Age-dependent gait abnormalities in mice lacking the Rnf170 gene linked to human autosomal-dominant sensory ataxia.

Really interesting new gene (RING) finger protein 170 (RNF170) is an E3 ubiquitin ligase known to mediate ubiquitination-dependent degradation of type-I inositol 1,4,5-trisphosphate receptors (ITPR1). It has recently been demonstrated that a point mutation of RNF170 gene is linked with autosomal-dominant sensory ataxia (ADSA), which is characterized by an age-dependent increase of walking abnormalities, a rare genetic disorder reported in only two families. Although this mutant allele is known to be dominant, the functional identity thereof has not been clearly established. Here, we generated mice lacking Rnf170 (Rnf170(-/-)) to evaluate the effect of its loss of function in vivo. Remarkably, Rnf170(-/-) mice began to develop gait abnormalities in old age (12 months) in the form of asynchronous stepping between diagonal limb pairs with a fixed step sequence during locomotion, while age-matched wild-type mice showed stable gait patterns using several step sequence repertoires. As reported in ADSA patients, they also showed a reduced sensitivity for proprioception and thermal nociception. Protein blot analysis revealed that the amount of Itpr1 protein was significantly elevated in the cerebellum and spinal cord but intact in the cerebral cortex in Rnf170(-/-) mice. These results suggest that the loss of Rnf170 gene function mediates ADSA-associated phenotypes and this gives insights on the cure of patients with ADSA and other age-dependent walking abnormalities.

Antenatal care inequalities in South Korea: An analysis of health insurance claims data (2013-2022) in a high-resource, high-use country.

OBJECTIVE: The aim of the present study was to explore inequalities in antenatal care (ANC) in South Korea. Based on the guidelines of the WHO, we categorized less than eight visits to an obstetrical facility as insufficient ANC. We examined ANC inequalities associated with age, disability, nationality, income, and geographic accessibility. METHODS: We extracted delivery event claimed from 2013 to 2022 from the National Health Insurance Service database. By tracing back 270 days from the delivery date, we counted the number of antenatal visits for each childbirth and calculated the proportion of women with insufficient ANC and assessed both absolute and relative inequalities for each population group. The logistic regression analysis for both underuse and overuse of ANC were conducted. RESULTS: Out of 3 416 517 childbirths, 104 109 women (3.0%) had fewer than eight ANC visits. Although the average number of ANC visits reached 18.7 in 2022, significant inequalities persisted across different population groups. The insufficient ANC rate was 28.1% for teenage women, 6.4% for disabled women, 10.7% for non-Korean women, and 15.2% for dependents of medical aid households. Women with low income and those living in obstetric care underserved areas also exhibited higher ANC insufficiency. From 2021 to 2022, sufficiency in ANC decreased for teenage, disabled, and non-Korean women, highlighting the effects of the COVID-19 pandemic. CONCLUSION: Antenatal care inequalities are evident in South Korea's well-resourced health system. There is a need for further investigation into these disparities and the qualitative aspects of maternity care services.

Thalamic ryanodine receptors are involved in controlling the tonic firing of thalamocortical neurons and inflammatory pain signal processing.

Ryanodine receptors (RyRs) are highly conductive intracellular Ca(2+) release channels which are widely expressed in the CNS. They rapidly increase the intracellular Ca(2+) concentrations in neuronal cells in response to Ca(2+) influx through voltage-gated Ca(2+) channels. A previous study reported that RyRs were expressed in thalamocortical (TC) neurons, but their physiological function has remained elusive. Here, we show that the activation of RyRs in TC neurons in mice decreases their tonic firing rate while blocking them induces the opposite response. Furthermore, activation of RyRs in ventroposteriomedial/ventroposteriolateral nuclei reduces the behavioral responses to inflammatory pain and blocking them increases the responses. This study highlights the importance of the intracellular Ca(2+) release via RyRs in controlling the excitability of TC neurons and in inflammatory pain signal processing in the thalamus.

Effects of Patellofemoral Pain Syndrome on Changes in Dynamic Postural Stability during Landing in Adult Women.

Background: This study investigated the effects of lower limb movements on dynamic postural stability (DPS) during drop landing in adult women with patellofemoral pain syndrome (PFPS). Methods: Thirty-eight adult women were recruited and divided into two groups, the PFPS group and the control group. The study participants performed a single-leg drop landing from a 30 cm box, and their lower limb movements and DPS were measured. Differences between groups were examined using independent sample t-tests. In addition, stepwise multiple linear regression was used to examine the kinematic parameters that contribute to the DPS. Results: The PFPS group had significantly lower hip flexion, internal rotation, knee flexion, ankle external rotation, pelvic oblique, tilt, rotation, and higher hip abduction, knee valgus, and ankle plantarflexion. In terms of DPS, the PFPS group had a significantly higher anteroposterior and a lower mediolateral than that of the control group. In the control group, regression analysis revealed a controlled anteroposterior using knee flexion, while the PFPS group controlled mediolateral through ankle plantarflexion. Conclusions: Patients with PFPS experienced more shock on their knee joint during landing than patients in the control group with greater anteroposterior instability and lower mediolateral instability.

Regional Differences in the Effects of Social Relations on Depression Among Korean Elderly and the Moderating Effect of Living Alone.

OBJECTIVES: Socioeconomic disadvantages interact with numerous factors which affect geriatric mental health. One of the main factors is the social relations of the elderly. The elderly have different experiences and meanings in their social lives depending on their socio-cultural environment. In this study, we compared the effects of social relations on depression among the elderly according to their living arrangement (living alone or living with others) and residential area. METHODS: We defined social relations as "meetings with neighbors" (MN). We then analyzed the impact of MN on depression using data from the Korean Longitudinal Study of Aging Panel with the generalized estimating equation model. We also examined the moderating effect of living alone and performed subgroup analysis by dividing the sample according to which area they lived in. RESULTS: MN was associated with a reduced risk of depressive symptoms among elderlies. The size of the effect was larger in rural areas than in large cities. However, elderly those who lived alone in rural areas had a smaller protective impact of MN on depression, comparing to those who lived with others. The moderating effect of living alone was significant only in rural areas. CONCLUSIONS: The social relations among elderlies had a positive effect on their mental health: The more frequent MN were held, the less risk of depressive symptoms occurred. However, the effect may vary depending on their living arrangement and environment. Thus, policies or programs targeting to enhance geriatric mental health should consider different socio-cultural backgrounds among elderlies.

Presence of Thrombectomy-capable Stroke Centers Within Hospital Service Areas Explains Regional Variation in the Case Fatality Rate of Acute Ischemic Stroke in Korea.

OBJECTIVES: This study aimed to explore the status of regional variations in acute ischemic stroke (AIS) treatment and investigate the association between the presence of a thrombectomy-capable stroke center (TSC) and the case fatality rate (CFR) of AIS within hospital service areas (HSAs). METHODS: This observational cross-sectional study analyzed acute stroke quality assessment program data from 262 hospitals between 2013 and 2016. TSCs were defined according to the criteria of the Joint Commission. In total, 64 HSAs were identified based on the addresses of hospitals. We analyzed the effects of structure factors, process factors, and the presence of a TSC on the CFR of AIS using multivariate logistic regression. RESULTS: Among 262 hospitals, 31 hospitals met the definition of a TSC. Of the 64 HSAs, only 20 had a TSC. At hospitals, the presence of a stroke unit, the presence of stroke specialists, and the rate of endovascular thrombectomy (EVT) treatment were associated with reductions in the CFR. In HSAs, the rate of EVT treatment (odds ratio [OR], 0.98; 95% confidence interval [CI], 0.97 to 0.99) and the presence of a TSC (OR, 0.93; 95% CI, 0.88 to 0.99) significantly reduced the CFR of AIS. CONCLUSIONS: The presence of a TSC within an HSA, corresponding to structure and process factors related to the quality of care, contributed significantly to lowering the CFR of AIS. The CFR also declined as the rate of treatment increased. This study highlights the importance of TSCs in the development of an acute stroke care system in Korea.

A blocker of N- and T-type voltage-gated calcium channels attenuates ethanol-induced intoxication, place preference, self-administration, and reinstatement.

There is a clear need for new therapeutics to treat alcoholism. Here, we test our hypothesis that selective inhibitors of neuronal calcium channels will reduce ethanol consumption and intoxication, based on our previous studies using knock-out mice and cell culture systems. We demonstrate that pretreatment with the novel mixed N-type and T-type calcium channel antagonist 1-(6,6-bis(4-fluorophenyl)hexyl)-4-(3,4,5-trimethoxybenzyl)piperazine (NP078585) reduced ethanol intoxication. NP078585 also attenuated the reinforcing and rewarding properties of ethanol, measured by operant self-administration and the expression of an ethanol conditioned place preference, and abolished stress-induced reinstatement of ethanol seeking. NP078585 did not affect alcohol responses in mice lacking N-type calcium channels. These results suggest that selective calcium channel inhibitors may be useful in reducing acute ethanol intoxication and alcohol consumption by human alcoholics.

Deletion of N-type calcium channels alters ethanol reward and reduces ethanol consumption in mice.

N-type calcium channels are modulated by acute and chronic ethanol exposure in vitro at concentrations known to affect humans, but it is not known whether N-type channels are important for behavioral responses to ethanol in vivo. Here, we show that in mice lacking functional N-type calcium channels, voluntary ethanol consumption is reduced and place preference is developed only at a low dose of ethanol. The hypnotic effects of ethanol are also substantially diminished, whereas ethanol-induced ataxia is mildly increased. These results demonstrate that N-type calcium channels modulate acute responses to ethanol and are important mediators of ethanol reward and preference.

Deletion of N-type Ca(2+) channel Ca(v)2.2 results in hyperaggressive behaviors in mice.

Voltage-dependent N-type Ca(2+) channels play important roles in the regulation of diverse neuronal functions in the brain, but little is known about its role in social aggressive behaviors. Mice lacking the alpha1B subunit (Ca(v)2.2) of N-type Ca(2+) channels showed markedly enhanced aggressive behaviors to an intruder mouse in the resident-intruder test. The dorsal raphe nucleus (DRN), which contains serotonin neurons, is known to be involved in aggression in animals. We thus examined the DRN neurons in the Ca(v)2.2-deficient (Ca(v)2.2(-/-)) mice. Microinjection of omega-conotoxin GVIA, an N-type Ca(2+) channel-specific blocker, into the DRN of wild type mice resulted in escalated aggression, mimicking the phenotypes of Ca(v)2.2(-/-). Electrophysiological analysis showed increased firing activity of serotonin neurons with a reduced inhibitory neurotransmission in the Ca(v)2.2(-/-) DRN. Ca(v)2.2(-/-) mice showed an elevated level of arginine vasopressin, an aggression-related hormone, in the cerebrospinal fluid. In addition, Ca(v)2.2(-/-) mice showed an increase of serotonin in the hypothalamus. These results suggest that N-type Ca(2+) channels at the DRN have a key role in the control of aggression.

Thalamic control of visceral nociception mediated by T-type Ca2+ channels.

Sensations from viscera, like fullness, easily become painful if the stimulus persists. Mice lacking alpha1G T-type Ca2+ channels show hyperalgesia to visceral pain. Thalamic infusion of a T-type blocker induced similar hyperalgesia in wild-type mice. In response to visceral pain, the ventroposterolateral thalamic neurons evokeda surge of single spikes, which then slowly decayed as T type-dependent burst spikes gradually increased. In alpha1G-deficient neurons, the single-spike response persisted without burst spikes. These results indicate that T-type Ca2+ channels underlie an antinociceptive mechanism operating in the thalamus andsupport the idea that burst firing plays a critical role in sensory gating in the thalamus.