N-methyl-D-aspartate (NMDA) receptors mediate a slow component of excitatory synaptic transmission, are widely distributed throughout the central nervous system, and regulate synaptic plasticity. ...NMDA receptor modulators have long been considered as potential treatments for psychiatric disorders including depression and schizophrenia, neurodevelopmental disorders such as Rett Syndrome, and neurodegenerative conditions such as Alzheimer's disease. New interest in NMDA receptors as therapeutic targets has been spurred by the findings that certain inhibitors of NMDA receptors produce surprisingly rapid and robust antidepressant activity by a novel mechanism, the induction of changes in the brain that well outlast the presence of drug in the body. These findings are driving research into an entirely new paradigm for using NMDA receptor antagonists in a host of related conditions. At the same time positive allosteric modulators of NMDA receptors are being pursued for enhancing synaptic function in diseases that feature NMDA receptor hypofunction. While there is great promise, developing the therapeutic potential of NMDA receptor modulators must also navigate the potential significant risks posed by the use of such agents. We review here the emerging pharmacology of agents that target different NMDA receptor subtypes, offering new avenues for capturing the therapeutic potential of targeting this important receptor class.
Developing cortical GABAergic interneurons rely on genetic programs, neuronal activity, and environmental cues to construct inhibitory circuits during early postnatal development. Disruption of these ...events can cause long-term changes in cortical inhibition and may be involved in neurological disorders associated with inhibitory circuit dysfunction. We hypothesized that tonic glutamate signaling in the neonatal cortex contributes to, and is necessary for, the maturation of cortical interneurons. To test this hypothesis, we used mice of both sexes to quantify extracellular glutamate concentrations in the cortex during development, measure ambient glutamate-mediated activation of developing cortical interneurons, and manipulate tonic glutamate signaling using subtype-specific NMDA receptor antagonists
and
We report that ambient glutamate levels are high (≈100 nm) in the neonatal cortex and decrease (to ≈50 nm) during the first weeks of life, coincident with increases in astrocytic glutamate uptake. Consistent with elevated ambient glutamate, putative parvalbumin-positive interneurons in the cortex (identified using
reporter mice) exhibit a transient, tonic NMDA current at the end of the first postnatal week. GluN2C/GluN2D-containing NMDA receptors mediate the majority of this current and contribute to the resting membrane potential and intrinsic properties of developing putative parvalbumin interneurons. Pharmacological blockade of GluN2C/GluN2D-containing NMDA receptors
during the period of tonic interneuron activation, but not later, leads to lasting decreases in interneuron morphological complexity and causes deficits in cortical inhibition later in life. These results demonstrate that dynamic ambient glutamate signaling contributes to cortical interneuron maturation via tonic activation of GluN2C/GluN2D-containing NMDA receptors.
Inhibitory GABAergic interneurons make up 20% of cortical neurons and are critical to controlling cortical network activity. Dysfunction of cortical inhibition is associated with multiple neurological disorders, including epilepsy. Establishing inhibitory cortical networks requires
proliferation, differentiation, and migration of immature GABAergic interneurons, and subsequent postnatal morphological maturation and circuit integration. Here, we demonstrate that ambient glutamate provides tonic activation of immature, putative parvalbumin-positive GABAergic interneurons in the neonatal cortex via high-affinity NMDA receptors. When this activation is blocked, GABAergic interneuron maturation is disrupted, and cortical networks exhibit lasting abnormal hyperexcitability. We conclude that temporally precise activation of developing cortical interneurons by ambient glutamate is critically important for establishing normal cortical inhibition.
The gall midge,
Asphondylia prosopidis
Cockerell, is considered a potential biological control agent for invasive mesquite (
Prosopis
species) populations in South Africa.
Asphondylia
species induce ...galls on mesquite plants by inserting an egg into a bud, and also carry conidia of specific fungal associates in their mycangia that are transferred into the galls. However, fungal associates have not been characterized in flower bud galls formed by
A. prosopidis
on mesquite. It is essential to identify the fungal associates in the galls formed on natural populations of mesquite prior to host specificity testing. In this study, we showed that
Botryosphaeria dothidea
(Moug. ex Fr.) Ces. & De Not. is the fungal associate in the flower bud galls on mesquite induced by
A. prosopidis
in New Mexico by characterization of the internal transcribed spacer (ITS) region. Further, isolates of
B. dothidea
in
A. prosopidis
galls formed on mesquite were genetically identical to isolates of
B. dothidea
carried by other
Asphondylia
species, particularly on the confamilial
Acacia
species in South Africa. Our result suggests that
A. prosopidis
is safe to utilize as a biological control agent for mesquite, if
A. prosopidis
shows a narrow host range in the pre-release risk assessment, since
B. dothidea
appears to be ubiquitous. To our knowledge, this is the first report of the association between
Asphondylia
species and
B. dothidea
in the United States. We anticipate that
A. prosopidis
will associate with indigenous
B. dothidea
in South Africa.
Bed bug populations are increasing around the world at an alarming rate and have become a major public health concern.The appearance of bed bug populations in areas where Chagas disease is endemic ...raises questions about the role of these insects in the transmission of Trypanosoma cruzi, the etiological agent of the disease. In a series of laboratory evaluations, bed bug adults and nymphs were experimentally fed with T. cruzi-infected blood to assess the ability of T. cruzi to survive inside the bed bug and throughout the insect's molting process. Live T. cruzi were observed in gut contents of experimentally infected bed bug adults via light microscopy and the identity of the parasite was confirmed via polymerase chain reaction analysis. T. cruzi persisted at least 97-d postinfection in adult bed bugs. Nymphal stage bed bugs that were infected with T. cruzi maintained the parasite after molting, indicating that transstadial passage of T. cruzi in bed bugs took place. This report provides further evidence of acquisition, maintenance, and for the first time, transstadial persistence of T. cruzi in bed bugs.
Interscalene brachial plexus blocks are a commonly performed procedure to reduce pain following total shoulder arthroplasty. Liposomal bupivacaine has been purported to prolong the duration of ...brachial plexus blocks for up to 72 hours; however, there has been controversy surrounding the analgesic benefits of this drug. Our hypothesis was that an interscalene block performed with bupivacaine alone would be non-inferior to a combination of liposomal bupivacaine and bupivacaine with respect to opioid consumption following total shoulder arthroplasty.
Subjects presenting for primary total shoulder arthroplasty were randomized in a 1:1 ratio to an ultrasound-guided, single-injection interscalene block with either a combination of liposomal bupivacaine and bupivacaine (LB group) or bupivacaine without additive (Bupi group). The primary outcome of this study was 72-hour postoperative cumulative opioid consumption (in oral morphine equivalents) with a non-inferiority margin of 22.5 mg. Secondary outcomes included pain scores, patient satisfaction with analgesia and patient reported duration of sensory block.
Seventy-six subjects, 38 from the Bupi group and 38 from the LB group, completed the study. Analysis of the primary outcome showed a 72-hour cumulative geometric mean oral morphine equivalent consumption difference of 11.9 mg (95% CI -6.9 to 30.8) between groups (calculated on the log scale). This difference constitutes approximately 1.5 tablets of oxycodone over 3 days. No secondary outcomes showed meaningful differences between groups.
Interscalene brachial plexus blocks performed with bupivacaine alone did not demonstrate non-inferiority compared to a mixture of liposomal bupivacaine plus bupivacaine with regards to 72-hour cumulative opioid consumption following total shoulder arthroplasty. However, the difference between groups did not appear to be clinically meaningful.
Verticillium wilt (
Verticillium dahliae
) is an economically important disease for many high-value crops. The pathogen is difficult to manage due to the long viability of its resting structures, ...wide host range, and the inability of fungicides to affect the pathogen once in the plant vascular system. In chile pepper (
Capsicum annuum
), breeding for resistance to Verticillium wilt is especially challenging due to the limited resistance sources. The dominant
Ve
locus in tomato (
Solanum lycopersicum
) contains two closely linked and inversely oriented genes,
Ve1
and
Ve2
. Homologs of
Ve1
have been characterized in diverse plant species, and interfamily transfer of
Ve1
confers race-specific resistance. Queries in the chile pepper WGS database in NCBI with
Ve1
and
Ve2
sequences identified one open reading frame (ORF) with homology to the tomato
Ve
genes. Comparison of the candidate
CaVe
(
Capsicum annuum Ve
) gene sequences from susceptible and resistant accessions revealed 16 single nucleotide polymorphisms (SNPs) and several haplotypes. A homozygous haplotype was identified for the susceptible accessions and for resistant accessions. We developed a cleaved amplified polymorphic sequence (CAPS) molecular marker within the coding region of
CaVe
and screened diverse germplasm that has been previously reported as being resistant to Verticillium wilt in other regions. Based on our phenotyping using the New Mexico
V
.
dahliae
isolate, the marker could select resistance accessions with 48% accuracy. This molecular marker is a promising tool towards marker-assisted selection for Verticillium wilt resistance and has the potential to improve the efficacy of chile pepper breeding programs, but does not eliminate the need for a bioassay. Furthermore, this work provides a basis for future research in this important pathosystem.
The National Institutes of Health Undiagnosed Diseases Program evaluates patients for whom no diagnosis has been discovered despite a comprehensive diagnostic workup. Failure to diagnose a condition ...may arise from the mutation of genes previously unassociated with disease. However, we hypothesized that this could also co-occur with multiple genetic disorders. Demonstrating a complex syndrome caused by multiple disorders, we report two siblings manifesting both similar and disparate signs and symptoms. They shared a history of episodes of hypoglycemia and lactic acidosis, but had differing exam findings and developmental courses. Clinical acumen and exome sequencing combined with biochemical and functional studies identified three genetic conditions. One sibling had Smith–Magenis Syndrome and a nonsense mutation in the RAI1 gene. The second sibling had a de novo mutation in GRIN2B, which resulted in markedly reduced glutamate potency of the encoded receptor. Both siblings had a protein-destabilizing homozygous mutation in PCK1, which encodes the cytosolic isoform of phosphoenolpyruvate carboxykinase (PEPCK-C). In summary, we present the first clinically-characterized mutation of PCK1 and demonstrate that complex medical disorders can represent the co-occurrence of multiple diseases.
Summary
Background: Laryngospasm is a common and often serious adverse respiratory event encountered during anesthetic care of children. We examined, in a case control design, the risk factors for ...laryngospasm in children.
Material and Methods: The records of 130 children identified as having experienced laryngospasm under general anesthesia were examined. Cases were identified from those prospectively entered into the Mayo Clinic performance improvement database between January 1, 1996 and December 31, 2005. Potential demographic, patient, surgical and anesthetic related risk factors were determined in a 1 : 2 case–control study.
Results: No individual demographic factors were found to be significantly associated with risk for laryngospasm. However, multivariate analysis demonstrated significant associations between laryngospasm and intercurrent upper respiratory infection (OR 2.03 P = 0.022) and the presence of an airway anomaly (OR = 3.35, P = 0.030). Among those experiencing laryngospasm during maintenance or emergence, the use of a laryngeal mask airway was strongly associated even when adjusted for the presence of upper respiratory infection and airway anomaly (P = 0.019). Ten patients experienced postoperatively one or more complications whereas only three complications were observed among controls (P = 0.008). No child required cardiopulmonary resuscitation and there were no deaths in either study cohort.
Conclusions: In our pediatric population, the risk of laryngospasm was increased in children with upper respiratory tract infection or an airway anomaly. The use of laryngeal mask airway was found to be associated with laryngospasm even when adjusted for the presence of upper respiratory tract infection and airway anomaly.
The Eastern, Western, and Egyptian strains of alfalfa weevil are pests introduced to North America on three separate occasions, now they share partially overlapping geographic ranges, covering most ...of the continental United States. Behavior, susceptibility to parasites, and subtle morphological differences separate the strains. The difficulty in differentiating among these strains morphologically has led to the application of molecular phylogeny approaches including restriction fragment-length polymorphism characterization and sequencing of mitochondrial genes. While valuable for strain identification, this approach cannot identify interstrain hybrids because mitochondrial markers are maternally inherited. The work reported here extends previous findings by comparing over 7 Kb of sequence from two mitochondrial and four nuclear loci to increase the resolution of molecular phylogeny for these weevils. The related clover leaf weevil, also an occasional pest of alfalfa, was included in the analysis because the molecular phylogeny of this weevil has not been examined to date. Analysis of nuclear loci indicate that the clover weevil is a distinct species. Furthermore, while the three alfalfa weevil strains are separable based on mitochondrial sequence data they cannot be separated using nuclear loci suggesting that they are all recently diverged members of the same species. These data refine the relationships among these strains and may find application in design of better control strategies.
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