Search

Background: The aim of this study was to evaluate the impact on the national health system of COVID-19 infection in vaccinated patients undergoing haemodialysis. Methods: From the cohort of vaccinated dialysis patients enrolled in 118 dialysis centres, we calculated hospitalisation incidence in COVID-19-infected subjects. COVID-19-related hospitalisations and ICU admissions were analysed over two time periods (prior to administration of the third dose and following administration of the third dose of vaccine) and adjusted for several co-variates. Using the general population as the reference, we then calculated the Standardized Incidence Ratio (SIR) of hospitalisation. Results: Eighty-two subjects out of 1096 infected patients were hospitalised (7.5%) and sixty-four hospitalisations occurred among the 824 infected persons after the third dose. Age ≥ 60 years (Adj RR 2.91; 95% CI 1.34–6.30) and lung disease (Adj RR = 2.45; 95% CI 1.32–4.54) were the only risk factors associated with hospitalisation. The risk of ICU admission in the second time period (Time 2) was reduced by 86% (RR = 0.14; 95% CI 0.03–0.71) compared to the first time period (Time 1). The SIR of hospitalisation (SIR 14.51; 95% CI 11.37–17.65) and ICU admission (SIR 14.58; 95% CI 2.91–26.24) showed an increase in the number of events in dialysis patients compared to the general population. Conclusions: Our analysis revealed that while the second variant of the virus increased infection rates, it was concurrently associated with mitigated severity of infections. Dialysis patients exhibited a higher susceptibility to both COVID-19 hospitalisation and ICU admission than the general population throughout the pandemic. Graphical abstract:

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.

A DC-nanogrid is a small-size DC smart grid (not over 10 kW) generally for residential applications, based on a DC bus, which can interconnect different generation plants with electric storage systems and at least an inverter to supply uninterruptible critical loads. In the next future, Renewable Energy Communities are intending to serve the power system in terms of flexibility, reliability and optimal management of distributed energy storage. The DC-nanogrids are the key technologies to the smart functioning of microgrids and key factors for building Renewable Energy Communities. In this study the environmental evaluation, via Life Cycle Assessment (LCA), of a DC-nanogrid for home application (called in ComESto project nGfHA) has been carried out. The focus of the study is twofold: the analysis of the nGfHA hardware and the use of a targeted approach for the detailed evaluation of the nGfHA operation. An experimental approach based on a four days’ timeline has been implemented for the dynamic LCA evaluation of the nGfHA operations. The results highlight that the hardware of the nGfHA has secondary effects on the environmental impacts of the complete nGfHA configuration; the highest contribution to the environmental impact comes from the Li-ion energy storage, followed by PV, use phase and nGfHA hardware. Nevertheless, a sensitivity analysis shows that an extended lifetime of energy storage leads to equivalent environmental performances.

Background: The aim of this study was to evaluate the efficacy and safety of COVID-19 vaccines in patients undergoing haemodialysis in Italy compared to the general population. Methods: In this cohort study, 118 dialysis centres from 18 Italian Regions participated. Individuals older than 16 years on dialysis treatment for at least 3 months, who provided informed consent were included. We collected demographic and clinical information, as well as data on vaccination status, hospitalisations, access to intensive care units and adverse events. We calculated the incidence, hospitalisation, mortality, and fatality rates in the vaccinated dialysis cohort, adjusted for several covariates. The incidence rates of infection in the dialysis cohort and the general population were compared through Standardised Incidence Rate Ratio. Results: The study included 6555 patients vaccinated against SARS-CoV-2 infection according to the schedule recommended in Italy. Between March 2021 and May 2022, there were 1096 cases of SARS-CoV-2 infection, with an incidence rate after completion of the three-dose vaccination cycle of 37.7 cases per 100 person-years. Compared to the general population, we observed a 14% reduction in the risk of infection for patients who received three vaccine doses (Standardised Incidence Rate Ratio: 0.86; 95% Confidence Interval: 0.81–0.91), whereas no statistically significant differences were found for COVID-19-related hospitalisations, intensive care unit admissions or death. No safety signals emerged from the reported adverse events. Conclusions: The vaccination program against SARS-CoV-2 in the haemodialysis population showed an effectiveness and safety profile comparable to that seen in the general population. Graphical abstract:

N-methyl-d-aspartate (NMDA)-type ionotropic glutamate receptors are critically involved in excitatory neurotransmission and their dysfunction is implicated in many brain disorders. Allosteric modulators with selectivity for specific NMDA receptor subtypes are therefore attractive as therapeutic agents, and sustained drug discovery efforts have resulted in a wide range of new allosteric modulators. However, evaluation of allosteric NMDA receptor modulators is limited by the lack of operational ligand-receptor models to describe modulator binding dissociation constants (KB) and effects on agonist binding affinity (α) and efficacy (β). Here, we describe a pharmacological equilibrium model that encapsulates activation and modulation of NMDA receptors, and we apply this model to afford deeper understanding of GluN2A-selective negative allosteric modulators, TCN-201, MPX-004, and MPX-007. We exploit slow negative allosteric modulator unbinding to examine receptors at hemi-equilibrium when fully occupied by agonists and modulators to demonstrate that TCN-201 display weaker binding and negative modulation of glycine binding affinity (KB = 42 nM, α = 0.0032) compared with MPX-004 (KB = 9.3 nM, α = 0.0018) and MPX-007 (KB = 1.1 nM, α = 0.00053). MPX-004 increases agonist efficacy (β = 1.19), whereas TCN-201 (β = 0.76) and MPX-007 (β = 0.82) reduce agonist efficacy. These values describing allosteric modulation of diheteromeric GluN1/2A receptors with 2 modulator binding sites are unchanged in triheteromeric GluN1/2A/2B receptors with a single binding site. This evaluation of NMDA receptor modulation reveals differences between ligand analogs that shape their utility as pharmacological tool compounds and facilitates the design of new modulators with therapeutic potential.

Objective The aetiologic diagnosis of non-traumatic acute myelopathies (AMs), and their differentiation from other mimicking conditions (i.e. ‘mimics’), are clinically challenging, especially in the emergency setting. Here, we sought to identify: (i) red flags suggesting diagnoses alternative to AMs and (ii) clinical signs and magnetic resonance imaging (MRI) features differentiating non-compressive from compressive AMs.Materials and methods We retrospectively retrieved MRI scans of spinal cord dictated at emergency room from January 2016 to December 2020 in the suspicion of AMs. Patients with traumatic myelopathies and those with subacute/chronic myelopathies (i.e. MRI scans acquired >48 h from symptom onset) were excluded from analysis.Results Our search retrieved 105 patients; after excluding 16 cases of traumatic myelopathies and 14 cases of subacute/chronic myelopathies, we identified 30 cases with non-compressive AMs, 30 cases with compressive AMs and 15 mimics. The presence of pyramidal signs (p= 0.012) and/or pain (p= 0.048) correctly identified 88% of cases with AMs. We failed to identify clinical indicators for distinguishing non-compressive and compressive AMs, although cases with inflammatory AMs were younger than cases with all the remaining conditions (p< 0.05). Different MRI patterns could be described according to the final diagnosis: among non-compressive AMs, inflammatory lesions were more often posterior or central; vascular malformation had a fairly widespread distribution; spine ischaemia was more often central. Anterior or lateral compression were more often associated with neoplasms and disc herniation , whereas hemorrhages and infections produced spine compression on all sides.Conclusion We propose a simple clinical indicator (i.e. pyramidal signs and/or pain) to distinguish AMs from their mimics in an emergency setting. Urgent spinal cord MRI remains essential to discriminate compressive and non-compressive aetiologies.

By April 13, 2022, more than 4 months after the approval of BNT162b2 (Pfizer–BioNTech) for children, less than 40% of 5–11-year-olds in Italy had been vaccinated against COVID-19. Estimating how effective vaccination is in 5–11-year-olds in the current epidemiological context dominated by the omicron variant (B.1.1.529) is important to inform public health bodies in defining vaccination policies and strategies.

Many physiologic effects of l-glutamate, the major excitatory neurotransmitter in the mammalian central nervous system, are mediated via signaling by ionotropic glutamate receptors (iGluRs). These ligand-gated ion channels are critical to brain function and are centrally implicated in numerous psychiatric and neurologic disorders. There are different classes of iGluRs with a variety of receptor subtypes in each class that play distinct roles in neuronal functions. The diversity in iGluR subtypes, with their unique functional properties and physiologic roles, has motivated a large number of studies. Our understanding of receptor subtypes has advanced considerably since the first iGluR subunit gene was cloned in 1989, and the research focus has expanded to encompass facets of biology that have been recently discovered and to exploit experimental paradigms made possible by technological advances. Here, we review insights from more than 3 decades of iGluR studies with an emphasis on the progress that has occurred in the past decade. We cover structure, function, pharmacology, roles in neurophysiology, and therapeutic implications for all classes of receptors assembled from the subunits encoded by the 18 ionotropic glutamate receptor genes.

Many physiologic effects of l-glutamate, the major excitatory neurotransmitter in the mammalian central nervous system, are mediated via signaling by ionotropic glutamate receptors (iGluRs). These ligand-gated ion channels are critical to brain function and are centrally implicated in numerous psychiatric and neurologic disorders. There are different classes of iGluRs with a variety of receptor subtypes in each class that play distinct roles in neuronal functions. The diversity in iGluR subtypes, with their unique functional properties and physiologic roles, has motivated a large number of studies. Our understanding of receptor subtypes has advanced considerably since the first iGluR subunit gene was cloned in 1989, and the research focus has expanded to encompass facets of biology that have been recently discovered and to exploit experimental paradigms made possible by technological advances. Here, we review insights from more than 3 decades of iGluR studies with an emphasis on the progress that has occurred in the past decade. We cover structure, function, pharmacology, roles in neurophysiology, and therapeutic implications for all classes of receptors assembled from the subunits encoded by the 18 ionotropic glutamate receptor genes.Significance StatementGlutamate receptors play important roles in virtually all aspects of brain function and are either involved in mediating some clinical features of neurological disease or represent a therapeutic target for treatment. Therefore, understanding the structure, function, and pharmacology of this class of receptors will advance our understanding of many aspects of brain function at molecular, cellular, and system levels and provide new opportunities to treat patients.

Ketamine, a pan-NMDA receptor channel blocker, and CP-101,606, an NR2B-selective negative allosteric modulator, have antidepressant effects in humans that develop rapidly after the drugs are cleared from the body. It has been proposed that the antidepressant effect of ketamine results from delayed synaptic potentiation. To further investigate this hypothesis and potential mechanistic underpinnings we compared the effects of ketamine and CP-101,606 on neurophysiological biomarkers in rats immediately after drug administration and after the drugs had been eliminated. Local field and auditory-evoked potentials (AEPs) were recorded from primary auditory cortex and hippocampus in freely moving rats. Effects of different doses of ketamine or CP-101,606 were evaluated on amplitude of AEPs, auditory gating, and absolute power of delta and gamma oscillations 5–30 min (drug-on) and 5–6 h (drug-off) after systemic administration. Both ketamine and CP-101,606 significantly enhanced AEPs in cortex and hippocampus in the drug-off phase. In contrast, ketamine but not CP-101,606 disrupted auditory gating and increased gamma-band power during the drug-on period. Although both drugs affected delta power, these changes did not correlate with increase in AEPs in the drug-off phase. Our findings show that both ketamine and CP-101,606 augment AEPs after drug elimination, consistent with synaptic potentiation as a mechanism for antidepressant efficacy. However, these drugs had different acute effects on neurophysiological parameters. These results have implications for understanding the underlying mechanisms for the rapid-onset antidepressant effects of NMDA receptor inhibition and for the use of electrophysiological measures as translatable biomarkers.

Two studies were conducted using adult dogs to evaluate the effect of increasing the inclusion of soybean meal (SBM) in an adult dog food on body composition, hematological and biochemical blood analyses, and total tract nutrient digestibility. Nutritionally complete and balanced diets were formulated with commercial-grade SBM (48% CP) to replace 0, 10, 20, or 30% of the protein provided by dried chicken protein resulting in final SBM inclusion of 0, 6.0, 11.5, and 17.0% (as-fed basis), respectively. In study 1, diets were fed during a 24-wk feeding trial using 36 female (spayed), adult hounds to evaluate food intake, BW, body composition, and blood measurements. There were no diet-related differences in food intake or BW. Body composition responded in a quadratic manner to increased dietary SBM inclusion with the percentage (%) of lean mass responding positively (P< 0.05) and absolute amounts of fat mass and percent body fat responding negatively (P< 0.05). All diagnostic blood components remained within normal physiological ranges for healthy, adult dogs. Serum concentrations of C-reactive protein and IGF-1 were similar among diets. In study 2, diets were evaluated in a digestibility study using 12 adult dogs in a 4 × 4 Latin square design. Increased SBM inclusion was associated with linear increases in the digestibility of CP (P< 0.05) and fat (P< 0.05) and CP retention (P< 0.05). Linear reductions in fecal DM content (P< 0.01) and increased fecal output (P< 0.05) were noted with increased SBM inclusion. All diets were similar in DE and ME content, but a quadratic trend was noted with increased SBM inclusion when DE (P= 0.083) and ME (P= 0.062) were expressed per unit of metabolic body size. Overall, it can be inferred from these results that the partial replacement of dried chicken protein with SBM in a nutritionally complete and balanced diet does not compromise the nutritional status and long-term health of adult dogs.

Veterinary graduates require effective communication skills training to successfully transition from university into practice. Although the literature has supported the need for veterinary student communication skills training programs, there is minimal research using learning theory to design programs and explore students' perceptions of such programs. This study investigated veterinary students' perceptions of (1) their communication skills and (2) the usefulness of a communication skills training program designed with Kolb's Experiential Learning Theory (ELT) as a framework and implemented in a primary care setting. Twenty-nine final-year veterinary students from the Ontario Veterinary College attended a 3-week communication skills training rotation. Pre- and post-training surveys explored their communication objectives, confidence in their communication skills, and the usefulness of specific communication training strategies. The results indicated that both before and after training, students were most confident in building rapport, displaying empathy, recognizing how bonded a client is with his or her pet, and listening. They were least confident in managing clients who were angry or not happy with the charges and who monopolized the appointment. Emotionally laden topics, such as breaking bad news and managing euthanasia discussions, were also identified as challenging and in need of improvement. Interactive small-group discussions and review of video-recorded authentic client appointments were most valuable for their learning and informed students' self-awareness of their non-verbal communication. These findings support the use of Kolb's ELT as a theoretical framework and of video review and reflection to guide veterinary students' learning of communication skills in a primary care setting.

α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) positive allosteric modulation (i.e., “potentiation”) has been proposed to overcome cognitive impairments in schizophrenia, but AMPAR overstimulation can be excitotoxic. Thus, it is critical to define carefully a potentiator’s mechanism-based therapeutic index (TI) and to determine confidently its translatability from rodents to higher-order species. Accordingly, the novel AMPAR potentiator N-{(3R,4S)-3-[4-(5-cyano-2-thienyl)phenyl]tetrahydro-2H-pyran-4-yl}propane-2-sulfonamide (PF-4778574) was characterized in a series of in vitro assays and single-dose animal studies evaluating AMPAR-mediated activities related to cognition and safety to afford an unbound brain compound concentration (Cb,u)–normalized interspecies exposure-response relationship. Because it is unknown which AMPAR subtype(s) may be selectively potentiated for an optimal TI, PF-4778574 binding affinity and functional potency were determined in rodent tissues expected to express a native mixture of AMPAR subunits and their associated proteins to afford composite pharmacological values. Functional activity was also quantified in recombinant cell lines stably expressing human GluA2 flip or flop homotetramers. Procognitive effects of PF-4778574 were evaluated in both rat electrophysiological and nonhuman primate (nhp) behavioral models of pharmacologically induced N-methyl-d-aspartate receptor hypofunction. Safety studies assessed cerebellum-based AMPAR activation (mouse) and motor coordination disruptions (mouse, dog, and nhp), as well as convulsion (mouse, rat, and dog). The resulting empirically derived exposure-response continuum for PF-4778574 defines a single-dose-based TI of 8- to 16-fold for self-limiting tremor, a readily monitorable clinical adverse event. Importantly, the Cb,umediating each physiological effect were highly consistent across species, with efficacy and convulsion occurring at just fractions of the in vitro–derived pharmacological values.

Introduction:The second messengers cAMP and cGMP mediate fundamental aspects of brain function relevant to memory, learning, and cognitive functions. Consequently, cyclic nucleotide phosphodiesterases (PDEs), the enzymes that inactivate the cyclic nucleotides, are promising targets for the development of cognition-enhancing drugs.Areas covered:PDE4 is the largest of the 11 mammalian PDE families. This review covers the properties and functions of the PDE4 family, highlighting procognitive and memory-enhancing effects associated with their inactivation.Expert opinion:PAN-selective PDE4 inhibitors exert a number of memory- and cognition-enhancing effects and have neuroprotective and neuroregenerative properties in preclinical models. The major hurdle for their clinical application is to target inhibitors to specific PDE4 isoforms relevant to particular cognitive disorders to realize the therapeutic potential while avoiding side effects, in particular emesis and nausea. The PDE4 family comprises four genes, PDE4A-D, each expressed as multiple variants. Progress to date stems from characterization of rodent models with selective ablation of individual PDE4 subtypes, revealing that individual subtypes exert unique and non-redundant functions in the brain. Thus, targeting specific PDE4 subtypes, as well as splicing variants or conformational states, represents a promising strategy to separate the therapeutic benefits from the side effects of PAN-PDE4 inhibitors.

Schizophrenia is a highly debilitating mental disorder which afflicts approximately 1 of the global population. Cognitive and negative deficits account for the lifelong disability associated with schizophrenia, whose symptoms are not effectively addressed by current treatments. New medicines are needed to treat these aspects of the disease. Neurodevelopmental, neuropathological, genetic, and behavioral pharmacological data indicate that schizophrenia stems from a dysfunction of glutamate synaptic transmission, particularly in frontal cortical networks. A number of novel pre- and postsynaptic mechanisms affecting glutamatergic synaptic transmission have emerged as viable targets for schizophrenia. While developing orthosteric glutamatergic agents for these targets has proven extremely difficult, targeting allosteric sites of these targets has emerged as a promising alternative. From a medicinal chemistry perspective, allosteric sites provide an opportunity of finding agents with better drug-like properties and greater target specificity. Furthermore, allosteric modulators are better suited to maintaining the highly precise temporal and spatial aspects of glutamatergic synaptic transmission. Herein, we review neuropathological and genomic/genetic evidence underscoring the importance of glutamate synaptic dysfunction in the etiology of schizophrenia and make a case for allosteric targets for therapeutic intervention. We review progress in identifying allosteric modulators of AMPA receptors, NMDA receptors, and metabotropic glutamate receptors, all with the aim of restoring physiological glutamatergic synaptic transmission. Challenges remain given the complexity of schizophrenia and the difficulty in studying cognition in animals and humans. Nonetheless, important compounds have emerged from these efforts and promising preclinical and variable clinical validation has been achieved.

Cyclic nucleotides are critical regulators of synaptic plasticity and participate in requisite signaling cascades implicated across multiple neurotransmitter systems. Phosphodiesterase 9A (PDE9A) is a high-affinity, cGMP-specific enzyme widely expressed in the rodent central nervous system. In the current study, we observed neuronal staining with antibodies raised against PDE9A protein in human cortex, cerebellum, and subiculum. We have also developed several potent, selective, and brain-penetrant PDE9A inhibitors and used them to probe the function of PDE9A in vivo. Administration of these compounds to animals led to dose-dependent accumulation of cGMP in brain tissue and cerebrospinal fluid, producing a range of biological effects that implied functional significance for PDE9A-regulated cGMP in dopaminergic, cholinergic, and serotonergic neurotransmission and were consistent with the widespread distribution of PDE9A. In vivo effects of PDE9A inhibition included reversal of the respective disruptions of working memory by ketamine, episodic and spatial memory by scopolamine, and auditory gating by amphetamine, as well as potentiation of risperidone-induced improvements in sensorimotor gating and reversal of the stereotypic scratching response to the hallucinogenic 5-hydroxytryptamine 2A agonist mescaline. The results suggested a role for PDE9A in the regulation of monoaminergic circuitry associated with sensory processing and memory. Thus, PDE9A activity regulates neuronal cGMP signaling downstream of multiple neurotransmitter systems, and inhibition of PDE9A may provide therapeutic benefits in psychiatric and neurodegenerative diseases promoted by the dysfunction of these diverse neurotransmitter systems.

Cyclic nucleotides are critical regulators of synaptic plasticity and participate in requisite signaling cascades implicated across multiple neurotransmitter systems. Phosphodiesterase 9A (PDE9A) is a high-affinity, cGMP-specific enzyme widely expressed in the rodent central nervous system. In the current study, we observed neuronal staining with antibodies raised against PDE9A protein in human cortex, cerebellum, and subiculum. We have also developed several potent, selective, and brain-penetrant PDE9A inhibitors and used them to probe the function of PDE9A in vivo. Administration of these compounds to animals led to dose-dependent accumulation of cGMP in brain tissue and cerebrospinal fluid, producing a range of biological effects that implied functional significance for PDE9A-regulated cGMP in dopaminergic, cholinergic, and serotonergic neurotransmission and were consistent with the widespread distribution of PDE9A. In vivo effects of PDE9A inhibition included reversal of the respective disruptions of working memory by ketamine, episodic and spatial memory by scopolamine, and auditory gating by amphetamine, as well as potentiation of risperidone-induced improvements in sensorimotor gating and reversal of the stereotypic scratching response to the hallucinogenic 5-hydroxytryptamine 2A agonist mescaline. The results suggested a role for PDE9A in the regulation of monoaminergic circuitry associated with sensory processing and memory. Thus, PDE9A activity regulates neuronal cGMP signaling downstream of multiple neurotransmitter systems, and inhibition of PDE9A may provide therapeutic benefits in psychiatric and neurodegenerative diseases promoted by the dysfunction of these diverse neurotransmitter systems.

There has been an increasing interest in the development of phosphodiesterase (PDE) inhibitors for the treatment of cognitive dysfunctions. In this editorial, the mechanism of action of PDEs is briefly described, while the effects of different PDE inhibitors in preclinical models are reviewed. Based on the expression of PDE mRNA in the human brain, it is suggested that PDE1 and PDE10 inhibitors are strong candidates for the development of cognition enhancers. However, the complex nature of the expression of PDEs in the brain warrants further research into the role of PDEs in the signaling pathways in brain circuits. The development of PDE inhibitors, which are selective for PDE splicing isoforms, may be promising for future drug development.

The article focuses on the health benefits of the Italian's urban gardening in Italy. Most of the older Italians have been observed for using horticultural therapy to strengthen their bodies and souls. The Italian Garden Project was created to be able to document and preserve the important aspects of the Italian American heritage.

The mammalian ionotropic glutamate receptor family encodes 18 gene products that coassemble to form ligand-gated ion channels containing an agonist recognition site, a transmembrane ion permeation pathway, and gating elements that couple agonist-induced conformational changes to the opening or closing of the permeation pore. Glutamate receptors mediate fast excitatory synaptic transmission in the central nervous system and are localized on neuronal and non-neuronal cells. These receptors regulate a broad spectrum of processes in the brain, spinal cord, retina, and peripheral nervous system. Glutamate receptors are postulated to play important roles in numerous neurological diseases and have attracted intense scrutiny. The description of glutamate receptor structure, including its transmembrane elements, reveals a complex assembly of multiple semiautonomous extracellular domains linked to a pore-forming element with striking resemblance to an inverted potassium channel. In this review we discuss International Union of Basic and Clinical Pharmacology glutamate receptor nomenclature, structure, assembly, accessory subunits, interacting proteins, gene expression and translation, post-translational modifications, agonist and antagonist pharmacology, allosteric modulation, mechanisms of gating and permeation, roles in normal physiological function, as well as the potential therapeutic use of pharmacological agents acting at glutamate receptors.

Phosphodiesterase 5A (PDE5A) inhibitors improve functional recovery after middle cerebral artery occlusion (MCA-o) in rats. We used the PDE5A inhibitor 3-(4-(2-hydroxyethyl)piperazin-1-yl)-7-(6-methoxypyridin-3-yl)-1-(2-propoxyethyl)pyrido[3,4-b]pyrazin-2(1H)-one hydrochloride (PF-5) to determine the timing, duration, and degree of inhibition that yields maximum efficacy. We also investigated the localization of PDE5A to determine the tissues and cells that would be targets for PDE5 inhibition and that may mediate efficacy. Nearly complete inhibition of PDE5A, starting 24 h after MCA-o and continued for 7 days, resulted in nearly complete recovery of sensorimotor function that was sustained for 3 months. Delaying administration until 72 h after MCA-o resulted in equivalent efficacy, whereas delaying treatment for 14 days was ineffective. Treatment for 7 days was equivalently efficacious to 28 or 84 days of treatment, whereas treatment for 1 day was less effective. In the normal forebrain, PDE5A immunoreactivity was prominent in smooth muscle of meningeal arteries and a few smaller blood vessels, with weak staining in a few widely scattered cortical neurons and glia. At 24 and 48 h after MCA-o, the number and intensity of blood vessel staining increased in the infarcted cortex and striatum. PDE5A immunoreactivity also was increased at 48 h in putative microglia in penumbra, whereas there was no change in staining of the scattered cortical neurons. Given the window for efficacy and the PDE5A distribution, we hypothesize that efficacy results from an effect on vasculature, and perhaps modulation of microglial function, both of which may facilitate recovery of neuronal function.

It is well established that cAMP signaling is an important regulator of the oocyte meiotic cell cycle. Conversely, the function of cGMP during oocyte maturation is less clear. Herein, we evaluated the expression of cGMP-hydrolyzing phosphodiesterases (PDEs) in the somatic and germ cell compartments of the mouse ovarian follicle and demonstrate that PDE5 is preferentially expressed in somatic cells. Cyclic GMP is a potent inhibitor of cAMP hydrolysis from oocyte extracts, with a 50% inhibitory concentration of 97 nM. Luteinizing hormone (LH) stimulation of cultured preovulatory follicles results in a marked decrease in cGMP content, and a nadir is reached in 1.5 h; similarly, oocyte cGMP levels decrease after gonadotropin stimulation in vivo. The LH-dependent decrease in cGMP requires activation of the epidermal growth factor network. Treatment of follicles with a PDE5 inhibitor increases cGMP in the follicle well above unstimulated levels. Although LH causes a decrease in cGMP in follicles preincubated with PDE5 inhibitors, the levels of this nucleotide remain above unstimulated levels. Under these conditions of elevated cGMP, LH stimulation does not cause oocyte maturation after 5 h of incubation. Microinjection of a cGMP-specific PDE into oocytes causes meiotic maturation of wild-type oocytes, suggesting that an intraoocyte pool of cGMP is involved in the maintenance of meiotic arrest. This effect is absent in PDE3A-deficient oocytes. Taken together, these findings provide evidence that cGMP and cAMP signaling cooperate in maintaining meiotic arrest via regulation of PDE3A and that a decrease in cGMP in the somatic compartment is one of the signals contributing to meiotic maturation.

For its current dimensions, stroke represents the world’s primary health challenge. In China stroke is the second most common cause of death. Traditional Chinese Medicine (TCM) has for many centuries been used, and it is still widely used today in countries of south and east Asia for the treatment of people with stroke. The objective of this systematic review was to evaluate whether complex Traditional Chinese Medicine (cTCM) improves poststroke motor recovery. In particular, we defined cTCM as intervention that included at least acupuncture and Chinese herbal medicine.

The cyclic nucleotide phosphodiesterase 10A (PDE10A) is highly expressed in striatal medium-sized spiny projection neurons (MSNs), apparently playing a critical role in the regulation of both cGMP and cAMP signaling cascades. Genetic disruption or pharmacological inhibition of PDE10A reverses behavioral abnormalities associated with subcortical hyperdopaminergia. Here, we investigate the effect of PDE10A inhibition on the activity of MSNs using single-unit extracellular recordings performed in the dorsal striatum of anesthetized rats. Antidromic stimulation of the substantia nigra pars reticulata was used to identify striatonigral (SNr+) MSNs. Intrastriatal infusion of the selective PDE10A inhibitors papaverine or TP-10 [2-{4-[-pyridin-4-yl-1-(2,2,2-trifluoroethyl)-1 H-pyrazol-3-yl]-phenoxymethyl}-quinoline succinic acid] by reverse microdialysis did not affect spontaneous firing but robustly increased measures of cortically evoked spike activity in a stimulus intensity-dependent manner. Systemic administration of TP-10 also increased cortically evoked spike activity in a stimulus intensity- and dose-dependent manner. A robust increase in cortically evoked activity was apparent in SNr- MSNs (primarily striatopallidal). It is interesting that TP-10 administration did not affect cortically evoked activity in SNr+ MSNs. However, TP-10 administration increased the incidence of antidromically activated (i.e., SNr+) MSNs. These findings indicate that inhibition of striatal PDE10A activity increases the responsiveness of MSNs to depolarizing stimuli. Furthermore, given the lack of effect of TP-10 on SNr+ MSNs, we speculate that PDE10A inhibition may have a greater facilitatory effect on corticostriatal synaptic activity in striatopallidal MSNs. These data support further investigation of selective targeting of PDE signaling pathways in MSN subpopulations because this may represent a promising novel approach for treating brain disorders involving dysfunctional glutamatergic and dopaminergic neurotransmission.

The cyclic nucleotide phosphodiesterase 10A (PDE10A) is highly expressed in striatal medium-sized spiny projection neurons (MSNs), apparently playing a critical role in the regulation of both cGMP and cAMP signaling cascades. Genetic disruption or pharmacological inhibition of PDE10A reverses behavioral abnormalities associated with subcortical hyperdopaminergia. Here, we investigate the effect of PDE10A inhibition on the activity of MSNs using single-unit extracellular recordings performed in the dorsal striatum of anesthetized rats. Antidromic stimulation of the substantia nigra pars reticulata was used to identify striatonigral (SNr+) MSNs. Intrastriatal infusion of the selective PDE10A inhibitors papaverine or TP-10 [2-{4-[-pyridin-4-yl-1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl]-phenoxymethyl}-quinoline succinic acid] by reverse microdialysis did not affect spontaneous firing but robustly increased measures of cortically evoked spike activity in a stimulus intensity-dependent manner. Systemic administration of TP-10 also increased cortically evoked spike activity in a stimulus intensity- and dose-dependent manner. A robust increase in cortically evoked activity was apparent in SNr- MSNs (primarily striatopallidal). It is interesting that TP-10 administration did not affect cortically evoked activity in SNr+ MSNs. However, TP-10 administration increased the incidence of antidromically activated (i.e., SNr+) MSNs. These findings indicate that inhibition of striatal PDE10A activity increases the responsiveness of MSNs to depolarizing stimuli. Furthermore, given the lack of effect of TP-10 on SNr+ MSNs, we speculate that PDE10A inhibition may have a greater facilitatory effect on corticostriatal synaptic activity in striatopallidal MSNs. These data support further investigation of selective targeting of PDE signaling pathways in MSN subpopulations because this may represent a promising novel approach for treating brain disorders involving dysfunctional glutamatergic and dopaminergic neurotransmission.

This randomized, placebo-controlled, double-blind study was the first to evaluate the antidepressant efficacy, safety, and tolerability of an NR2B subunit-selective N-methyl-D-aspartate receptor antagonist, CP-101,606. Subjects had major depression, according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Editioncriteria and a history of treatment refractoriness to least 1 adequate trial of a selective serotonin reuptake inhibitor. The study had 2 treatment periods. In period 1, subjects first received a 6-week open-label trial of paroxetine and a single-blind, intravenous placebo infusion. Period 1 nonresponders (n = 30) then received a randomized double-blind single infusion of CP-101,606 or placebo plus continued treatment with paroxetine for up to an additional 4 weeks (period 2). Depression severity was assessed using the Montgomery-Åsberg Depression Rating Scale and 17-item Hamilton Depression Rating Scale. On the prespecified main outcome measure (change from baseline in the Montgomery-Åsberg Depression Rating Scale total score at day 5 of period 2), CP-101,606 produced a greater decrease than did placebo (mean difference, 8.6; 80% confidence interval, −12.3 to −4.5) (P< 0.10). Hamilton Depression Rating Scale response rate was 60% for CP-101,606 versus 20% for placebo. Seventy-eight percent of CP-101,606-treated responders maintained response status for at least 1 week after the infusion. CP-101,606 was safe, generally well tolerated, and capable of producing an antidepressant response without also producing a dissociative reaction. Antagonism of the NR2B subtype of the N-methyl-D-aspartate receptor may be a fruitful target for the development of a new antidepressant with more robust effects and a faster onset compared with those currently available and capable of working when existing antidepressants do not.

We have recently proposed the hypothesis that inhibition of the cyclic nucleotide phosphodiesterase (PDE) 10A may represent a new pharmacological approach to the treatment of schizophrenia (Curr Opin Invest Drug8:54–59, 2007). PDE10A is highly expressed in the medium spiny neurons of the mammalian striatum (Brain Res985:113–126, 2003; J Histochem Cytochem54:1205–1213, 2006; Neuroscience139:597–607, 2006), where the enzyme is hypothesized to regulate both cAMP and cGMP signaling cascades to impact early signal processing in the corticostriatothalamic circuit (Neuropharmacology51:374–385, 2006; Neuropharmacology51:386–396, 2006). Our current understanding of the physiological role of PDE10A and the therapeutic utility of PDE10A inhibitors derives in part from studies with papaverine, the only pharmacological tool for this target extensively profiled to date. However, this agent has significant limitations in this regard, namely, relatively poor potency and selectivity and a very short exposure half-life after systemic administration. In the present report, we describe the discovery of a new class of PDE10A inhibitors exemplified by TP-10 (2-{4-[-pyridin-4-yl-1-(2,2,2-trifluoro-ethyl)-1 H-pyrazol-3-yl]-phenoxymethyl}-quinoline succinic acid), an agent with greatly improved potency, selectivity, and pharmaceutical properties. These new pharmacological tools enabled studies that provide further evidence that inhibition of PDE10A represents an important new target for the treatment of schizophrenia and related disorders of basal ganglia function.

We have recently proposed the hypothesis that inhibition of the cyclic nucleotide phosphodiesterase (PDE) 10A may represent a new pharmacological approach to the treatment of schizophrenia (Curr Opin Invest Drug 8:54-59, 2007). PDE10A is highly expressed in the medium spiny neurons of the mammalian striatum (Brain Res 985:113-126, 2003; J Histochem Cytochem 54:1205-1213, 2006; Neuroscience 139:597-607, 2006), where the enzyme is hypothesized to regulate both cAMP and cGMP signaling cascades to impact early signal processing in the corticostriatothalamic circuit (Neuropharmacology 51:374-385, 2006; Neuropharmacology 51:386-396, 2006). Our current understanding of the physiological role of PDE10A and the therapeutic utility of PDE10A inhibitors derives in part from studies with papaverine, the only pharmacological tool for this target extensively profiled to date. However, this agent has significant limitations in this regard, namely, relatively poor potency and selectivity and a very short exposure half-life after systemic administration. In the present report, we describe the discovery of a new class of PDE10A inhibitors exemplified by TP-10 (2-{4-[-pyridin-4-yl-1-(2,2,2-trifluoro-ethyl)-1H-pyrazol-3-yl]-phenoxymethyl}-quinoline succinic acid), an agent with greatly improved potency, selectivity, and pharmaceutical properties. These new pharmacological tools enabled studies that provide further evidence that inhibition of PDE10A represents an important new target for the treatment of schizophrenia and related disorders of basal ganglia function.

Drugs acting at cannabinoid type 1 receptors (CB1) have modulatory effects on glutamate and GABA neurotransmission in basal ganglia; thus, they potentially affect motor behavior in the parkinsonian setting. Preclinical trials with diverse cannabinoid agents have shown varied results, and the precise effects of blocking cannabinoid CB1 receptors remain uncertain. We tested behavioral effects of the selective antagonist 1-[7-(2-chlorophenyl)-8-(4-chlorophenyl)-2-methylpyrazolo[1,5-a]-[1,3,5]triazin-4-yl]-3-ethylaminoazetidine-3-carboxylic acid amide benzenesulfonate (CE) as monotherapy and in combination with l-DOPA in treatment-naive and l-DOPA-primed 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated rhesus monkeys with moderate and severe parkinsonism. Motor disability and l-DOPA-induced dyskinesias were scored with a standardized scale after subcutaneous drug administration, and plasma levels of l-DOPA were determined by high-performance liquid chromatography/electrochemical detection. CE doses ranged from 0.03 to 1 mg/kg, and l-DOPA methyl ester doses were selected as optimal and suboptimal doses (maximal and 50% of maximal responses, respectively). CE had no intrinsic effects on motor behavior regardless of the degree of parkinsonism (moderate or severe groups) or previous drug exposure (“de novo” or after l-DOPA priming). Initial CE administration did not affect development of l-DOPA antiparkinsonian responses. In coadministration trials, CE, in a dose-dependent manner, increased responses to l-DOPA (suboptimal doses). These effects were seen in both moderate and severely parkinsonian monkeys as a 30% increase of, predominantly, response duration with no effects on l-DOPA pharmacokinetics. CE did not modify levodopa-induced dyskinesias. These results suggest that selective cannabinoid CB1 antagonists may enhance the antiparkinsonian action of dopaminomimetics and possibly facilitate the use of lower doses, thereby reducing side effects.

Drugs acting at cannabinoid type 1 receptors (CB1) have modulatory effects on glutamate and GABA neurotransmission in basal ganglia; thus, they potentially affect motor behavior in the parkinsonian setting. Preclinical trials with diverse cannabinoid agents have shown varied results, and the precise effects of blocking cannabinoid CB1 receptors remain uncertain. We tested behavioral effects of the selective antagonist 1-[7-(2-chlorophenyl)-8-(4-chlorophenyl)-2-methylpyrazolo[1,5-a]-[1,3,5]triazin-4-yl]-3-ethylaminoazetidine-3-carboxylic acid amide benzenesulfonate (CE) as monotherapy and in combination with l-DOPA in treatment-naive and L-DOPA-primed 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated rhesus monkeys with moderate and severe parkinsonism. Motor disability and L-DOPA-induced dyskinesias were scored with a standardized scale after subcutaneous drug administration, and plasma levels of L-DOPA were determined by high-performance liquid chromatography/electrochemical detection. CE doses ranged from 0.03 to 1 mg/kg, and L-DOPA methyl ester doses were selected as optimal and suboptimal doses (maximal and 50% of maximal responses, respectively). CE had no intrinsic effects on motor behavior regardless of the degree of parkinsonism (moderate or severe groups) or previous drug exposure ("de novo" or after L-DOPA priming). Initial CE administration did not affect development of L-DOPA antiparkinsonian responses. In coadministration trials, CE, in a dose-dependent manner, increased responses to L-DOPA (suboptimal doses). These effects were seen in both moderate and severely parkinsonian monkeys as a 30% increase of, predominantly, response duration with no effects on L-DOPA pharmacokinetics. CE did not modify levodopa-induced dyskinesias. These results suggest that selective cannabinoid CB1 antagonists may enhance the antiparkinsonian action of dopaminomimetics and possibly facilitate the use of lower doses, thereby reducing side effects.

This paper describes the synthesis of racemic 3,5-dihydro-5-methyl-7,8-methylenedioxy-4H-2,3-benzodiazepin-4-one (±)-5, attempted stereoselective synthesis of its enantiomers, chiral HPLC resolution of the racemate, and assignment of the absolute configuration. Enantiomer (5S)-(−)-5 is provided with an in vivo anticonvulsant activity 8 times higher than its enantiomer (5R)-(+)-5. This result is confirmed in the in vitro test by the ability to inhibit the kainate-induced increase of the [Ca2+]i in a primary culture of rat cerebellar granule cells which express α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors. Binding affinity of compound (±)-5 at the AMPA and N-methyl-d-aspartic acid (NMDA) receptors was also evaluated.

This paper describes the synthesis of racemic 3,5-dihydro-5-methyl-7,8-methylenedioxy-4H-2,3-benzodiazepin-4-one (±)-5, attempted stereoselective synthesis of its enantiomers, chiral HPLC resolution of the racemate, and assignment of the absolute configuration. Enantiomer (5S)-(−)-5 is provided with an in vivo anticonvulsant activity 8 times higher than its enantiomer (5R)-(+)-5. This result is confirmed in the in vitro test by the ability to inhibit the kainate-induced increase of the [Ca2+]i in a primary culture of rat cerebellar granule cells which express α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors. Binding affinity of compound (±)-5 at the AMPA and N-methyl-d-aspartic acid (NMDA) receptors was also evaluated.

In this paper a Command Governor strategy is used for voltage regulation in Medium and Low Voltage (MV/LV) distribution networks subject to load voltage drops. The voltage regulation is formulated as a constrained tracking problem by imposing that the voltages at the LV customer loads have minimum deviation from their nominal values, each other compatible with prescribed bounds on their maximum deviations. Simulations studies show the effectiveness of the proposed approach.