cells liraglutide, but not metformin, also blunted dilation of the ER induced by palmitate treatment, and enhanced abundance and expression of MC4R at the cell surface. Thus, liraglutide counteracts, more effectively than metformin, altered ER proteostasis, morphology, and folding capacity in neurons exposed to fat. In palmitate-treated hypothalamic neurons, mitochondrial fragmentation took place together with loss of CoxIV and decreased mitochondrial membrane potential (MMP). Metformin, but not liraglutide, reverted mitochondrial fragmentation, and both liraglutide and metformin did not protect against either loss of CoxIV abundance or MMP. Thus, ER recovery from lipid stress can take place in hypothalamic neurons in the absence of recovered mitochondrial homeostasis.

The melanocortin-4 receptor (MC4R) is a G protein-coupled receptor (GPCR) that is expressed in several brain locations encompassing the hypothalamus and the brainstem, where the receptor controls several body functions, including metabolism. In a well-defined pathway to decrease appetite, hypothalamic proopiomelanocortin (POMC) neurons localized in the arcuate nucleus (Arc) project to MC4R neurons in the paraventricular nuclei (PVN) to release the natural MC4R agonist α-melanocyte-stimulating hormone (α-MSH). Arc neurons also project excitatory glutamatergic fibers to the MC4R neurons in the PVN for a fast synaptic transmission to regulate a satiety pathway potentiated by α-MSH. By using super-resolution microscopy, we found that in hypothalamic neurons in a primary culture, postsynaptic density protein 95 (PSD95) colocalizes with GluN1, a subunit of the ionotropic N-methyl-D-aspartate receptor (NMDAR). Thus, hypothalamic neurons form excitatory postsynaptic specializations. To study the MC4R distribution at these sites, tagged HA-MC4R under the synapsin promoter was expressed in neurons by adeno-associated virus (AAV) gene transduction. HA-MC4R immunofluorescence peaked at the center and in proximity to the PSD95- and NMDAR-expressing sites. These data provide morphological evidence that MC4R localizes together with glutamate receptors at postsynaptic and peri-postsynaptic sites.

Canonical transient receptor potential channels (TRPCs) are a family of calcium-permeable cation channels. Previous studies have shown that heteromeric channels comprising TRPC1 and TRPC4 mediate epileptiform bursting in lateral septal neurons and hippocampal CA1 pyramidal neurons, suggesting that TRPC1/4 channels play a pro-seizure role. In this study, we utilized electroencephalography (EEG) recording and spectral analysis to assess the role of TRPC1/4 channels in the pilocarpine model of status epilepticus (SE). We found that, surprisingly, TRPC1/4 double knockout (DKO) mice exhibited an increased susceptibility to pilocarpine-induced SE. Furthermore, SE latency was also significantly reduced in TRPC1/4 DKO mice. Further studies are needed to reveal the underlying mechanisms of our unexpected results.

Status epilepticus (SE) is a life-threatening disease that has been recognized since antiquity but still causes over 50,000 deaths annually in the United States. The prevailing view on the pathophysiology of SE is that it is sustained by a loss of normal inhibitory mechanisms of neuronal activity. However, the early process leading to the initiation of SE is not well understood. Here, we show that, as seen in electroencephalograms, SE induced by the muscarinic agonist pilocarpine in mice is preceded by a specific increase in the gamma wave, and genetic ablation of canonical transient receptor potential channel (TRPC) 7 significantly reduces this pilocarpine-induced increase of gamma wave activity, preventing the occurrence of SE. At the cellular level, TRPC7 plays a critical role in the generation of spontaneous epileptiform burst firing in cornu ammonis (CA) 3 pyramidal neurons in brain slices. At the synaptic level, TRPC7 plays a significant role in the long-term potentiation at the CA3 recurrent collateral synapses and Schaffer collateral-CA1 synapses, but not at the mossy fiber-CA3 synapses. Taken together, our data suggest that epileptiform burst firing generated in the CA3 region by activity-dependent enhancement of recurrent collateral synapses may be an early event in the initiation process of SE and that TRPC7 plays a critical role in this cellular event. Our findings reveal that TRPC7 is intimately involved in the initiation of seizures both in vitro and in vivo. To our knowledge, this contribution to initiation of seizures is the first identified functional role for the TRPC7 ion channel.

Human status epilepticus (SE) is associated with a pathological reduction in cerebral blood flow termed the inverse hemodynamic response (IHR). Canonical transient receptor potential 3 (TRPC3) channels are integral to the propagation of seizures in SE, and vascular smooth muscle cell (VSMC) TRPC3 channels participate in vasoconstriction. Therefore, we hypothesize that cerebrovascular TRPC3 channels may contribute to seizure-induced IHR. To examine this possibility, we developed a smooth muscle-specific TRPC3 knockout (TRPC3smcKO) mouse. To quantify changes in neurovascular coupling, we combined laser speckle contrast imaging with simultaneous electroencephalogram recordings. Control mice exhibited multiple IHRs, and a limited increase in cerebral blood flow during SE with a high degree of moment-to-moment variability in which blood flow was not correlated with neuronal activity. In contrast, TRPC3smcKO mice showed a greater increase in blood flow that was less variable and was positively correlated with neuronal activity. Genetic ablation of smooth muscle TRPC3 channels shortened the duration of SE by eliminating a secondary phase of intense seizures, which was evident in littermate controls. Our results are consistent with the idea that TRPC3 channels expressed by cerebral VSMCs contribute to the IHR during SE, which is a critical factor in the progression of SE.