Jasper Akerboom
Oct 3, 2012; 32:13819-13840
Cellular

P Seguela
Feb 1, 1993; 13:596-604
Articles

Zhengui Xia
Sep 1, 1996; 16:5425-5436
Articles

To determine whether Cav1.2 voltage-gated Ca²⁺ channels contribute to astrocyte activation, we generated an inducible conditional knock-out mouse in which the Cav1.2 α subunit was deleted in GFAP-positive astrocytes. This astrocytic Cav1.2 knock-out mouse was tested in the cuprizone model of myelin injury and repair which causes astrocyte and microglia activation in the absence of a lymphocytic response. Deletion of Cav1.2 channels in GFAP-positive astrocytes during cuprizone-induced demyelination leads to a significant reduction in the degree of astrocyte and microglia activation and proliferation in mice of either sex. Concomitantly, the production of proinflammatory factors such as TNFα, IL1β and TGFβ1 was significantly decreased in the corpus callosum and cortex of Cav1.2 knock-out mice through demyelination. Furthermore, this mild inflammatory environment promotes oligodendrocyte progenitor cells maturation and myelin regeneration across the remyelination phase of the cuprizone model. Similar results were found in animals treated with nimodipine, a Cav1.2 Ca²⁺ channel inhibitor with high affinity to the CNS. Mice of either sex injected with nimodipine during the demyelination stage of the cuprizone treatment displayed a reduced number of reactive astrocytes and showed a faster and more efficient brain remyelination. Together, these results indicate that Cav1.2 Ca²⁺ channels play a crucial role in the induction and proliferation of reactive astrocytes during demyelination; and that attenuation of astrocytic voltage-gated Ca²⁺ influx may be an effective therapy to reduce brain inflammation and promote myelin recovery in demyelinating diseases.

SIGNIFICANCE STATEMENT Reducing voltage-gated Ca²⁺ influx in astrocytes during brain demyelination significantly attenuates brain inflammation and astrocyte reactivity. Furthermore, these changes promote myelin restoration and oligodendrocyte maturation throughout remyelination.

Calcineurin inhibitors, such as tacrolimus (FK506) and cyclosporine, are widely used as standard immunosuppressants in organ transplantation recipients. However, these drugs can cause severe pain in patients, commonly referred to as calcineurin inhibitor-induced pain syndrome (CIPS). Although calcineurin inhibition increases NMDAR activity in the spinal cord, the underlying mechanism remains enigmatic. Using an animal model of CIPS, we found that systemic administration of FK506 in male and female mice significantly increased the amount of α2-1–GluN1 complexes in the spinal cord and the level of α2-1–bound GluN1 proteins in spinal synaptosomes. Treatment with FK506 significantly increased the frequency of mEPSCs and the amplitudes of monosynaptic EPSCs evoked from the dorsal root and puff NMDAR currents in spinal dorsal horn neurons. Inhibiting α2-1 with gabapentin or disrupting the α2-1–NMDAR interaction with α2-1Tat peptide completely reversed the effects of FK506. In α2-1 gene KO mice, treatment with FK506 failed to increase the frequency of NMDAR-mediated mEPSCs and the amplitudes of evoked EPSCs and puff NMDAR currents in spinal dorsal horn neurons. Furthermore, systemic administration of gabapentin or intrathecal injection of α2-1Tat peptide reversed thermal and mechanical hypersensitivity in FK506-treated mice. In addition, genetically deleting GluN1 in dorsal root ganglion neurons or α2-1 genetic KO similarly attenuated FK506-induced thermal and mechanical hypersensitivity. Together, our findings indicate that α2-1–bound NMDARs mediate calcineurin inhibitor-induced tonic activation of presynaptic and postsynaptic NMDARs at the spinal cord level and that presynaptic NMDARs play a prominent role in the development of CIPS.

SIGNIFICANCE STATEMENT Calcineurin inhibitors are immunosuppressants used to prevent rejection of transplanted organs and tissues. However, these drugs can cause severe, unexplained pain. We showed that calcineurin inhibition enhances physical interaction between α2-1 and NMDARs and their synaptic trafficking in the spinal cord. α2-1 is essential for calcineurin inhibitor-induced aberrant activation of presynaptic and postsynaptic NMDARs in the spinal cord. Furthermore, inhibiting α2-1 or disrupting α2-1–NMDAR interaction reduces calcineurin inhibitor-induced pain hypersensitivity. Eliminating NMDARs in primary sensory neurons or α2-1 KO also attenuates calcineurin inhibitor-induced pain hypersensitivity. This new information extends our mechanistic understanding of the role of endogenous calcineurin in regulating synaptic plasticity and nociceptive transmission and suggests new strategies for treating this painful condition.

After 85 years, officials plan to remove the old, undetonated bombs that were part of a 1935 plan to divert lava flow on Mauna Loa

The spacecraft Hayabusa2 hurled a four-pound copper ball toward the asteroid's surface at about 4,500 miles an hour to create an artificial crater

Researchers compared tree rings from around the world to determine that a volcano on Santorini probably erupted in 1560 B.C.

Nuclear bomb tests caused a spike in a radioactive form of carbon that accumulated in living things

This eruption is the longest since 2018 when the volcano caused a deadly tsunami

Some 50 artists around the Prenzlauer Berg district displayed works of art for passersby to enjoy

Buenos Aires, Argentina :: Miembros de la comunidad japonesa encuentran amigos en un barco de visita y escuchan el evangelio en su lengua materna.

An idea that began when a classicist went to a brewery to sip beers and ponder the history of hops has brought to life an ancient ale.

The Royal Canadian Mint's newest offering features Manitoba's most famous UFO encounter, which happened in 1967 when Stefan Michalak went looking for precious metals near Falcon Lake.

The post Steampunk 1577 Changes Lives with Electric Wheelchair Kit Designed in SOLIDWORKS appeared first on SOLIDWORKS Education Blog.

Qualcomm CEO Steve Mollenkopf in an interview on Thursday said the chipmaker's relationship with Apple has greatly improved since the two companies ended a bitter legal battle over patent licensing and royalties in 2019.

Alcoholism in both men and woman is a huge problem in Poland. One young woman decides she’s had enough and turns to Christ.

Veracruz, Mexico :: Logos Hope is welcomed to Mexico with fanfare and excitement as people get behind the endeavour of sharing knowledge, help and hope.

Founded by Wendy H Gilmour in 2011, Thankfifi began as a fashion blog and has since grown to cover lifestyle, travel and interiors.

SCOTS have been urged to give up smoking and cut down their alcohol consumption in a bid to reduce “complications linked to conroavirus”.

"I am reminded that we are called to be hospitable (Romans 12:13) and we demonstrate this by how we welcome new believers and each other," says Heather. "This is easy to do when we all have similar backgrounds and have known each other for years. But as the Church, and our movement, becomes more diverse, do we merely tolerate or do we warmly welcome newcomers?"

IN April 2004, the Victoria & Albert museum in London staged an exhibition of the work of Vivienne Westwood. The show was a celebration and a culmination of the fashion designer’s move from the margins of the industry in the 1970s, where she was creating clothes for the punks who hung around the King’s Road, to her 21st-century incarnation as first among equals in British haute couture.

The business of buying things for schools is a key part of making sure that hard-fought K-12 funding actually turns into a quality education at the school and classroom level.

The American Academy of Pediatrics recommends routine alcohol screening for all adolescents. Problem-based substance use screens for adolescents exist, but have limitations. A consumption-based alcohol screen could provide an empirically validated, very brief method to screen youth for alcohol-related problems.

National sample data indicate that frequency of alcohol use has high sensitivity and specificity in identifying youth with alcohol-related problems. A range of age-specific frequency cut scores perform well; specific cut points can be selected based on the screening context. (Read the full article)

Eating disorders are characterized by preoccupation with weight and shape, which is manifested by a refusal to maintain a normal weight. An exact determination of expected body weight (EBW) is critical for diagnosis and clinical management of these disorders.

The McLaren and Moore methods present with several limitations when calculating EBW for adolescents with eating disorders. A commonly agreed upon method for EBW calculation such as the BMI percentile method is recommended for clinical and research purposes. (Read the full article)

Some studies reveal an association between exposure to alcohol consumption in movies and youth drinking, but the evidence is sparse.

Exposure to alcohol consumption in movies is associated with youth binge drinking, is little influenced by cultural differences between countries (Germany, Iceland, Italy, Netherlands, Poland, and Scotland), and is specific to movie alcohol, not movie smoking, depictions. (Read the full article)

Some but not all randomized trials have shown effects of probiotics on incidence and duration of diarrhea and respiratory tract infections among children in developing countries. Calcium improves resistance to intestinal infections in adults, but efficacy in children is unknown.

Lactobacillus reuteri DSM17938 may prevent diarrhea, especially in children with lower nutritional status. Regular calcium milk, alone or with Lactobacillus casei CRL431, did not reduce diarrhea. None of the interventions affected respiratory tract infections in these Indonesian children. (Read the full article)

Alcohol consumption during adolescence and early adulthood has been associated with an increased risk of biopsy-confirmed benign breast disease (BBD), an established risk factor of breast cancer.

This is the first study to analyze the association between adolescent alcohol consumption and risk of biopsy-confirmed proliferative BBD by adolescent folate intake. The result provides no evidence for protective effects of adolescent folate intake on risk of alcohol-associated BBD. (Read the full article)

Youth violence and alcohol misuse are a preventable public health problem. Previous studies have demonstrated the efficacy of brief interventions in the emergency department (ED) in reducing alcohol misuse and related consequences among older adolescents and adults.

This study supports the efficacy of brief interventions in the ED in reducing peer aggression and victimization 12 months after ED visit. The previous reductions in alcohol consequences noted at 6 months follow-up were not sustained at 12 months. (Read the full article)

Late-onset hypocalcemia is common in neonates, often presents with seizures or tetany, and is often attributed to transient hypoparathyroidism.

Late-onset hypocalcemia in neonates is often a sign of coexisting vitamin D deficiency and hypomagnesemia and is readily managed with therapy of limited duration, and neonates presenting with tetany or seizures due to hypocalcemia are unlikely to benefit from neuroimaging studies. (Read the full article)

First drink before age 15 greatly increases the likelihood for later alcohol abuse or dependence. Separate investigations have linked many variables to alcohol initiation, but few have attempted to identify the optimal combination of predictors for age of alcohol initiation.

This article supports the screening questions selected in the joint National Institute on Alcohol Abuse and Alcoholism and the American Academy of Pediatrics initiative to identify and initiate intervention in youth at risk for early use of alcohol. (Read the full article)

Prenatal alcohol exposure causes a continuum of effects. The most severe phenotype, fetal alcohol syndrome, involves facial dysmorphism, growth deficits, and neurocognitive problems. The classic facial characteristics include short palpebral fissures, smooth philtrum, and thin upper vermillion.

This study develops novel strategies to help detect facial dysmorphism across the fetal alcohol spectrum, especially in children with heavy alcohol exposure but without classic facial characteristics. The methods show potential for identifying which of these children are cognitively affected. (Read the full article)

Reductions in infant mortality in the 20th century have not continued. Racial and socioeconomic inequalities in both infant mortality and sudden infant death syndrome (SIDS) persist. Rates of infant mortality in English-speaking countries are higher than the Organisation for Economic Co-operation and Development average.

At least 16.4% of SIDS and 3.4% of infant deaths not classified as SIDS are attributable to maternal alcohol use. Maternal alcohol-use disorder increases the risk of infant mortality through direct effects on the fetus and indirectly through environmental risk factors. (Read the full article)

Prompt, high-quality diagnosis of acute pyelonephritis and later identification of children with scarring are important to prevent future complications. Examination by dimercaptosuccinic acid scan is the current clinical gold standard but is not routinely performed.

Procalcitonin demonstrated a more robust predictive ability, compared with C-reactive protein or white blood cell count, to selectively identify both children who had acute pyelonephritis during the early stage of urinary tract infections, as well as those with late scarring. (Read the full article)

Children exposed to alcohol prenatally have increased risk of a range of developmental problems such as language delay, behavior problems, learning, and memory and cognitive deficits, all of which can have a negative impact on educational achievement.

The expression of learning problems varied with the dose, pattern, and timing of prenatal alcohol exposure. Test scores below national benchmarks for reading were associated with first trimester heavy alcohol exposure and for writing after late pregnancy occasional binge drinking. (Read the full article)

In January 2006, a public health advisory and boxed warning for long-term safety and the risk of malignancies and a medication guide were issued for topical calcineurin inhibitors, tacrolimus and pimecrolimus.

Evaluation of off-label use of topical calcineurin inhibitors in children before and after regulatory action by the Food and Drug Administration is important to understand the impact of regulatory action. (Read the full article)

Prenatal and postnatal organophosphate (cholinesterase inhibitor) pesticide exposure has been associated with delays in attention, memory, intelligence, and inhibitory control. Two recent studies reported decreased attention and working memory with greater exposure to organophosphates in boys but not in girls.

This is the first study to report associations between decreased acetylcholinesterase activity, a stable marker of cholinesterase inhibitor pesticide exposure, and lower overall neurodevelopment, attention, inhibitory control, and memory. These associations were present in boys but not in girls. (Read the full article)

Youth are frequent consumers of movies that contain high levels of violence, and violent content in films, especially those rated PG-13, has been increasing over time.

Content analyses seldom examine how violence is portrayed with other health risk behaviors, such smoking, drinking, and sex. This study presents an innovative way to characterize on-screen violent content and demonstrates the extent to which risk behaviors co-occur within films. (Read the full article)

Biomarkers such as C-reactive protein (CRP) and procalcitonin are elevated in children with severe bacterial infections. Children with severe malnutrition are at increased risk of bacterial infections and early markers for the diagnosis of infection in these children are needed.

Despite elevated values in severely malnourished children with invasive bacterial infection or infectious diarrhea, CRP and procalcitonin have limited diagnostic value. CRP could predict death in these children with a good negative predictive value. (Read the full article)

The widely disseminated National Institute on Alcohol Abuse and Alcoholism screening tool for adolescent alcohol use was developed based on epidemiologic data. It has not been validated in a clinical sample and does not screen for tobacco or drug use.

This study found that a measure that expanded the National Institute on Alcohol Abuse and Alcoholism adolescent alcohol use tool to include tobacco and drugs was sensitive and specific for identifying substance use disorders in a pediatric clinic patient population. (Read the full article)

Approximately 20% of US child passenger deaths involve an alcohol-impaired driver, typically in the child’s own vehicle. The higher the blood alcohol concentration of a driver, the more likely his or her child passenger was unrestrained in the fatal crash.

The risk of a child passenger dying while being transported with an alcohol-impaired driver varies meaningfully across states. These state-specific rates may help to inform renewed prevention efforts. (Read the full article)

Several experimental and observational studies reveal an association between exposure to alcohol consumption in movies and youth drinking, but little is known about the effect of such exposure on drinking onset among low-risk adolescents.

In a longitudinal study, exposure to alcohol consumption in movies was associated with drinking initiation in a sample of adolescents from 6 European countries who had never drunk alcohol and were attitudinally nonsusceptible to future use at the time of exposure. (Read the full article)

Most studies of fetal alcohol syndrome and fetal alcohol spectrum disorders (FASD) prevalence in the general population of the United States have been carried out using passive methods (surveillance or clinic-based studies), which underestimate rates of FASD.

Using active case ascertainment methods among children in a representative middle class community, rates of fetal alcohol syndrome and total FASD are found to be substantially higher than most often cited estimates for the general US population. (Read the full article)

Lead is an ubiquitous environmental pollutant, and no safe threshold for blood lead level in children has been discovered yet. Prenatal lead exposure affects growth of children.

Low level of prenatal lead exposure of <5.0 μg/dL affects postnatal children’s growth, which was further intensified by low calcium intake. (Read the full article)

Prenatal alcohol exposure can cause congenital neuropsychological and behavioral disabilities in later life. These usually lead to secondary disabilities (adverse outcome when the individual interacts with environmental settings), such as problems with school, the law, alcohol, or drugs.

This was a 30-year psychosocial register–based follow-up on adults with fetal alcohol syndrome and state care comparison group. The FAS-group had lower education and higher rates of unemployment, social welfare, and mental health problems than peers. Rates of criminality did not differ. (Read the full article)

Researchers speculate that children with fetal alcohol spectrum disorders often are not recognized or diagnosed correctly.

This is the first study to assess the rate of missed diagnoses and misdiagnosis in foster and adopted children with fetal alcohol spectrum disorders. (Read the full article)