Characterizing left ventricular systolic dysfunction in sickle cell disease: three contrasting case reports.

Background: Left ventricular systolic dysfunction (LVSD) is an uncommon but life-threatening complication of sickle cell disease (SCD), with poorly characterized aetiology. We present three SCD patients with LVSD due to different underlying mechanisms. Case summary: The first case describes rapid deterioration in LV function secondary to severe cardiac iron overload in a 37-year-old female with poor chelation compliance after 10 years of top-up transfusions for SCD. The second case is a severe non-ischaemic dilated cardiomyopathy (DCM) in a 42-year-old SCD patient with longstanding sickle nephropathy and hypertension. The final case demonstrates severe LVSD with large transmural infarcts (ischaemic DCM) in the absence of epicardial coronary disease in a 52-year-old SCD patient. Discussion: This case series presents the first attempt to characterize the aetiology of LVSD in SCD. We identified three phenotypes: iron-overload cardiomyopathy, non-ischaemic DCM, and ischaemic DCM. These contrasting cases highlight the significance of understanding the underlying pathology in determining individualized treatment plans for these high-risk patients. We discuss the role of cardiac MRI (CMR) in characterizing LV dysfunction, and we believe that this case series will form the basis of prospective studies to further delineate the pathophysiology of LVSD in SCD.

Chemical composition and toxicity of commercial Mentha spicata and Eucalyptus citriodora essential oils on Culex quinquefasciatus and non-target insects.

Current vector control strategies based on synthetic chemicals are not eco-friendly against non-target organisms; hence, alternative approaches are highly required. Commercially purchased oil of Mentha spicata (Spearmint) and Eucalyptus citriodora (Citriodora) were examined against the medical pest Cx. quinquefasciatus (Say) and their non-toxicity on the aquatic species was evaluated. Chemical screening with gas chromatography coupled with mass spectrometry (GC-MS) analysis revealed a total of 14 and 11 compounds in Citriodora and Spearmint oils, respectively, with the highest peak (%) at carvone (70.44%) and isopulegol (30.4%). The larvicidal activity on the fourth instar larvae of Cx. quinquefasciatus showed dose-dependent mortality and significance at a 100 ppm concentration 48 h post-treatment with Citriodora (76.4%, P ≤ 0.001) and Spearmint (100%, P ≤ 0.001). Additionally, the photomicrograph of the fourth instar larvae revealed significant physical abnormalities in the head and midgut tissues post-exposure to Spearmint and Citriodora oils. Moreover, the histological assay revealed severe damage in the epithelial cells and gut lumen 2 to 24 h post-treatment. The repellency percentage of adult Culex mosquitoes was prominent across both oils at 150 ppm 210 min post-exposure. Non-target toxicity on the aquatic predator showed both essential oils (Spearmint oil (17.2%) and Citriodora oil (15.2%)) are safer at the maximum treatment (200 ppm) compared to temephos (75.4% at 1 ppm). The in silico screening of phyto-compounds derived by both essential oils with BeeTox (online server) showed no contact toxicity to the honey bee Apis mellifera. Overall, the present research revealed that Spearmint and Citriodora essential oils and their active phyto-compounds were toxic to Cx. quinquefasciatus and harmless to the aquatic predator and honey bee.

Pitch discrimination in electric hearing with inconsistent and consistent amplitude-modulation and inter-pulse rate cues.

Users of cochlear implants (CIs) struggle in situations that require selective hearing to focus on a target source while ignoring other sources. One major reason for that is the limited access to timing cues such as temporal pitch or interaural time differences (ITDs). Various approaches to improve timing-cue sensitivity while maintaining speech understanding have been proposed, among them inserting extra pulses with short inter-pulse intervals (SIPIs) into amplitude-modulated (AM) high-rate pulse trains. Indeed, SIPI rates matching the naturally occurring AM rates improve pitch discrimination. For ITD, however, low SIPI rates are required, potentially mismatching the naturally occurring AM rates and thus creating unknown pitch effects. In this study, we investigated the perceptual contribution of AM and SIPI rate to pitch discrimination in five CI listeners and with two AM depths (0.1 and 0.5). Our results show that the SIPI-rate cue generally dominated the percept for both consistent and inconsistent cues. When tested with inconsistent cues, also the AM rate contributed, however, at the large AM depth only. These findings have implications when aiming at jointly improving temporal-pitch and ITD sensitivity in a future mixed-rate stimulation approach.

Developmental Transcriptome Analysis of Red-Spotted Apollo Butterfly, Parnassius bremeri.

Parnassius bremeri (P. bremeri), a member of the genus Snow Apollo in the swallowtail family (Papilionidae), is a high alpine butterfly that lives in Russia, Korea, and China. It is an endangered wildlife (Class I) in South Korea and is a globally endangered species. The lack of transcriptomic and genomic resources of P. bremeri significantly hinders the study of its population genetics and conservation. The detailed information of the developmental stage-specific gene expression patterns of P. bremeri is of great demand for its conservation. However, the molecular mechanism underlying the metamorphic development of P. bremeri is still unknown. In the present study, the differentially expressed genes (DEGs) across the metamorphic developmental stages were compared using high-throughput transcriptome sequencing. We identified a total of 72,161 DEGs from eight comparisons. GO enrichment analysis showed that a range of DEGs were responsible for cuticle development and the melanin biosynthetic pathway during larval development. Pathway analysis suggested that the signaling pathways, such as the Wnt signaling pathway, hedgehog signaling pathway and Notch signaling pathway, are regulated during the developmental stages of P. bremeri. Furthermore, sensory receptors were also activated, especially during the larval to adult transition stage. Collectively, the results of this study provide a preliminary foundation and understanding of the molecular mechanism in their transcriptomes for further research on the metamorphic development of P. bremeri.

Identification of Novel Ribonucleotide Reductase Inhibitors for Therapeutic Application in Bile Tract Cancer: An Advanced Pharmacoinformatics Study.

Biliary tract cancer (BTC) is constituted by a heterogeneous group of malignant tumors that may develop in the biliary tract, and it is the second most common liver cancer. Human ribonucleotide reductase M1 (hRRM1) has already been proven to be a potential BTC target. In the current study, a de novo design approach was used to generate novel and effective chemical therapeutics for BTC. A set of comprehensive pharmacoinformatics approaches was implemented and, finally, seventeen potential molecules were found to be effective for the modulation of hRRM1 activity. Molecular docking, negative image-based ShaEP scoring, absolute binding free energy, in silico pharmacokinetics, and toxicity assessments corroborated the potentiality of the selected molecules. Almost all molecules showed higher affinity in comparison to gemcitabine and naphthyl salicylic acyl hydrazone (NSAH). On binding interaction analysis, a number of critical amino acids was found to hold the molecules at the active site cavity. The molecular dynamics (MD) simulation study also indicated the stability between protein and ligands. High negative MM-GBSA (molecular mechanics generalized Born and surface area) binding free energy indicated the potentiality of the molecules. Therefore, the proposed molecules might have the potential to be effective therapeutics for the management of BTC.

Identification of Potential Cytochrome P450 3A5 Inhibitors: An Extensive Virtual Screening through Molecular Docking, Negative Image-Based Screening, Machine Learning and Molecular Dynamics Simulation Studies.

Cytochrome P450 3A5 (CYP3A5) is one of the crucial CYP family members and has already proven to be an important drug target for cardiovascular diseases. In the current study, the PubChem database was screened through molecular docking and high-affinity molecules were adopted for further assessment. A negative image-based (NIB) model was used for a similarity search by considering the complementary shape and electrostatics of the target and small molecules. Further, the molecules were segregated into active and inactive groups through six machine learning (ML) matrices. The active molecules found in each ML model were used for in silico pharmacokinetics and toxicity assessments. A total of five molecules followed the acceptable pharmacokinetics and toxicity profiles. Several potential binding interactions between the proposed molecules and CYP3A5 were observed. The dynamic behavior of the selected molecules in the CYP3A5 was explored through a molecular dynamics (MD) simulation study. Several parameters obtained from the MD simulation trajectory explained the stability of the protein-ligand complexes in dynamic states. The high binding affinity of each molecule was revealed by the binding free energy calculation through the MM-GBSA methods. Therefore, it can be concluded that the proposed molecules might be potential CYP3A5 molecules for therapeutic application in cardiovascular diseases subjected to in vitro/in vivo validations.

Screening of ß1- and ß2-Adrenergic Receptor Modulators through Advanced Pharmacoinformatics and Machine Learning Approaches.

Cardiovascular diseases (CDs) are a major concern in the human race and one of the leading causes of death worldwide. ß-Adrenergic receptors (ß1-AR and ß2-AR) play a crucial role in the overall regulation of cardiac function. In the present study, structure-based virtual screening, machine learning (ML), and a ligand-based similarity search were conducted for the PubChem database against both ß1- and ß2-AR. Initially, all docked molecules were screened using the threshold binding energy value. Molecules with a better binding affinity were further used for segregation as active and inactive through ML. The pharmacokinetic assessment was carried out on molecules retained in the above step. Further, similarity searching of the ChEMBL and DrugBank databases was performed. From detailed analysis of the above data, four compounds for each of ß1- and ß2-AR were found to be promising in nature. A number of critical ligand-binding amino acids formed potential hydrogen bonds and hydrophobic interactions. Finally, a molecular dynamics (MD) simulation study of each molecule bound with the respective target was performed. A number of parameters obtained from the MD simulation trajectories were calculated and substantiated the stability between the protein-ligand complex. Hence, it can be postulated that the final molecules might be crucial for CDs subjected to experimental validation.

Temporal-pitch sensitivity in electric hearing with amplitude modulation and inserted pulses with short inter-pulse intervals.

Listeners with cochlear implants (CIs) typically show poor sensitivity to the temporal-envelope pitch of high-rate pulse trains. Sensitivity to interaural time differences improves when adding pulses with short inter-pulse intervals (SIPIs) to high-rate pulse trains. In the current study, monaural temporal-pitch sensitivity with SIPI pulses was investigated for six CI listeners. Amplitude-modulated single-electrode stimuli, representing the coding of the fundamental frequency (F0) in the envelope of a high-rate carrier, were used. Two SIPI-insertion approaches, five modulation depths, two typical speech-F0s, and two carrier rates were tested. SIPI pulses were inserted either in every amplitude-modulation period (full-rate SIPI) to support the F0 cue or in every other amplitude-modulation period (half-rate SIPI) to circumvent a potential rate limitation at higher F0s. The results demonstrate that full-rate SIPI pulses improve temporal-pitch sensitivity across F0s and particularly at low modulation depths where envelope-pitch cues are weak. The half-rate SIPI pulses did not circumvent the limitation and further increased variability across listeners. Further, no effect of the carrier rate was found. Thus, the SIPI approach appears to be a promising approach to enhance CI listeners' access to temporal-envelope pitch cues at pulse rates used clinically.

Improving Interaural Time Difference Sensitivity Using Short Inter-pulse Intervals with Amplitude-Modulated Pulse Trains in Bilateral Cochlear Implants.

Interaural time differences (ITDs) at low frequencies are important for sound localization and spatial speech unmasking. These ITD cues are not encoded in commonly used envelope-based stimulation strategies for cochlear implants (CIs) using high pulse rates. However, ITD sensitivity can be improved by adding extra pulses with short inter-pulse intervals (SIPIs) in unmodulated high-rate trains. Here, we investigated whether this improvement also applies to amplitude-modulated (AM) high-rate pulse trains. To this end, we systematically varied the temporal position of SIPI pulses within the envelope cycle (SIPI phase), the fundamental frequency (F0) of AM (125 Hz and 250 Hz), and AM depth (from 0.1 to 0.9). Stimuli were presented at an interaurally place-matched electrode pair at a reference pulse rate of 1000 pulses/s. Participants performed an ITD-based left/right discrimination task. SIPI insertion resulted in improved ITD sensitivity throughout the range of modulation depths and for both male and female F0s. The improvements were largest for insertion at and around the envelope peak. These results are promising for conveying salient ITD cues at high pulse rates commonly used to encode speech information.

Renal SGLT mRNA expression in human health and disease: a study in two cohorts.

Pharmacological Na+-glucose linked cotransporter (SGLT)2 inhibition is being examined as a renal protection strategy in nondiabetic chronic kidney disease. We quantified renal SGLT mRNA expression in healthy controls (HC), glomerulonephritis (GN), and diabetic kidney disease (DKD) to identify differences in expression across a spectrum of renal diseases. mRNA expression of SGLT1 and SGLT2 in renal tubules and glomeruli, obtained using microdissection and microarray techniques, was evaluated in two large cohorts. The European Renal cDNA bank included HC, GN, and DKD (98 glomeruli and 93 tubulointerstitium). The Nephrotic Syndrome Study Network cohort included 124 adults with membranous nephropathy, minimal change disease, focal segmental glomerulosclerosis, and IgA nephropathy. Within the European Renal cDNA bank, SGLT2 tubular and glomerular log2 mRNA expression significantly differed across HC, GN, and DKD (P = 0.0009 and P = 0.0004), with the highest expression in HC. Within the Nephrotic Syndrome Study Network, there were no differences in SGLT log2 mRNA expression across GN subtypes. Tubular SGLT2 log2 mRNA expression positively correlated with estimated glomerular filtration rate (by the Modification of Diet in Renal Disease Study equation) and glycated hemoglobin (r = 0.33 and 0.34, P < 0.05) and inversely correlated with interstitial fibrosis (r = -0.21, P < 0.05). In conclusion, SGLT2 mRNA expression was lower in DKD compared with HC or GN and inversely related to interstitial fibrosis. The relationships between SGLT mRNA, protein expression, and transporter activity require further elucidation.

Variation of High-Sensitivity Troponin T Results in Patients Undergoing Continuous Renal Replacement Therapy.

BACKGROUND: Cardiac troponins are the preferred biomarker to diagnose myocardial injury. Complicating the interpretation of serial troponins in patients with end-stage renal disease, it has been shown that the hemodialysis procedure results in a small but significant decline in high-sensitivity cardiac troponins (hs-cTnT). This raises the possibility that continuous renal replacement therapy (CRRT) might similarly alter cardiac troponin levels and affect their interpretation when cardiac ischemia is being considered. OBJECTIVE: We sought to determine the effect of CRRT on hs-cTnT levels over time in a group of patients without active myocardial injury. DESIGN: Prospective, observational study. SETTING: Single tertiary care hospital, Montreal, Quebec. PATIENTS: Ten critically ill patients with acute kidney injury (AKI) undergoing CRRT. Cardiac ICU (intensive care unit) patients and acute coronary syndrome patients were excluded from the study. The CRRT prescription was at the discretion of the treating intensivist and relatively high doses were used in this study. MEASUREMENTS: The hs-cTnT levels were drawn pre-CRRT, within 6 hours of initiation, and approximately every 6 hours thereafter along with routine CRRT blood work. METHODS: Changes in hs-cTnT, creatinine, and albumin levels were recorded over the course of CRRT. Mean change in serum analyte concentration and 95% confidence interval was determined for specified time intervals relative to baseline, with paired t tests used to determine statistical significance. RESULTS: Among the 10 patients included in the study, the cause of AKI was primarily acute tubular necrosis from septic shock or hemorrhagic shock. Compared with baseline hs-cTnT levels prior to CRRT initiation, mean hs-cTnT level fell by 42% at 5 to 10 hours post-CRRT initiation, followed by a plateauing of levels for the duration of time on CRRT. LIMITATIONS: Single-center study only applicable to hs-cTnT assay. CONCLUSIONS: This study demonstrates a significant decrease in hs-cTnT within 5 to 10 hours of CRRT initiation. This suggests that interpretation of cardiac troponin changes during CRRT must take into consideration the timing of dialysis initiation relative to the time of sample collection.

CONTEXTE: Les troponines cardiaques constituent le biomarqueur de choix pour diagnostiquer les lésions myocardiques. L'hémodialyse, qui provoque un léger et significatif déclin des troponines cardiaques à haute sensibilité (hs-cTnT), complique leur interprétation chez les patients atteints d'insuffisance rénale terminale. Cette observation suggère que la thérapie de remplacement rénal continue (TRRC) pourrait modifier similairement les taux de troponines cardiaques et affecter leur interprétation lorsqu'une ischémie cardiaque est examinée. OBJECTIF: Nous souhaitions évaluer l'effet dans le temps d'une TRRC sur les taux de hs-cTnT chez des patients sans lésions myocardiques actives. TYPE D'ÉTUDE: Une étude observationnelle prospective. CADRE: Un hôpital de soins tertiaires de Montréal (Québec). SUJETS: Un groupe de dix patients gravement malades, souffrant d'insuffisance rénale aiguë (IRA) et suivant une TRRC. Les patients hospitalisés aux soins intensifs cardiaques ou atteints d'un syndrome coronarien aigu ont été exclus. La prescription d'une TRRC était laissée à la discrétion du médecin intensiviste traitant et des doses relativement élevées ont été administrées au cours de l'étude. MESURES: Les taux de hs-cTnT ont été mesurés conjointement aux prélèvements sanguins de routine requis pour une TRRC; soit avant son initiation, dans les six heures suivantes, puis aux six heures environ par la suite. MÉTHODOLOGIE: Les variations des taux de hs-cTnT, de créatinine et d'albumine ont été colligées pour la durée de la TRRC. La variation moyenne des concentrations d'analytes sériques par rapport aux valeurs initiales et les intervalles de confiance à 95 % ont été déterminés pour des périodes de temps précises. Des tests t couplés ont été employés pour établir la signification statistique des résultats. RÉSULTATS: Chez les patients examinés, l'IRA était principalement due à une nécrose tubulaire aiguë causée par un choc septique ou hémorragique. Le taux moyen de hs-cTnT a chuté de 42 % dans les 5 à 10 heures suivant l'initiation de la TRRC par rapport aux valeurs observées pré-TRRC. Les taux ont ensuite plafonné pour la durée de la TRRC. LIMITES: Il s'agit d'une étude monocentrique applicable uniquement aux mesures de hs-cTnT. CONCLUSION: Cette étude démontre une baisse significative des hs-cTnT dans les 5 à 10 heures suivant l'initiation d'une TRRC. Ce résultat suggère que l'interprétation des variations observées dans les taux de troponines cardiaques au cours d'une TRRC devrait tenir compte du moment où l'échantillon est prélevé par rapport à son initiation.

Introducing Short Interpulse Intervals in High-Rate Pulse Trains Enhances Binaural Timing Sensitivity in Electric Hearing.

Common envelope-based stimulation strategies for cochlear implants (CIs) use relatively high carrier rates in order to properly encode the speech envelope. For such rates, CI listeners show poor sensitivity to interaural time differences (ITDs), which are important for horizontal-plane sound localization and spatial unmasking of speech. Based on the findings from previous studies, we predicted that ITD sensitivity can be enhanced by including pulses with short interpulse intervals (SIPIs), to a 1000-pulses-per-second (pps) reference pulse train. We measured the sensitivity of eight bilateral CI listeners to ITD while systematically varying both the rate at which SIPIs are introduced ("SIPI rate") and the time interval between the two pulses forming a SIPI ("SIPI fraction"). Results showed largely enhanced ITD sensitivity relative to the reference condition, with the size of the improvement increasing with decreasing SIPI rate and decreasing SIPI fraction. For the lowest SIPI fraction, insertion of extra pulses brought ITD sensitivity to the level measured for low-rate pulse trains with rates matching the SIPI rates. The results appear promising for the goal of enhancing ITD sensitivity with envelope-based CI strategies by inserting SIPI pulses at strategic times in speech stimuli.

Interaural attention modulates outer hair cell function.

Mounting evidence suggests that auditory attention tasks may modulate the sensitivity of the cochlea by way of the corticofugal and the medial olivocochlear (MOC) efferent pathways. Here, we studied the extent to which a separate efferent tract, the 'uncrossed' MOC, which functionally connects the two ears, mediates inter-aural selective attention. We compared distortion product otoacoustic emissions (DPOAEs) in one ear with binaurally presented primaries, using an intermodal target detection task in which participants were instructed to report the occurrence of brief target events (visual changes, tones). Three tasks were compared under identical physical stimulation: (i) report brief tones in the ear in which DPOAE responses were recorded; (ii) report brief tones presented to the contralateral, non-recorded ear; and (iii) report brief phase shifts of a visual grating at fixation. Effects of attention were observed as parallel shifts in overall DPOAE contour level, with DPOAEs relatively higher in overall level when subjects ignored the auditory stimuli and attended to the visual stimulus, compared with both of the auditory-attending conditions. Importantly, DPOAE levels were statistically lowest when attention was directed to the ipsilateral ear in which the DPOAE recordings were made. These data corroborate notions that top-down mechanisms, via the corticofugal and medial efferent pathways, mediate cochlear responses during intermodal attention. New findings show attending to one ear can significantly alter the physiological response of the contralateral, unattended ear, probably through the uncrossed-medial olivocochlear efferent fibers connecting the two ears.

A putatively novel form of spontaneous coordination in neural activity.

We simultaneously recorded local field potentials from three sites along the olfactory-entorhinal axis in rats lightly anesthetized with isoflurane, as part of another experiment. While analyzing the initial data from that experiment with spectrograms, we discovered a potentially novel form of correlated neural activity, with near-simultaneous occurrence across the three widely separated brain sites. After validating their existence further, we named these events Synchronous Frequency Bursts (SFBs). Here we report our initial investigations into their properties and their potential functional significance. In Experiment 1, we found that SFBs have highly regular properties, consisting of brief (approximately 250 ms), high amplitude bursts of LFP energy spanning frequency ranges from the delta band (1-4 Hz) to at least the low gamma band (30-50 Hz). SFBs occurred almost simultaneously across recording sites, usually with onsets <25 ms apart, and there was no clear pattern of temporal leading or lagging among the sites. While the SFBs had fairly typical, exponentially decaying power spectral density plots, their coherence structure was unusual, with high peaks in several narrow frequency ranges and little coherence in other bands. In Experiment 2, we found that SFBs occurred far more often under light anesthesia than deeper anesthetic states, and were especially prevalent as the animals regained consciousness. Finally, in Experiment 3 we showed that SFBs occur simultaneously at a significant rate across brain sites from putatively different functional subsystems--olfactory versus motor pathways. We suggest that SFBs do not carry information per se, but rather, play a role in coordinating activity in different frequency bands, potentially brain-wide, as animals progress from sleep or anesthesia toward full consciousness.

Concurrent B-cell chronic lymphocytic leukemia and multiple myeloma treated successfully with lenalidomide.

The occurrence of multiple myeloma and chronic lymphocytic leukemia in the same patient is very uncommon. The immunomodulatory agent lenalidomide has been shown to have high response rates in multiple myeloma and appears to be quite active in advanced CLL. We report two patients with concurrent CLL and MM who were both treated successfully with lenalidomide.

Trastuzumab-induced hepatotoxicity.

OBJECTIVE: To report a case of probable trastuzumab-induced hepatotoxicity. CASE SUMMARY: A 54-year-old African American woman presented with locally advanced right-sided breast cancer that was found to be strongly positive for human epidermal growth factor receptor 2 (HER2) by fluorescence in situ hybridization. She was treated with neoadjuvant chemotherapy with 4 cycles of dose-dense doxorubicin and cyclophosphamide. Laboratory test results, including liver function tests (LFTs), were normal at that time. Therapy consisting of weekly doses of paclitaxel 80 mg/m(2) and a loading dose of trastuzumab 4 mg/kg for the first week and 2 mg/kg weekly thereafter was started. Alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase levels began to increase after the initial dose; the levels were significantly elevated after the fifth cycle. Paclitaxel was withheld, and trastuzumab was continued, as there were no prior reported cases of trastuzumab-induced hepatotoxicity at that time. Other possible etiologies for the elevated enzyme levels, including metastasis to the liver, were excluded. The patient continued to receive trastuzumab for a total of 8 weeks; it was discontinued at that time because enzyme levels continued to increase. When trastuzumab was discontinued, enzyme levels returned to normal. Subsequently, surgical resection of the cancer was performed. The patient's lymph nodes were found to be involved and, because of the high risk of disease recurrence, she was rechallenged with trastuzumab. LFTs showed enzyme levels rising again and trastuzumab was discontinued after 2 cycles, with subsequent normalization of the levels. She was then treated with weekly paclitaxel and her LFT values continued to be in the near-normal range. DISCUSSION: There were no comorbidities in this patient and, on initiation of trastuzumab, her liver enzyme levels were normal. The levels became elevated after initiation of trastuzumab, normalized after its discontinuation, and increased upon rechallenge. According to a validated drug-induced hepatotoxicity scale, trastuzumab was the probable cause of hepatotoxicity in this patient. CONCLUSIONS: Liver enzyme levels must be closely monitored in patients receiving trastuzumab. To our knowledge, this is the first report of trastuzumab-induced hepatotoxicity requiring discontinuation of the drug.