Uniparental disomy (UPD) exclusion in embryos following Preimplantation Genetic Testing for Structural Rearrangements (PGT-SR).

Purpose: Uniparental disomy (UPD) is a genetic condition which both copies of a chromosome are inherited from a single parent, potentially leading to imprinting disorders. This study aimed to assess the integration of Short Tandem Repeat (STR) analysis into Preimplantation Genetic Testing for Structural Rearrangements (PGT-SR) to assess UPD risk and its impact on selecting euploid embryos for embryo transfer in couples with chromosomal translocations involving imprinted chromosomes.

Methods: This study evaluated three couples carrying balanced chromosomal translocations: 45,XX,der(13;14)(q10;q10), 46,XX,t(10;11)(q22;q13), and 45,XY,der(14;15)(q10;q10).

Pharmacological modulation of respiratory control: Ampakines as a therapeutic strategy.

Ampakines are a class of compounds that are positive allosteric modulators of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors and enhance glutamatergic neurotransmission. Glutamatergic synaptic transmission and AMPA receptor activation are fundamentally important to the genesis and propagation of the neural impulses driving breathing, including respiratory motoneuron depolarization. Ampakines therefore have the potential to modulate the neural control of breathing.

Nonsedating anxiolytics.

Anxiety disorders are the most prevalent psychiatric pathology with substantial cost to society, but the existing treatments are often inadequate. This has rekindled the interest in the GABA-receptor (GABAR) positive allosteric modulator (PAM) compounds, which have a long history in treatment of anxiety beginning with diazepam, chlordiazepoxide, and alprazolam. While the GABAR PAMs possess remarkable anxiolytic efficacy, they have fallen out of favor due to a host of adverse effects including sedation, motor impairment, addictive potential and tolerance development.

High Impact AMPAkines Induce a Gq-Protein Coupled Endoplasmic Calcium Release in Cortical Neurons: A Possible Mechanism for Explaining the Toxicity of High Impact AMPAkines.

α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) positive allosteric modulators (AMPAkines) have a multitude of promising therapeutic properties. The pharmaceutical development of high impact AMPAkines has, however, been limited by the appearance of calcium-dependent neuronal toxicity and convulsions in vivo. Such toxicity is not observed at exceptionally high concentrations of low impact AMPAkines.

Safety, Tolerability, and Pharmacokinetic Profile of the Low-Impact Ampakine CX1739 in Young Healthy Volunteers.

AMPA-type glutamate receptors (AMPARs) mediate the majority of fast excitatory synaptic transmission in the mammalian brain. Ampakines, positive allosteric modulators of AMPAR, hold significant potential for the treatment of a wide range of neurological/neuropsychiatric disorders in which excitatory synaptic transmission is compromised. Low-impact ampakines are a distinct subset of ampakines that accelerate channel opening yet minimally affect receptor desensitization, which may explain their lack of seizurogenic effects at therapeutic doses in preclinical models.

Preclinical characterization of a water-soluble low-impact ampakine prodrug, CX1942 and its active moiety, CX1763.

AMPA-glutamate receptor (AMPAR) dysfunction mediates multiple neurological/neuropsychiatric disorders. Ampakines bind AMPARs and allosterically enhance glutamate-elicited currents. This report describes the activity of the water-soluble ampakine CX1942 prodrug and the active moiety CX1763.

AMPA receptors play an important role in the biological consequences of spinal cord injury: Implications for AMPA receptor modulators for therapeutic benefit.

Spinal cord injury (SCI) afflicts millions of individuals globally. There are few therapies available to patients. Ascending and descending excitatory glutamatergic neural circuits in the central nervous system are disrupted by SCI, making α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) a potential therapeutic drug target.

KRM-II-81 suppresses epileptifom activity across the neural network of cortical tissue from a patient with pharmacoresistant epilepsy.

A clinical case of a 19-year-old male patient with pharmacoresistant seizures occurring following parieto-occipital tumor-resection at age 6 is described. Seizure surgery work-up included prolonged video EEG monitoring and head CT without contrast. Seizure focus was localized to the left temporal lobe, and we felt that the patient was an excellent candidate for seizure surgery.

New Imidazodiazepine Analogue, 5-(8-Bromo-6-(pyridin-2-yl)-4-benzo[]imidazo[1,5-][1,4]diazepin-3-yl)oxazole, Provides a Simplified Synthetic Scheme, High Oral Plasma and Brain Exposures, and Produces Antiseizure Efficacy in Mice, and Antiepileptogenic Activity in Neural Networks in Brain Slices from a Patient with Mesial Temporal Lobe Epilepsy.

KRM-II-81 (1) is an imidazodiazepine GABA receptor (GABAAR) potentiator with broad antiseizure efficacy and a low sedative burden. A brominated analogue, DS-II-73 (5), was synthesized and pharmacologically characterized as a potential backup compound as KRM-II-81 moves forward into development. The synthesis from 2-amino-5-bromophenyl)(pyridin-2yl)methanone (6) was processed in five steps with an overall yield of 38% and without the need for a palladium catalyst.

Pharmacokinetics, Safety, and Tolerability of Anti-SARS-CoV-2 Monoclonal Antibody, Sotrovimab, Delivered Intravenously or Intramuscularly in Japanese and Caucasian Healthy Volunteers.

Background And Objective: Sotrovimab 500 mg administered by a single intravenous (IV) infusion has been granted special approval for emergency use in Japan for treatment of SARS-CoV-2 infection in adults and children aged ≥ 12 years weighing ≥ 40 kg. This Phase 1, single-dose study investigated the pharmacokinetics, safety, and tolerability of IV or intramuscular (IM) sotrovimab 500 mg doses versus placebo in healthy Japanese and Caucasian volunteers.

Methods: This was a two-part, Phase 1, randomized, placebo-controlled, single-blind study.

Comparative anticonvulsant activity of the GABAkine KRM-II-81 and a deuterated analog.

A series of imidazodiazepines has been developed that possess reduced sedative liabilities but retain efficacy in anticonvulsant screening models. The latest of these compounds, (5-(8-ethynyl-6-(pyridin-2-yl)-4H-benzo[f]imidazole[1,5-α][1,4]diazepin-3-yl) oxazole known as KRM-II-81) is currently awaiting advancement into the clinic. A deuterated structural analog (D5-KRM-II-81) was made as a potential backup compound and studied here in comparison to KRM-II-81.

Structural Analogs of the GABAkine KRM-II-81 Are Orally Bioavailable Anticonvulsants without Sedation.

To provide back-up compounds to support the development of the GABA receptor (GABAAR) potentiator KRM-II-81, three novel analogs were designed: replacing the pyridinyl with 2'-Cl-phenyl (FR-II-60), changing the positions of the N and O atoms in the oxazole ring with addition of an ethyl group (KPP-III-34 and KPP-III-51), or substituting a Br atom for the ethynyl of KRM-II-81 (KPP-III-34). The compounds bound to brain GABAARs. Intraperitoneal administration of FR-II-60 and KPP-III-34 produced anticonvulsant activity in mice [maximal electroshock (MES)-induced seizures or 6 Hz-induced seizures], whereas KPP-III-51 did not.

Hydrochloride Salt of the GABAkine KRM-II-81.

Imidazodiazepine (5-(8-ethynyl-6-(pyridin-2-yl)-4-benzo[]imidazole[1,5-α][1,4]diazepin-3-yl) oxazole or KRM-II-81) is a potentiator of GABA receptors (a GABAkine) undergoing preparation for clinical development. KRM-II-81 is active against many seizure and pain models in rodents, where it exhibits improved pharmacological properties over standard-of-care agents. Since salts can be utilized to create opportunities for increased solubility, enhanced absorption, and distribution, as well as for efficient methods of bulk synthesis, a hydrochloride salt of KRM-II-81 was prepared.

Metabolism, pharmacokinetics, and anticonvulsant activity of a deuterated analog of the α2/3-selective GABAkine KRM-II-81.

The imidazodiazepine, (5-(8-ethynyl-6-(pyridin-2-yl)-4H-benzo [f]imidazole[1,5-α][1,4]diazepin-3-yl) oxazole or KRM-II-81) is a new α2/3-selective GABAkine (gamma aminobutyric acid A receptor potentiator) with anticonvulsant, anxiolytic, and antinociceptive activity in preclinical models. Reducing metabolism was utilized as a means of potentially extending the half-life of KRM-II-81. In vitro and in vivo studies were conducted to evaluate metabolic liabilities.

Novel anti-repression mechanism of H-NS proteins by a phage protein.

H-NS family proteins, bacterial xenogeneic silencers, play central roles in genome organization and in the regulation of foreign genes. It is thought that gene repression is directly dependent on the DNA binding modes of H-NS family proteins. These proteins form lateral protofilaments along DNA.

H-NS-like proteins in Pseudomonas aeruginosa coordinately silence intragenic transcription.

The H-NS-like proteins MvaT and MvaU act coordinately as global repressors in Pseudomonas aeruginosa by binding to AT-rich regions of the chromosome. Although cells can tolerate loss of either protein, identifying their combined regulatory effects has been challenging because the loss of both proteins is lethal due to induction of prophage Pf4 and subsequent superinfection of the cell. In other bacteria, H-NS promotes the cellular fitness by inhibiting intragenic transcription from AT-rich target regions, preventing them from sequestering RNA polymerase; however, it is not known whether MvaT and MvaU function similarly.

Assisted reproduction and Coronavirus in Italy.

Objective: A novel type of Coronavirus was identified in China in December 2019. The first cases of a form of pneumonia of unknown etiology were detected at the beginning of that month in Wuhan. The virus is believed to have emerged at the Wuhan Huanan Seafood Market, where transmission of a zoonotic pathogen to humans occurred.

Progressive multifocal leukoencephalopathy presenting with acute sensorineural hearing loss in an intestinal transplant recipient.

A 20-year-old male presented 3.5 years after intestinal transplantation with rapidly progressive sensorineural hearing loss. Initial brain imaging was consistent with inflammation and/or demyelination.

Myo-inositol impact on sperm motility in vagina and evaluation of its effects on foetal development.

Objective: To counteract the arising problem of couple infertility, having good quality gametes is increasingly important. A molecule that seems to be useful to favor this condition is myo-inositol (MI), the most common stereoisomer of the inositol family, involved as second messenger in several cell pathways (osmoregulation, chromatin remodeling, gene expression, etc.).

Efficacy of the synergic action of myoinositol, tyrosine, selenium and chromium in women with PCOS.

Objective: The aim of the study is to investigate the efficacy of a treatment with myoinositol plus L-tyrosine, selenium, and chromium in women with polycystic ovarian syndrome (PCOS).

Patients And Methods: One hundred and eighty-six women, with diagnosis of PCOS, were divided in four groups according to their clinical features. Phenotype A: androgen excess + ovulatory dysfunction + polycystic ovarian morphology.

Tarps differentially affect the pharmacology of ampakines.

Transmembrane AMPA receptor regulatory proteins (TARPs) govern AMPA receptor cell surface expression and distinct physiological properties including agonist affinity, desensitization and deactivation kinetics. The prototypical TARP, STG or γ2 and TARPs γ3, γ4, γ7 and γ8 are all expressed to varying degrees in the mammalian brain and differentially regulate AMPAR gating parameters. Positive allosteric AMPA receptor modulators or ampakines alter receptor rates of agonist binding/unbinding, channel opening and can offset receptor desensitization and deactivation.