New Imidazodiazepine Analogue, 5-(8-Bromo-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,5-a][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 GABAA 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. GABAAR binding occurred with a Ki of 150 nM, and only 3 of 41 screened binding sites produced inhibition ≥50% at 10 µM, and the potency to induce cytotoxicity was ≥240 mM. DS-II-73 was selective for α2/3/5- over that of α1-containing GABAARs. Oral exposure of plasma and brain of rats was more than sufficient to functionally impact GABAARs. Tonic convulsions in mice and lethality induced by pentylenetetrazol were suppressed by DS-II-73 after oral administration and latencies to clonic and tonic seizures were prolonged. Cortical slice preparations from a patient with pharmacoresistant epilepsy (mesial temporal lobe) showed decreases in the frequency of local field potentials by DS-II-73. As with KRM-II-81, the motor-impairing effects of DS-II-73 were low compared to diazepam. Molecular docking studies of DS-II-73 with the α1ß3γ2L-configured GABAAR showed low interaction with α1His102 that is suggested as a potential molecular mechanism for its low sedative side effects. These findings support the viability of DS-II-73 as a backup molecule for its ethynyl analogue, KRM-II-81, with the human tissue data providing translational credibility.

Evaluation of programmed cell death ligand 1 expression in a contemporary cohort of penile squamous cell carcinoma and its correlation with clinicopathologic and survival parameters: A study of 134 patients.

OBJECTIVES: Penile squamous cell carcinomas (PCs) are rare malignancies with a dismal prognosis in a metastatic setting; therefore, novel immunotherapeutic modalities are an unmet need. One such modality is the immune checkpoint molecule programmed cell death ligand 1 (PD-L1). We sought to analyze PD-L1 expression and its correlation with various clinicopathologic parameters in a contemporary cohort of 134 patients with PC. METHODS: A cohort of 134 patients with PC was studied for PD-L1 immunohistochemistry. The PD-L1 expression was evaluated using a combined proportion score with a cutoff of 1 or higher to define positivity. The results were correlated with various clinicopathologic parameters. RESULTS: Overall, 77 (57%) patients had positive PD-L1 expression. Significantly high PD-L1 expression was observed in high-grade tumors (P = .006). We found that 37% of human papillomavirus (HPV)-associated subtypes and 73% of other histotype tumors expressed PD-L1, while 63% of HPV-associated tumors and 27% of other histotype tumors did not (odds ratio, 1.35; P = .002 when compared for HPV-associated groups vs all others). Similarly, PD-L1-positive tumors had a 3.61-times higher chance of being node positive than PD-L1-negative tumors (P = .0009). In addition, PD-L1 high-positive tumors had a 5-times higher chance of being p16ink4a negative than PD-L1 low-positive tumors (P = .004). The PD-L1-positive tumors had a lower overall survival and cancer-specific survival than PD-L1-negative tumors. CONCLUSIONS: Overall, PD-L1 expression is associated with high-grade and metastatic tumors. Lower PD-L1 expression is observed more frequently in HPV-associated (warty or basaloid) subtypes than in other, predominantly HPV-independent types. As a result, PD-L1 positivity, including higher expression, portends lower overall and cancer-specific survival. These data provide a rational for further investigating PD-L1-based immunotherapeutics in PC.

Vascular effects of midazolam, flumazenil, and a novel imidazobenzodiazepine MP-III-058 on isolated rat aorta.

Hypotensive influences of benzodiazepines and other GABAA receptor ligands, recognized in clinical practice, seem to stem from the existence of "vascular" GABAA receptors in peripheral blood vessels, besides any mechanisms in the central and peripheral nervous systems. We aimed to further elucidate the vasodilatatory effects of ligands acting through GABAA receptors. Using immunohistochemistry, the rat aortic smooth muscle layer was found to express GABAA γ2 and α1-5 subunit proteins. To confirm the role of "vascular" GABAA receptors, we investigated the vascular effects of standard benzodiazepines, midazolam, and flumazenil, as well as the novel compound MP-III-058. Using two-electrode voltage clamp electrophysiology and radioligand binding assays, MP-III-058 was found to have modest binding but substantial functional selectivity for α5ß3γ2 over other αxß3γ2 GABAA receptors. Tissue bath assays revealed comparable vasodilatory effects of MP-III-058 and midazolam, both of which at 100 µmol/L concentrations had efficacy similar to prazosin. Flumazenil exhibited weak vasoactivity per se, but significantly prevented the relaxant effects of midazolam and MP-III-058. These studies indicate the existence of functional GABAA receptors in the rat aorta, where ligands exert vasodilatory effects by positive modulation of the benzodiazepine binding site, suggesting the potential for further quest for leads with optimized pharmacokinetic properties as prospective adjuvant vasodilators.

The electrocardiographic manifestations of pectus excavatum before and after surgical correction.

BACKGROUND: Pectus excavatum (PEx) can cause cardiopulmonary limitations due to cardiac compression and displacement. There is limited data on electrocardiogram (ECG) alterations before and after PEx surgical repair, and ECG findings suggesting cardiopulmonary limitations have not been reported. The aim of this study is to explore ECG manifestations of PEx before and after surgery including associations with exercise capacity. METHODS: A retrospective review of PEx patients who underwent primary repair was performed. ECGs before and after surgical correction were evaluated and the associations between preoperative ECG abnormalities and cardiopulmonary function were investigated. RESULTS: In total, 310 patients were included (mean age 35.1 ± 11.6 years). Preoperative ECG findings included a predominant negative P wave morphology in V1, and this abnormal pattern significantly decreased from 86.9% to 57.4% (p < 0.001) postoperatively. The presence of abnormal P wave amplitude in lead II (>2.5 mm) significantly decreased from 7.1% to 1.6% postoperatively (p < 0.001). Right bundle branch block (RBBB) (9.4% versus 3.9%, p < 0.001), rsr' patterns (40.6% versus 12.9%, p < 0.001), and T wave inversion in leads V1-V3 (62.3% vs 37.7%, p < 0.001) were observed less frequently after surgery. Preoperative presence of RBBB (OR = 4.8; 95%CI 1.1-21.6) and T wave inversion in leads V1-3 (OR = 2.3; 95%CI 1.3-4.2) were associated with abnormal results in cardiopulmonary exercise testings. CONCLUSION: Electrocardiographic abnormalities in PEx are frequent and can revert to normal following surgery. Preoperative RBBB and T wave inversion in leads V1-3 suggested a reduction in exercise capacity, serving as a marker for the need for further cardiovascular evaluation of these patients.

Development of an all-solid-state air-cooled high-power blue diode laser for metal processing.

We present the design and development of an all-solid-state (fluid/refrigerant-free) 100 W scale blue-laser system and show its applications in precision copper works. We combine powerful laser-diode arrays with Peltier chips on a compact laser head to achieve stable thermal and optical performance. Good agreement between the thermal simulation of the 3D laser head and experiments validates stable thermal performance. The laser system emits 40-100 W continuous wave at λ = 452.2 ± 2.5 nm with 98% power stability and ∼24% wall-plug efficiency inside a portable enclosure. This is the first, to the best of our knowledge, all-solid-state air-cooled laser with a 100 W class output. We achieved kW/cm2 intensity level on an mm-size focus with this source and demonstrated cutting, bending, and soldering copper on a battery pack. Furthermore, the copper-solder joints have nanoscale adhesion without cracks. Additionally, we unveil that 0.5-4 kW/cm2 intensity laser annealing scan makes copper strips mechanically resilient to withstand extreme loading cycles without nanoscale cracks.

Sex differences in minutiae frequencies of thumbprint with respect to dermatoglyphic patterns.

Abstract: The present study is an attempt to study the sex differences in minutiae frequencies of thumbprint with respect to dermatoglyphic patterns. A sample of 100 subjects (50 males and 50 females) were gathered from Shimla, Himachal Pradesh (North India). In regards to pattern type, maximum number of minutiae was present in loop pat-tern followed by whorls and least minutiae were in the arches in the right hand of both the sexes and left hand of females only, whereas in left hand of the males highest frequency of minutiae were noticed in whorls followed by loops and lowest in the arches, thereby indicating the lessened bimanual symmetry in males. It can be inferred from the present study that the simple pattern (arch) has less discontinuance in the regular flow of the ridges, while the complex patterns (loops and whorls) exhibited more interruptions in the dermal ridges.

Nanodiamonds enable femtosecond-processed ultrathin glass as a hybrid quantum sensor.

The quantum properties of fluorescent nanodiamonds offer great promise for fabricating quantum-enabled devices for physical applications. However, the nanodiamonds need to be suitably combined with a substrate to exploit their properties. Here, we show that ultrathin and flexible glass (thickness 30 microns) can be functionalized by nanodiamonds and nano-shaped using intense femtosecond pulses to design cantilever-based nanomechanical hybrid quantum sensors. Thus fabricated ultrathin glass cantilevers show stable optical, electronic, and magnetic properties of nitrogen-vacancy centers, including well-defined fluorescence with zero-phonon lines and optically detected magnetic resonance (ODMR) near 2.87 GHz. We demonstrate several sensing applications of the fluorescent ultrathin glass cantilever by measuring acoustic pulses, external magnetic field using Zeeman splitting of the NV centers, or CW laser-induced heating by measuring thermal shifting of ODMR lines. This work demonstrates the suitability of the femtosecond-processed fluorescent ultrathin glass as a new versatile substrate for multifunctional quantum devices.

Temporary hypoxemia at high altitude in an intensive care unit physician.

A 42-year-old pediatric intensive care unit physician traveled to Nepal and took a helicopter trip to Everest Base Camp. The helicopter reached an altitude of 5500 m during flight and descended at different destinations with varying altitudes. At Hotel Everest View at 3820 m, his oxygen saturation was 79%. He had mild tachypnea and deep breathing but was able to walk around, jump, and take photographs. He returned to Kathmandu (altitude, 1324 m) without using any supplemental oxygen during the entire trip. Based on calculations with the alveolar gas equation, he observed that he and his fellow passengers probably had hypoxemia during the trip. In summary, temporary hypoxemia associated with high altitude in healthy individuals without cardiorespiratory compromise may not require oxygen therapy. In contrast, intensive care unit patients who have respiratory failure may have similar oxygen saturation levels but may require oxygen therapy and mechanical ventilation. The oxygen saturation level must be interpreted in consideration of the clinical scenario before deciding about the need for oxygen therapy.

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 GABAA 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. Although all compounds were orally bioavailable, structural changes reduced the plasma and brain (FR-II-60 and KPP-III-51) exposures relative to KRM-II-81. Oral administration of each compound produced dose-dependent increases in the latency for both clonic and tonic seizures and the lethality induced by pentylenetetrazol (PTZ) in mice. Since KPP-III-34 produced the highest brain area under the curve (AUC) exposures, it was selected for further profiling. Oral administration of KPP-III-34 suppressed seizures in corneal-kindled mice, hippocampal paroxysmal discharges in mesial temporal lobe epileptic mice, and PTZ-induced convulsions in rats. Only transient sensorimotor impairment was observed in mice, and doses of KPP-III-34 up to 500 mg/kg did not produce impairment in rats. Molecular docking studies demonstrated that all compounds displayed a reduced propensity for binding to α1His102 compared with the sedating compound alprazolam; the bromine-substituted KPP-III-34 achieved the least interaction. Overall, these findings document the oral bioavailability and anticonvulsant efficacy of three novel analogs of KRM-II-81 with reduced sedative effects. SIGNIFICANCE STATEMENT: A new non-sedating compound, KRM-II-81, with reduced propensity for tolerance is moving into clinical development. Three new analogs were orally bioavailable, produced anticonvulsant effects in rodents, and displayed low sensorimotor impairment. KPP-III-34 demonstrated efficacy in models of pharmacoresistant epilepsy. Docking studies demonstrated a low propensity for compound binding to the α1His102 residue implicated in sedation. Thus, three additional structures have been added to the list of non-sedating imidazodiazepine anticonvulsants that could serve as backups in the clinical development of KRM-II-81.

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. In the present study, both compounds significantly prevented seizures in mice induced by 6 Hz (44 mA) electrical stimulation without significantly altering motoric function on a rotarod after intraperitoneal administration. Both compounds also significantly prevented clonic seizures, tonic seizures, and lethality induced by pentylenetetrazol in mice when given orally. D5-KRM-II-81 had a slightly longer duration of action against clonic and tonic seizures than KRM-II-81. Oral administration of 100 mg/kg of either KRM-II-81 or D5-KRM-II-81 was significantly less disruptive of sensorimotor function in mice than diazepam (5 mg/kg, p.o.). The present report documents that D5-KRM-II-81 represents another in this series of imidazodiazepines with anticonvulsant activity at doses that do not impair sensorimotor function.

Plasma concentration of orally administered amoxicillin and clindamycin in patients receiving haemodialysis.

OBJECTIVES: In the randomized controlled trial PANTHEM, the prophylactic effect of oral amoxicillin or clindamycin is investigated in patients receiving chronic haemodialysis (HD). However, data on plasma concentrations of these antibiotics during HD are sparse. This study aims to determine if the plasma concentration of amoxicillin and clindamycin is sufficient during HD after oral administration of amoxicillin and clindamycin at three different time intervals prior to the HD procedure. METHODS: Adult patients receiving chronic HD were investigated twice with an interval of at least 7 days starting with either a tablet of 500/125 mg amoxicillin/clavulanic acid or a tablet of 600 mg clindamycin. Patients were randomized to take the antibiotics either 30, 60 or 120 min prior to the HD procedure. Plasma antibiotic concentrations were measured at start, midway and at the end of HD. A lower threshold was set at 2.0 mg/L for amoxicillin and at 1.0 mg/L for clindamycin. In addition, a population pharmacokinetic (PK) analysis was performed, assessing PTA. RESULTS: In the amoxicillin cohort (n = 37), 84% of patients and 95% of all plasma amoxicillin concentrations were above or at the threshold throughout the dialysis procedure. In the clindamycin cohort (n = 33), all concentrations were above the threshold throughout the dialysis procedure. Further, in all patients, the mean plasma concentration of both amoxicillin and clindamycin across the HD period was well above the threshold. Finally, the PK model predicted a high PTA in the majority of patients. DISCUSSION: In patients on chronic HD, oral administration of amoxicillin/clavulanic acid (500/125 mg) or clindamycin (600 mg) within 30-120 min prior to HD leads to a sufficient prophylactic plasma concentration across the HD period.

Widely tunable XUV harmonics using double IR pulses.

Tunable attosecond pulses are necessary for various attosecond resolved spectroscopic applications, which can potentially be obtained through the tuning of high harmonic generation. Here we show theoretically, using the time-dependent Schrödinger equation and strong field approximation, a continuously tunable spectral shift of high-order harmonics by exploiting the interaction of two delayed identical infrared (IR) pulses within the single-atom response. The tuning spans more than twice the driving frequency (∼2ω) range, for several near-cutoff harmonics, with respect to only one control parameter: the change in delay between the two IR pulses. We show that two distinct mechanisms contribute to the spectral shift of the harmonic spectra. The dominant part of the spectral shift of the harmonics is due to the modulation of the central frequency of the composite IR-IR pulse with respect to delay. The second contribution comes from the non-adiabatic phase-shift of the recolliding electron wavepacket due to the change in amplitude of the subcycle electric field within the double pulse envelope. For optical few-cycle pulses this scheme can produce tunable attosecond pulse trains (APT), and in the single-cycle regime the same can be used for tuning isolated attosecond pulses (IAP). We quantify the dependence of tuning range and tuning rate on the laser pulse duration. We envision that the proposed scheme can be easily implemented with compact in-line setups for generating frequency tunable APT/IAP.

Hydrochloride Salt of the GABAkine KRM-II-81.

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 potentiator of GABAA 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. KRM-II-81·HCl was produced from the free base with anhydrous hydrochloric acid. The formation of the monohydrochloride salt was confirmed by X-ray crystallography, as well as 1H NMR and 13C NMR analyses. High water solubility and a lower partition coefficient (octanol/water) were exhibited by KRM-II-81·HCl as compared to the free base. Oral administration of either KRM-II-81·HCl or the free base resulted in high concentrations in the brain and plasma of rats. Oral dosing in mice significantly increased the latency to both clonic and tonic convulsions and decreased pentylenetetrazol-induced lethality. The increased water solubility of the HCl salt enables intravenous dosing and the potential for higher concentration formulations compared with the free base without impacting anticonvulsant potency. Thus, KRM-II-81·HCl adds an important new compound to facilitate the development of these imidazodiazepines for clinical evaluation.

Clinical investigations of compounds targeting metabotropic glutamate receptors.

Pharmacological modulation of glutamate has long been considered to be of immense therapeutic utility. The metabotropic glutamate receptors (mGluRs) are potential targets for safely altering glutamate-driven excitation. Data support the potential therapeutic use of mGluR modulators in the treatment of anxiety, depression, schizophrenia, and other psychiatric disorders, pain, epilepsy, as well as neurodegenerative and neurodevelopmental disorders. For each of the three mGluR groups, compounds have been constructed that produce either potentiation or functional blockade. PET ligands for mGlu5Rs have been studied in a range of patient populations and several mGlu5R antagonists have been tested for potential efficacy in patients including mavoglurant, diploglurant, basimglurant, GET 73, and ADX10059. Efficacy with mGlu5R antagonists has been reported in trials with patients with gastroesophageal reflux disease; data from patients with Parkinson's disease or Fragile X syndrome have not been as robust as hoped. Fenobam was approved for use as an anxiolytic prior to its recognition as an mGlu5R antagonist. mGlu2/3R agonists (pomaglumated methionil) and mGlu2R agonists (JNJ-40411813, AZD 8529, and LY2979165) have been studied in patients with schizophrenia with promising but mixed results. Antagonists of mGlu2/3Rs (decoglurant and TS-161) have been studied in depression where TS-161 has advanced into a planned Phase 2 study in treatment-resistant depression. The Group III mGluRs are the least developed of the mGluR receptor targets. The mGlu4R potentiator, foliglurax, did not meet its primary endpoint in patients with Parkinson's disease. Ongoing efforts to develop mGluR-targeted compounds continue to promise these glutamate modulators as medicines for psychiatric and neurological disorders.

Atrial Arrhythmia Ablation in Patients With D-Transposition of the Great Arteries and Atrial Switch.

BACKGROUND: Patients with D-transposition of the great arteries and atrial switch have a high incidence of atrial arrhythmias. We sought to analyze the arrhythmia substrate, ablation strategies, and outcomes for catheter ablation in this population. METHODS: An in-depth analysis of all clinical and procedural data in patients with D-transposition of the great arteries, atrial baffles, and atrial arrhythmia ablation was performed. RESULTS: A cohort of 32 patients (72% male, mean age 38±7 years) underwent ablation for non-AV nodal reentrant tachycardia atrial arrhythmias, and 4 patients underwent AV nodal reentrant tachycardia ablation. Cavotricuspid isthmus flutter (CTI-flutter) was the most common arrhythmia, encountered in 75% of patients, followed by scar-related intraatrial reentrant tachycardia (non-CTI intraatrial reentrant tachycardia, 53%) and focal atrial tachycardia (focal atrial tachycardia, 6%). Among the 32 patients, 26 underwent 31 procedures at our institution. For patients with prior outside intervention, the index ablation at our institution revealed CTI-dependent flutter in 3/5 cases. However, redo ablation after an index ablation with demonstrated bidirectional CTI block revealed different/new arrhythmia substrates (80% non-CTI intraatrial reentrant tachycardia, 40% focal atrial tachycardia). Achieving bidirectional block across the CTI often required ablating on both sides of the baffle (retroaortic access, 81%; using a baffle leak, 11.5%; or transbaffle puncture, 7.7%). Combined approaches were necessary in 19% to reach the critical tissue. Acute procedural success was 81%, and recurrence was documented in 58% of patients. Despite recurrence, clinical arrhythmia burden was significantly reduced post-ablation (P<0.001), with rare episodes, amenable to antiarrhythmic therapy. Redo ablation was required in 5 (19%) patients and uncovered new arrhythmia substrates. AV nodal reentrant tachycardia ablation also required transbaffle approaches in 3/4 patients. CONCLUSIONS: CTI-dependent flutter was the most common arrhythmia in patients with Dextro-Transposition of the Great Arteries and atrial switch. Transbaffle approaches were often necessary, and, provided that bidirectional CTI block was achieved at the index ablation, late recurrence was due to different arrhythmia mechanisms. Despite recurrence, ablation was associated with significant clinical improvement.

Attosecond stable dispersion-free delay line for easy ultrafast metrology.

We demonstrate a dispersion-free wavefront splitting attosecond resolved interferometric delay line for easy ultrafast metrology of broadband femtosecond pulses. Using a pair of knife-edge prisms, we symmetrically split and later recombine the two wavefronts with a few tens of attosecond resolution and stability and employ a single-pixel analysis of interference fringes with good contrast using a phone camera without any iris or nonlinear detector. Our all-reflective delay line is theoretically analyzed and experimentally validated by measuring 1st and 2nd order autocorrelations and the SHG-FROG trace of a NIR femtosecond pulse. Our setup is compact, offers attosecond stability with flexibility for independent beam-shaping of the two arms. Furthermore, we suggest that our compact and in-line setup can be employed for attosecond resolved pump-probe experiments of matter with few-cycle pulses.

Ultrathin picoscale white light interferometer.

White light interferometry is a well established technique with diverse precision applications, however, the conventional interferometers such as Michelson, Mach-Zehnder or Linnik are large in size, demand tedious alignment for obtaining white light fringes, require noise-isolation techniques to achieve sub-nanometric stability and importantly, exhibit unbalanced dispersion causing uncertainty in absolute zero delay reference. Here, we demonstrate an ultrathin white light interferometer enabling picometer resolution by exploiting the wavefront division of a broadband incoherent light beam after transmission through a pair of micrometer thin identical glass plates. Spatial overlap between the two diffracted split wavefronts readily produce high-contrast and stable white light fringes, with unambiguous reference to absolute zero path-delay position. The colored fringes evolve when one of the ultrathin plates is rotated to tune the interferometer with picometric resolution over tens of µm range. Our theoretical analysis validates formation of fringes and highlights self-calibration of the interferometer for picoscale measurements. We demonstrate measurement of coherence length of several broadband incoherent sources as small as a few micrometer with picoscale resolution. Furthermore, we propose a versatile double-pass configuration using the ultrathin interferometer enabling a sample cavity for additional applications in probing dynamical properties of matter.

Sleep Apnea Screening in Children With Sickle Cell Anemia.

BACKGROUND: Screening for obstructive sleep apnea (OSA) is recommended by current guidelines in children with sickle cell anemia (SCA), but no specific approach is described. The Pediatric Sleep Questionnaire (PSQ) is a validated detection tool for OSA in children. We assessed the utility of PSQ to screen for OSA in children with concomitant SCA and snoring. MATERIALS AND METHODS: A prospective study, in children 4 to 18 years old with SCA. Subjects were assessed for snoring and PSQ administered at the same visit. All children with snoring were then referred for polysomnography. RESULTS: A total of 106 subjects were screened. Habitual snoring prevalence was 51/106 (48.1%). In the snoring group, OSA was detected in 83.9% (apnea-hypopnea index [AHI] ≥1.0/h) and 22.6% (AHI ≥5.0/h), respectively. Sensitivity and specificity of PSQ in children with snoring was 46.2% and 20.0% (AHI ≥1.0/h), and 57.1% and 50.0% (AHI ≥5.0/h), respectively. Physician assessment for snoring had a high sensitivity of 70.3% but low specificity of 58.4% (AHI ≥1.0/h), and 87.5% and 41.5% (AHI ≥5.0/h), respectively. CONCLUSION: PSQ is a poor screening tool for detection of OSA in those children with SCA who snore. Physician assessment for snoring could however be an initial approach before polysomnography.

Completion of the Total Synthesis of Several Bioactive Sarpagine/Macroline Alkaloids including the Important NF-κB Inhibitor N4-Methyltalpinine.

The unification of the general synthetic strategy regarding the important and emerging group of C-19 methyl-substituted sarpagine/macroline alkaloids has culminated in the completion of the total synthesis of several bioactive alkaloids. Key transformations include an ACE-Cl mediated late-stage N(4)-demethylation and an anhydrous acid-mediated intramolecular quaternary hemiaminal formation between a tertiary amine and an aldehyde function to allow efficient access to several biologically important alkaloids from this group. Herein, the enantiospecific total synthesis of the first known sarpagine/macroline alkaloid with NF-κB inhibitory activity, N(4)-methyltalpinine (as a chloride salt), as well as the anticancer alkaloids talpinine, O-acetyltalpinine, and macrocarpines F-G, are described.

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. Incubation of KRM-II-81 in hepatocytes revealed sites of potential metabolism on the oxazole and the diazepine rings. These sites were targeted in the design of a deuterated analog (D5-KRM-II-81) that could be evaluated as a potentially longer-acting analog. In contrast to computer predictions, peak plasma concentrations of D5-KRM-II-81 in rats were not significantly greater than those produced by KRM-II-81 after oral administration. Furthermore, brain disposition of KRM-II-81 was higher than that of D5-KRM-II-81. The half-life of the two compounds in either plasma or brain did not statistically differ from one another but the tmax for D5-KRM-II-81 occurred slightly earlier than for KRM-II-81. Non-metabolic considerations might be relevant to the lack of increases in exposure by D5-KRM-II-81. Alternative sites of metabolism on KRM-II-81, not targeted by the current deuteration process, are also possible. Despite its lack of augmented exposure, D5-KRM-II-81, like KRM-II-81, significantly prevented seizures induced by pentylenetetrazol when given orally. The present findings introduce a new orally active anticonvulsant GABAkine, D5-KRM-II-81.