The KCNT1 gene encodes the sodium-activated potassium channel Slack (KCNT1, KNa1.1), a regulator of neuronal excitability. Gain-of-function mutations in humans cause cortical network ...hyperexcitability, seizures, and severe intellectual disability. Using a mouse model expressing the Slack-R455H mutation, we find that Na+-dependent K+ (KNa) and voltage-dependent sodium (NaV) currents are increased in both excitatory and inhibitory cortical neurons. These increased currents, however, enhance the firing of excitability neurons but suppress that of inhibitory neurons. We further show that the expression of NaV channel subunits, particularly that of NaV1.6, is upregulated and that the length of the axon initial segment and of axonal NaV immunostaining is increased in both neuron types. Our study on the coordinate regulation of KNa currents and the expression of NaV channels may provide an avenue for understanding and treating epilepsies and other neurological disorders.
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•Slack GOF increases K+ currents and voltage-dependent Na+ (NaV) currents in cortical neurons•Slack GOF enhances firing of excitability neurons but suppresses that of inhibitory neurons•Slack GOF upregulates NaV channel expression and increases AIS length in cortical neurons•Proximity of the AIS to the soma is different between excitatory and inhibitory neurons
Wu et al. show that increased potassium and sodium currents lead to hyperexcitability in excitatory neurons while suppressing excitability in inhibitory interneurons in a childhood epilepsy mouse model caused by a Slack gain-of-function mutation. Unlike in heterologous systems, this mutation significantly alters sodium channel expression, elongating axonal initial segments.
Disease-causing mutations in ion channels generally alter intrinsic gating properties such as activation, inactivation, and voltage dependence. We examined nine different mutations of the KCNT1 ...(Slack) Na(+)-activated K(+) channel that give rise to three distinct forms of epilepsy. All produced many-fold increases in current amplitude compared to the wild-type channel. This could not be accounted for by increases in the intrinsic open probability of individual channels. Rather, greatly increased opening was a consequence of cooperative interactions between multiple channels in a patch. The degree of cooperative gating was much greater for all of the mutant channels than for the wild-type channel, and could explain increases in current even in a mutant with reduced unitary conductance. We also found that the same mutation gave rise to different forms of epilepsy in different individuals. Our findings indicate that a major consequence of these mutations is to alter channel-channel interactions.
The aim of this study was to compare intraocular pressure (IOP) outcomes in eyes with cataract and glaucoma undergoing phacoemulsification (phaco) in combination with goniotomy using the Kahook Dual ...Blade (KDB) or implantation of a single iStent trabecular bypass device.
Retrospective analysis of IOP and IOP-lowering medication reduction in eyes undergoing phaco-goniotomy with KDB (n=237) or phaco-iStent (n=198). Preoperative, intraoperative, and postoperative data were collected through 6 months of follow-up. Outcome measures included mean IOP reduction, mean reduction in IOP-lowering medications, and the proportion of eyes achieving ≥20% IOP reduction or ≥1 medication reduction from baseline.
Mean IOP in the phaco-goniotomy with KDB group decreased from 17.9±4.4 mmHg at baseline to 13.6±2.7 mmHg at Month 6 (
<0.001), with mean medication use decreasing from 1.7±0.9 to 0.6±1.0 (
<0.001). In the phaco-iStent group, mean IOP decreased from 16.7±4.4 mmHg to 13.9±2.7 mmHg (
<0.001), with mean IOP-lowering medication use decreasing from 1.9±0.9 to 1.0±1.0 (
<0.001). Mean IOP reduction from baseline was significantly greater in the phaco-goniotomy with KDB group at Month 6 (phaco-goniotomy with KDB -4.2 mmHg 23.7% vs phaco-iStent -2.7 mmHg 16.4%;
<0.001). IOP-lowering medication reduction was greater in the phaco-goniotomy with KDB group compared to the phaco-iStent group (1.1 vs 0.9 medications, respectively;
=0.001). The most common adverse event was IOP spikes occurring in 12.6% of phaco-iStent eyes and 6.3% of phaco-goniotomy with KDB eyes (
=0.024).
Goniotomy with the KDB combined with cataract surgery significantly lowers both IOP and the need for IOP-lowering medications compared to cataract extraction with iStent implantation in glaucomatous eyes through 6 months of postoperative follow-up.
Early medical checkups during and after delivery are key strategies to detect, prevent and treat maternal health concerns. Knowledge of interrelationships between early Antenatal Care (ANC), skilled ...delivery and early postnatal care (EPNC) is essential for focused and well-targeted interventions. This paper investigated the interconnectedness between maternal health services in Uganda.
This study examines the predictors of interrelationships between early antenatal care, health facility delivery and early postnatal care.
We used a sample of 10,152 women of reproductive ages (15-49), who delivered a child five years prior to the 2016 Uganda Demographic and Health Survey. A generalized Structural Equation Model and STATA 13.0 software were used.
Early ANC was a mediating factor for health facility delivery (aOR=1.04; 95% CI=1.01-1.14) and EPNC (aOR=1.1; 95% CI=1.05-1.26). Increased odds of early ANC utilization was directly associated with: Adult women aged 35-49 (aOR=1.18; 95% CI=1.10-1.35), having completed primary seven (aOR=1.68; 95% CI=1.56-1.84); distance to a health facility (aOR=1.35; 95% CI=1.23-1.73) and costs (aOR=1.85; 95% CI=1.31-2.12) not being a problem, available community workers (aOR=1.06; 95% CI=1.04-1.17), pregnancy complications (aOR=2.04; 95% CI=1.85-2.26) and desire for pregnancy (aOR=1.15; 95% CI=1.07-1.36). Through early ANC utilization, being married (aOR=1.16; (=1.04*1.10)), no distance issues ((aOR=1.40; (=1.04*1.35)) and complications (aOR=2.12; (=1.04*2.04)) indirectly influenced utilization of health facility delivery. Women aged 20-34 (aOR=1.01; (=0.92*1.1)), completing primary seven (aOR=1.85; (=1.69*1.1)) and no cost problems (aOR=2.04; (=1.85*1.1)) indirectly influenced EPNC.
Early antenatal care was a mediating factor for health facility delivery and EPNC; and hence, there is need for more focus on factors for increased early antenatal care utilization. Women with higher education and those with no cost problems were more likely to have early ANC utilization, skilled delivery and EPNC; therefore there is need to design and implement policies targeting social and economically disadvantaged women.
Using a two-year dataset (2016–17) from 17 one-minute rain gauges located in the moist forest region of Ghana, the performance of Integrated Multisatellite Retrievals for GPM, version 6b (IMERG), is ...evaluated based on a subdaily time scale, down to the level of the underlying passive microwave (PMW) and infrared (IR) sources. Additionally, the spaceborne cloud product Cloud Property Dataset Using SEVIRI, edition 2 (CLAAS-2), available every 15 min, is used to link IMERG rainfall to cloud-top properties. Several important issues are identified: 1) IMERG’s proneness to low-intensity false alarms, accounting for more than a fifth of total rainfall; 2) IMERG’s overestimation of the rainfall amount from frequently occurring weak convective events, while that of relatively rare but strong mesoscale convective systems is underestimated, resulting in an error compensation; and 3) a decrease of skill during the little dry season in July and August, known to feature enhanced low-level cloudiness and warmrain. These findings are related to 1) a general oversensitivity for clouds with lowice and liquid water path and a particular oversensitivity for low cloud optical thickness, a problem which is slightly reduced for direct PMW overpasses; 2) a pronounced negative bias for high rain intensities, strongest when IR data are included; and 3) a large fraction of missed events linked with rainfall out of warm clouds, which are inherently misinterpreted by IMERG and its sources. This paper emphasizes the potential of validating spaceborne rainfall products with high-resolution rain gauges on a subdaily time scale, particularly for the understudied West African region.
Channelopathies caused by mutations in genes encoding ion channels generally produce a clear change in channel function. Accordingly, mutations in
, which encodes the voltage-dependent Kv3.1 ...potassium channel, result in progressive myoclonus epilepsy as well as other developmental and epileptic encephalopathies, and these have been shown to reduce or fully abolish current amplitude. One exception to this is the mutation A513V Kv3.1b, located in the cytoplasmic C-terminal domain of the channel protein. This de novo variant was detected in a patient with epilepsy of infancy with focal migrating seizures (EIFMS), but no difference could be detected between A513V Kv3.1 current and that of wild-type Kv3.1. Using both biochemical and electrophysiological approaches, we have now confirmed that this variant produces functional channels but find that the A513V mutation renders the channel completely insensitive to regulation by phosphorylation at S503, a nearby regulatory site in the C-terminus. In this respect, the mutation resembles those in another channel, KCNT1, which are the major cause of EIFMS. Because the amplitude of Kv3.1 current is constantly adjusted by phosphorylation in vivo, our findings suggest that loss of such regulation contributes to EIFMS phenotype and emphasize the role of channel modulation for normal neuronal function.
Ion channel mutations that cause serious human diseases generally alter the biophysical properties or expression of the channel. We describe a de novo mutation in the Kv3.1 potassium channel that causes severe intellectual disability with early-onset epilepsy. The properties of this channel appear identical to those of wild-type channels, but the mutation prevents phosphorylation of the channel by protein kinase C. Our findings emphasize the role of channel modulation in normal brain function.
Purpose
To compare the efficacy and safety of combined cataract extraction and either excisional goniotomy performed with the Kahook Dual Blade (KDB; phaco-KDB group) or single iStent trabecular ...bypass implantation (phaco-iStent group) in eyes with mild to moderate glaucoma and visually significant cataract.
Methods
This was a retrospective analysis of 315 eyes from 230 adults with mild or moderate glaucoma treated with one or more intraocular pressure (IOP)-lowering medications (190 eyes of 134 subjects in the phaco-KDB group and 125 eyes of 96 subjects in the phaco-iStent group) that required no subsequent surgical intervention for IOP control through 12 months of follow-up. Data included best-corrected visual acuity (BCVA), IOP, and IOP-lowering medications, collected preoperatively and at 1 week and 1, 3, 6, and 12 months postoperatively as well as intraoperative and postoperative adverse events. The primary efficacy outcomes were the proportion of subjects in each group achieving ≥ 20% IOP reduction and ≥ 1 medication reduction at month 12. Subgroup analysis by baseline IOP (≤ 18 mmHg vs. > 18 mmHg) was also performed.
Results
Mean (standard error) baseline IOP was 18.2 (0.3) mmHg in the phaco-KDB group and 16.7 (0.3) mmHg in the phaco-iStent group (
p
= 0.001). Statistically significant mean IOP and mean IOP medication reductions from baseline were achieved at all time points in both groups. Mean IOP reductions were significantly greater in the phaco-KDB group than in the phaco-iStent group at all time points including month 12 − 5.0 (0.3) mmHg vs. − 2.3 (0.4) mmHg,
p
< 0.001, while mean medication reductions were similar between groups at all time points except week 1, when greater mean medication reduction was seen in the phaco-iStent group (− 1.23 vs. − 0.60 medications,
p
< 0.001). At month 12, IOP reductions ≥ 20% were achieved by 64.2% and 41.6% (
p
< 0.001) in the phaco-KDB and phaco-iStent groups, respectively, and IOP medication reductions of ≥ 1 medication were achieved by 80.4% and 77.4% (
p
= 0.522), respectively. Intraocular pressure subgroup analysis revealed significant reductions in IOP-lowering medications without compromise of IOP control in lower IOP subgroups and significant reductions in both IOP and IOP-lowering medications in the higher IOP subgroups. The most common adverse events were transient IOP elevations and transient anterior chamber inflammation, which occurred with similar frequency in both groups and resolved spontaneously.
Conclusion
Goniotomy with the KDB lowered IOP significantly more than iStent implantation, with few adverse events in both groups. In eyes with mild to moderate glaucoma undergoing combined cataract extraction and glaucoma surgery, goniotomy with the KDB can safely deliver statistically significant and clinically meaningful reductions in both IOP and IOP medication burden through 12 months of follow-up.
Funding
New World Medical, Inc., provided funding for the study, medical writing assistance, Rapid Service Fees, and the open access fee.
Fragile X mental retardation protein (FMRP) is an RNA-binding protein that regulates synaptic plasticity by repressing translation of specific mRNAs. We found that FMRP binds mRNA encoding the ...voltage-gated potassium channel Kv3.1b in brainstem synaptosomes. To explore the regulation of Kv3.1b by FMRP, we investigated Kv3.1b immunoreactivity and potassium currents in the auditory brainstem sound localization circuit of male mice. The unique features of this circuit allowed us to control neuronal activity in vivo by exposing animals to high-frequency, amplitude-modulated stimuli, which elicit predictable and stereotyped patterns of input to the anterior ventral cochlear nucleus (AVCN) and medial nucleus of the trapezoid body (MNTB). In wild-type (WT) animals, Kv3.1b is expressed along a tonotopic gradient in the MNTB, with highest levels in neurons at the medial, high-frequency end. At baseline, Fmr1(-/-) mice, which lack FMRP, displayed dramatically flattened tonotopicity in Kv3.1b immunoreactivity and K(+) currents relative to WT controls. Moreover, after 30 min of acoustic stimulation, levels of Kv3.1b immunoreactivity were significantly elevated in both the MNTB and AVCN of WT, but not Fmr1(-/-), mice. These results suggest that FMRP is necessary for maintenance of the gradient in Kv3.1b protein levels across the tonotopic axis of the MNTB, and are consistent with a role for FMRP as a repressor of protein translation. Using numerical simulations, we demonstrate that Kv3.1b tonotopicity may be required for accurate encoding of stimulus features such as modulation rate, and that disruption of this gradient, as occurs in Fmr1(-/-) animals, degrades processing of this information.
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