Intravenous Ganaxolone: Pharmacokinetics, Pharmacodynamics, Safety, and Tolerability in Healthy Adults.

Ganaxolone, a neuroactive steroid anticonvulsant that modulates both synaptic and extrasynaptic γ-aminobutyric acid type A (GABA ) receptors, is in development for treatment of status epilepticus (SE) and rare epileptic disorders, and has been approved in the United States for treatment of seizures associated with cyclin-dependent kinase-like 5 deficiency disorder in patients ≥2 years old. This phase 1 study in 36 healthy volunteers evaluated the pharmacokinetics, pharmacodynamics, and safety of intravenous ganaxolone administered as a (i) single bolus, (ii) infusion, and (iii) bolus followed by continuous infusion. After a single bolus over 2 minutes (20 mg) or 5 minutes (10 or 30 mg), ganaxolone was detected in plasma with a median T of 5 minutes, whereas a 60-minute infusion (10 or 30 mg) or a bolus (6 mg over 5 minutes) followed by infusion (20 mg/h) for 4 hours achieved a median T of approximately 1 and 3 hours, respectively.

Microfluidic-Assisted Formulation of ε-Polycaprolactone Nanoparticles and Evaluation of Their Properties and In Vitro Cell Uptake.

The nanoprecipitation method was used to formulate ε-polycaprolactone (PCL) into fluorescent nanoparticles. Two methods of mixing the phases were evaluated: introducing the organic phase into the aqueous phase dropwise and via a specially designed microfluidic device. As a result of the nanoprecipitation process, fluorescein-loaded nanoparticles (NPs) with a mean diameter of 127 ± 3 nm and polydispersity index (PDI) of 0.

Long-term treatment with ganaxolone for seizures associated with cyclin-dependent kinase-like 5 deficiency disorder: Two-year open-label extension follow-up.

Objective: In the placebo-controlled, double-blind phase of the Marigold study (NCT03572933), ganaxolone significantly reduced major motor seizure frequency (MMSF) in patients with cyclin-dependent kinase-like 5 deficiency disorder (CDD). We report 2-year safety and clinical outcomes data from the open-label extension (OLE) phase of Marigold.

Methods: Patients with CDD who completed the double-blind phase were eligible to continue in the OLE.

Expression of human thrombomodulin by GalTKO.hCD46 pigs modulates coagulation cascade activation by endothelial cells and during ex vivo lung perfusion with human blood.

Thrombomodulin is important for the production of activated protein C (APC), a molecule with significant regulatory roles in coagulation and inflammation. To address known molecular incompatibilities between pig thrombomodulin and human thrombin that affect the conversion of protein C into APC, GalTKO.hCD46 pigs have been genetically modified to express human thrombomodulin (hTBM).

Increased human complement pathway regulatory protein gene dose is associated with increased endothelial expression and prolonged survival during ex-vivo perfusion of GTKO pig lungs with human blood.

Introduction: Expression of human complement pathway regulatory proteins (hCPRP's) such as CD46 or CD55 has been associated with improved survival of pig organ xenografts in multiple different models. Here we evaluate the hypothesis that an increased human CD46 gene dose, through homozygosity or additional expression of a second hCPRP, is associated with increased protein expression and with improved protection from injury when GTKO lung xenografts are perfused with human blood.

Methods: Twenty three GTKO lungs heterozygous for human CD46 (GTKO.

Fibrinogen Concentrate for the Treatment of Thrombolysis-Associated Hemorrhage in Adult Ischemic Stroke Patients.

In patients with ischemic stroke who receive systemic recombinant tissue plasminogen activator (rt-PA), the risk of secondary hemorrhage is 1-7%. Fibrinogen supplementation with cryoprecipitate is recommended in patients with rt-PA-associated symptomatic hemorrhage. We examined whether fibrinogen concentrate can be used safely in this setting.

Electropolymerized hydrophilic coating on stainless steel for biomedical applications.

Current metal implants (e.g. stents) covered with drug-eluting coatings are not robust for long-term usage.

Selective CD28 Inhibition Modulates Alloimmunity and Cardiac Allograft Vasculopathy in Anti-CD154-Treated Monkeys.

Background: Selective CD28 inhibition is actively pursued as an alternative to B7 blockade using cytotoxic T lymphocyte antigen 4 Ig based on the hypothesis that the checkpoint immune regulators cytotoxic T lymphocyte antigen 4 and programmed death ligand 1 will induce tolerogenic immune signals. We previously showed that blocking CD28 using a monovalent nonactivating reagent (single-chain anti-CD28 Fv fragment linked to alpha-1 antitrypsin [sc28AT]) synergizes with calcineurin inhibitors in nonhuman primate (NHP) kidney and heart transplantation. Here, we explored the efficacy of combining a 3-week "induction" sc28AT treatment with prolonged CD154 blockade.

Clinical Disease after Cardiac Transplantation in a Cynomolgus Macaque ().

A cynomolgus macaque received a heterotopic cardiac allograft as part of a transplant study, with monoclonal antibodies targeted to specific immune costimulation molecules (CD154, CD28) but no traditional immunosuppressive therapy after surgery. Clinical anemia was detected on postoperative day (POD) 35 and had worsened (Hgb, 2.3 g/dL; Hct = 7.

Direct oral anticoagulants in patients with atrial fibrillation and renal impairment, extremes in weight, or advanced age.

A growing number of patients with an indication for stroke prevention in atrial fibrillation have kidney-, age-, or weight-related alterations in pharmacokinetics that affect dosing of direct oral anticoagulants. Because these patients were excluded from or comprised a small number of patients in clinical trials, there is a lack of evidence to guide clinicians. As a consequence, many patients do not receive oral anticoagulation despite a high risk for atrial fibrillation-related stroke.

Preemptive CD20+ B cell Depletion Attenuates Cardiac Allograft Vasculopathy in CD154-Treated Monkeys.

Background: Anti-CD154 monotherapy is associated with antidonor allo-antibody (Ab) elaboration, cardiac allograft vasculopathy (CAV), and allograft failure in preclinical primate cell and organ transplant models. In the context of calcineurin inhibitors (CNI), these pathogenic phenomena are delayed by preemptive "induction" B cell depletion.

Methods: αCD154 (IDEC-131)-treated cynomolgus monkey heart allograft recipients were given peritransplant rituximab (αCD20) alone or with rabbit antihuman thymocyte globulin.

Platelet sequestration and activation during GalTKO.hCD46 pig lung perfusion by human blood is primarily mediated by GPIb, GPIIb/IIIa, and von Willebrand Factor.

Background: Here, we ask whether platelet GPIb and GPIIb/IIIa receptors modulate platelet sequestration and activation during GalTKO.hCD46 pig lung xenograft perfusion.

Methods: GalTKO.

Evaluation of Warfarin Reversal with 4-Factor Prothrombin Complex Concentrate Compared to 3-Factor Prothrombin Complex Concentrate at a Tertiary Academic Medical Center.

Background: The U.S. Food and Drug Administration recently approved a four-factor prothrombin complex concentrate (4-PCC) for warfarin reversal.

Expression of human CD46 modulates inflammation associated with GalTKO lung xenograft injury.

Evaluation of lungs from GalTKO.hCD46 pigs, genetically modified to lack the galactose-α(1,3)-galactose epitope (GalTKO) and to express human CD46, a complement regulatory protein, has not previously been described. Physiologic, hematologic and biochemical parameters during perfusion with heparinized fresh human blood were measured for 33 GalTKO.

Pig-to-baboon liver xenoperfusion utilizing GalTKO.hCD46 pigs and glycoprotein Ib blockade.

Background: Although transplantation of genetically modified porcine livers into baboons has yielded recipient survival for up to 7 days, survival is limited by profound thrombocytopenia, which becomes manifest almost immediately after revascularization, and by subsequent coagulopathy. Porcine von Willebrand's factor (VWF), a glycoprotein that adheres to activated platelets to initiate thrombus formation, has been shown to constitutively activate human platelets via their glycoprotein Ib (GPIb) receptors. Here, we report our pig-to-primate liver xenoperfusion model and evaluate whether targeting the GPIb-VWF axis prevents platelet sequestration.

Premature formation of nucleolar channel systems indicates advanced endometrial maturation following controlled ovarian hyperstimulation.

Study Question: Is there a shift in the timing of nucleolar channel system (NCS) formation following controlled ovarian hyperstimulation (COH)?

Summary Answer: NCSs appear prematurely following COH compared with natural cycles.

What Is Known Already: During natural cycles, NCSs of endometrial epithelial cell (EEC) nuclei are exclusively present during the window of implantation and are uniformly distributed throughout the upper endometrial cavity.

Study Design, Size, Duration: Prospective two-cohort study.

Quantification of nucleolar channel systems: uniform presence throughout the upper endometrial cavity.

Objective: To determine the prevalence of nucleolar channel systems (NCSs) by uterine region, applying continuous quantification.

Design: Prospective clinical study.

Setting: Tertiary care academic medical center.

Selective CD28 blockade attenuates acute and chronic rejection of murine cardiac allografts in a CTLA-4-dependent manner.

Selective blockade of CD28 is a promising therapy to inhibit pathogenic alloimmunity. However, evaluation of this approach in transplantation has been very limited. Using a novel nonactivating single-chain Fv-based reagent (α28scFv), we have investigated the role of CD28 and cytotoxic T lymphocyte antigen 4 (CTLA-4) in a murine cardiac transplant model.

The nucleolar channel system reliably marks the midluteal endometrium regardless of fertility status: a fresh look at an old organelle.

Objective: To determine whether nucleolar channel systems (NCSs) in the midluteal endometrium are associated with overall fertility status and/or with unexplained infertility.

Design: Retrospective and prospective clinical studies.

Setting: Repository of stored specimens from prior multicenter study and private infertility center.

Hippocratic ideal, Faustian bargain and Damocles' sword: erosion of patient autonomy in obstetrics.

Respect for patient autonomy remains a foundational principle guiding the ethical practice of medicine-a mission first articulated by Hippocrates. Damocles, another figure from ancient Greece, provides a useful parable for describing performance under distress: Damocles loses his desire for opulence and power when he notices a sword dangling precariously above his head. Contemporary obstetricians deciding whether to forestall or impose major abdominal surgery on parturients entrusted to their care struggle valiantly in the chasm dividing Hippocratic idealism from the economic realism driven by the medicolegal sword of Damocles.

Egg freezing, procreative liberty, and ICSI: the double standards confronting elective self-donation of oocytes.

The consensus view among relevant professional societies opposing the offering of elective oocyte cryopreservation for potential future self-donation withstands neither clinical nor ethical scrutiny. The favorable risk-benefit ratio of this technology mandates both the prioritization of patient autonomy for informed women seeking to maximize-not guarantee-their chances of having genetically related children, and a justification for viewing egg freezing differently from intracytoplasmic sperm injection.

Sibling and self ovum donation for sisters with an intermediate FMR1 mutation: what's a program to do?

Objective: To increase awareness of the unique clinical and ethical considerations invoked by the request of a patient with premature ovarian failure (POF) and her nulliparous sister, both with intermediate-size mutations in fragile X mental retardation 1 (FMR1), to pursue sibling ovum donation.

Design: Case report.

Setting: Academic medical center.

Explained compared with unexplained fever in postoperative myomectomy and hysterectomy patients.

Objective: To confirm that fever with localized findings is less prevalent among febrile postoperative myomectomy patients than it is among hysterectomy patients.

Methods: Hospital records of 341 hysterectomy patients and 250 myomectomy patients were reviewed. Rate of overall febrile morbidity, proportion of fever with localized findings, proportion of febrile patients worked-up, and other perioperative parameters were recorded.

[Correlations between mental maturity and higher mental function in preschool children].

This communication presents the results of comparative study of 23 quantitative characteristics of the mental development of a child (the data of neuropsychological diagnosis of higher cortical functions by the procedure developed by I. F. Markovskaya, 1993) and 112 parameters of higher mental functions (perception, memory, assimilation and reproduction of rhythmic stimuli, behavioral strategy in the determined environment) recorded by a complex of microprocessor psychophysiological apparatuses, such as "Rhythmotest", "Mnemotest", and "Binatest".