Widespread Production of Polyunsaturated Aldehydes by Benthic Diatoms of the North Pacific Ocean's Salish Sea.

Diatoms are key primary producers across marine, freshwater, and terrestrial ecosystems. They are responsible for photosynthesis and secondary production that, in part, support complex food webs. Diatoms can produce phytochemicals that have transtrophic ecological effects which increase their competitive fitness. Polyunsaturated aldehydes (PUAs) are one class of diatom-derived phytochemicals that are known to have allelopathic and anti-herbivory properties. The anti-herbivory capability of PUAs results from their negative effect on grazer fecundity. Since their discovery, research has focused on their production by pelagic marine diatoms, and their effects on copepod egg production, hatching success, and juvenile survival and development. Few investigations have explored PUA production by the prolific suite of benthic marine diatoms, despite their importance to coastal trophic systems. In this study, we tested eight species of benthic diatoms for the production of the bioactive PUAs 2,4-heptadienal, 2,4-octadienal, and 2,4-decadienal. Benthic diatom species were isolated from the Salish Sea, an inland sea within the North Pacific ecosystem. All species were found to be producers of at least two PUAs in detectable concentrations, with five species producing all three PUAs in quantifiable concentrations. Our results indicate that production of PUAs from Salish Sea benthic diatoms may be widespread, and thus these compounds may contribute to benthic coastal food web dynamics through heretofore unrecognized pathways. Future studies should expand the geographic scope of investigations into benthic diatom PUA production and explore the effects of benthic diatoms on benthic consumer fecundity.

Characterizing the Stability of Angiotensin II in 0.9% Sodium Chloride Using High Performance Liquid Chromatography and Liquid Chromatography Tandem Mass Spectrometry.

Purpose: The purpose of this study was to evaluate the stability of angiotensin II in 0.9% sodium chloride for up to 5 days. Methods: We prepared angiotensin II dilutions, by aseptically diluting 2.5 mg (1 mL) in 249 mL 0.9% sodium chloride creating a solution of 10 000 ng/mL. Admixtures were stored under refrigeration (5 ± 3°C). Stability of the dilution was assessed by: preservation of clarity, consistency of pH, and retention of concentration. Solutions were sampled at times 0, 24, 48, 72, 96, 120 hours. Solutions were analyzed via High-Performance Liquid Chromatography (HPLC-UV) and Liquid Chromatography Mass Spectrometry (LC-MS/MS). Retention of concentration was set a priori at > 90% of initial concentration. Results: Clarity, color, and pH at all sample time points remained constant. Both methods of analysis confirmed similar results. When stored under refrigeration, the concentration of angiotensin II solution remained above 90% of initial concentration throughout the entire sampling period. Conclusions: Angiotensin II in 0.9% sodium chloride stored in infusion bags under refrigeration (5 ± 3°C) maintained at least 90% of their original concentrations for up to 5 days. Stability was also demonstrated based on turbidity, color, and pH assessment.

Acetogenins from the Stem of Uvaria rufa and Their Cytotoxic Activity.

Four new adjacent bis-tetrahydrofuran acetogenins, bullacin C (7), uvarirufin (9), and uvariasolins III (12) and IV (13), along with 11 known acetogenins, were isolated from the stem of Uvaria rufa. Their structures were elucidated based on spectroscopic data analysis, including 1D and 2D NMR, HRESIMS, and MALDI-MS/MS of the lithium adducts. Absolute configurations were assigned using Mosher ester analysis and ECD measurements. Uvarirufin (9) possesses a unique C-39 skeleton among acetogenins. Most tested acetogenins exhibited cytotoxicity against human cancer cell lines (HCT 116, 22Rv1, MDA-MB-435, OVCAR3). Squamocin (8) and uvarirufin (9) were found to be the most potent, with an IC50 value of 1.2 µM for both in HCT 116 colon cancer cells. Additionally, a new application of Dragendorff's reagent is proposed herein for the TLC detection of acetogenins.

The use and timing of angio-embolization in pediatric blunt liver and spleen injury.

BACKGROUND: Nonoperative management (NOM) is the standard of care for the management of blunt liver and spleen injuries (BLSI) in the stable pediatric patient. Angiography with embolization (AE) is utilized as an adjunctive therapy in the management of adult BLSI patients, but it is rarely utilized in the pediatric population. In this planned secondary analysis, we describe the current utilization patterns of AE in the management of pediatric BLSI. METHODS: After obtaining IRB approval at each center, cohort data was collected prospectively for children admitted with BLSI confirmed on CT at 10 Level 1 pediatric trauma centers (PTCs) throughout the United States from April 2013 to January 2016. All patients who underwent angiography with or without embolization for a BLSI were included in this analysis. Data collected included patient demographics, injury details, organ injured and grade of injury, CT finding specifics such as contrast blush, complications, failure of NOM, time to angiography and techniques for embolization. RESULTS: Data were collected for 1004 pediatric patients treated for BLSI over the study period, 30 (3.0%) of which underwent angiography with or without embolization for BLSI. Ten of the patients who underwent angiography for BLSI failed NOM. For patients with embolized splenic injuries, splenic salvage was 100%. Four of 9 patients undergoing embolization of the liver ultimately required an operative intervention, but only one patient required hepatorrhaphy and no patient required hepatectomy after AE. Few angiography studies were obtained early during hospitalization for BLSI, with only 1 patient undergoing angiography within 1 hour of arrival at the PTC, and 7 within 3 hours. CONCLUSIONS: Angioembolization is rarely utilized in the management of BLSI in pediatric trauma patients with blunt abdominal trauma and is generally utilized in a delayed fashion. However, when implemented, angioembolization is associated with 100% splenic salvage for splenic injuries. LEVEL OF EVIDENCE: Level IV, therapeutic/care management.

Fibroids and unexplained infertility treatment with epigallocatechin gallate: a natural compound in green tea (FRIEND) - protocol for a randomised placebo-controlled US multicentre clinical trial of EGCG to improve fertility in women with uterine fibroids.

INTRODUCTION: Uterine fibroids affect 30%-77% of reproductive-age women and are a significant cause of infertility. Surgical myomectomies can restore fertility, but they often have limited and temporary benefits, with postoperative complications such as adhesions negatively impacting fertility. Existing medical therapies, such as oral contraceptives, gonadotropin hormone-releasing hormone (GnRH) analogues and GnRH antagonists, can manage fibroid symptoms but are not fertility friendly. This study addresses the pressing need for non-hormonal, non-surgical treatment options for women with fibroids desiring pregnancy. Previous preclinical and clinical studies have shown that epigallocatechin gallate (EGCG) effectively reduces uterine fibroid size. We hypothesise that EGCG from green tea extract will shrink fibroids, enhance endometrial quality and increase pregnancy likelihood. To investigate this hypothesis, we initiated a National Institute of Child Health and Human Development Confirm-funded trial to assess EGCG's efficacy in treating women with fibroids and unexplained infertility. METHODS AND ANALYSIS: This multicentre, prospective, interventional, randomised, double-blinded clinical trial aims to enrol 200 participants with fibroids and unexplained infertility undergoing intrauterine insemination (IUI). Participants will be randomly assigned in a 3:1 ratio to two groups: green tea extract (1650 mg daily) or a matched placebo, combined with clomiphene citrate-induced ovarian stimulation and timed IUI for up to four cycles. EGCG constitutes approximately 45% of the green tea extract. The primary outcome is the cumulative live birth rate, with secondary outcomes including conception rate, time to conception, miscarriage rate, change in fibroid volume and symptom severity scores and health-related quality of life questionnaire scores. ETHICS AND DISSEMINATION: The FRIEND trial received approval from the Food and Drug adminstration (FDA) (investigational new drug number 150951), the central Institutional Review Board (IRB) at Johns Hopkins University and FRIEND-collaborative site local IRBs. The data will be disseminated at major conferences, published in peer-reviewed journals and support a large-scale clinical trial. TRIAL REGISTRATION NUMBER: NCT05364008.

Pediatric Traumatic Lumbar Hernias and Associated Injuries: A Case Series.

OBJECTIVE: Traumatic lumbar hernias are a rare entity mostly seen with high-impact, blunt abdominal trauma. This injury occurs when there is disruption of the posterior musculature along with bony structures, allowing for herniation of abdominal contents. There are minimal cases of this entity reported in adults, but even fewer in the pediatric population. METHODS: We describe 3 cases of traumatic lumbar hernia at our institution as well as provide a review of the literature to elucidate the most common mechanisms, severity of injury, and associated injuries. RESULTS: Traumatic lumbar hernia is most commonly seen in restrained passengers involved in motor vehicle collisions. A majority of cases are diagnosed using computed tomography imaging and less frequently during primary surgical exploration. The most common associated injuries were mesenteric and bowel injuries, followed by spinal and chest trauma. Traumatic lumbar hernia often leads to prolonged hospital stays and increased need for posthospital rehabilitation because of associated traumatic comorbidities. CONCLUSIONS: Traumatic lumbar hernia is a rare entity in children, and early suspicion and identification of associated injuries is necessary in the management of these patients.

Binary reversals: a diagnostic sign in primary progressive aphasia.

BACKGROUND: Binary reversals (exemplified by 'yes'/'no' confusions) have been described in patients with primary progressive aphasia (PPA) but their diagnostic value and phenotypic correlates have not been defined. METHODS: We conducted a retrospective cohort study analysing demographic, clinical, neuropsychological, linguistic and behavioural data from patients representing all major PPA syndromes (non-fluent/agrammatic variant, nfvPPA; logopenic variant, lvPPA; semantic variant, svPPA) and behavioural variant frontotemporal dementia (bvFTD). The prevalence of binary reversals and behavioural abnormalities, illness duration, parkinsonian features and neuropsychological test scores were compared between neurodegenerative syndromes, and the diagnostic predictive value of binary reversals was assessed using logistic regression. RESULTS: Data were obtained for 83 patients (21 nfvPPA, 13 lvPPA, 22 svPPA, 27 bvFTD). Binary reversals occurred in all patients with nfvPPA, but significantly less frequently and later in lvPPA (54%), svPPA (9%) and bvFTD (44%). Patients with bvFTD with binary reversals had significantly more severe language (but not general executive or behavioural) deficits than those without reversals. Controlling for potentially confounding variables, binary reversals strongly predicted a diagnosis of nfvPPA over other syndromes. CONCLUSIONS: Binary reversals are a sensitive (though not specific) neurolinguistic feature of nfvPPA, and should suggest this diagnosis if present as a prominent early symptom.

Characterization of organic crystals for second-harmonic generation.

Second-harmonic generation (SHG) is a common technique with many applications. Common inorganic single-crystalline materials used to produce SHG light are effective using short IR/visible wavelengths but generally do not perform well at longer, technologically relevant IR wavelengths such as 1300, 1550, and 2000 nm. Efficient SHG materials possess many of the same key material properties as terahertz (THz) generators, and certain single-crystalline organic THz generation materials have been reported to perform at longer IR wavelengths. Consequently, this work focuses on characterizing three efficient organic THz generators for SHG, namely, DAST (trans-4-[4-(dimethylamino)-N-methylstilbazolium] p-tosylate), DSTMS (4-N,N-dimethylamino-4'-N'-methylstilbazolium 2,4,6-trimethylbenzenesulfonate), and the recently discovered generator PNPA ((E)-4-((4-nitrobenzylidene)amino)-N-phenylaniline). All three of these crystals outperform the beta-barium borate (BBO), an inorganic material commonly used for SHG, using IR pump wavelengths (1200-2000 nm).

Postglacial phylogeography, admixture, and evolution of red spruce (Picea rubens Sarg.) in Eastern North America.

Climate change is a major evolutionary force that can affect the structure of forest ecosystems worldwide. Red spruce (Picea rubens Sarg.) has recently faced a considerable decline in the Southern Appalachians due to rapid environmental change, which includes historical land use, and atmospheric pollution. In the northern part of its range, red spruce is sympatric with closely related black spruce (Picea mariana (Mill.) B.S.P.), where introgressive hybridization commonly occurs. We investigated range-wide population genetic diversity and structure and inferred postglacial migration patterns and evolution of red spruce using nuclear microsatellites. Moderate genetic diversity and differentiation were observed in red spruce. Genetic distance, maximum likelihood and Bayesian analyses identified two distinct population clusters: southern glacial populations, and the evolutionarily younger northern populations. Approximate Bayesian computation suggests that patterns of admixture are the result of divergence of red spruce and black spruce from a common ancestor and then introgressive hybridization during post-glacial migration. Genetic diversity, effective population size (Ne) and genetic differentiation were higher in the northern than in the southern populations. Our results along with previously available fossil data suggest that Picea rubens and Picea mariana occupied separate southern refugia during the last glaciation. After initial expansion in the early Holocene, these two species faced a period of recession and formed a secondary coastal refugium, where introgressive hybridization occurred, and then both species migrated northward. As a result, various levels of black spruce alleles are present in the sympatric red spruce populations. Allopatric populations of P. rubens and P. mariana have many species-specific alleles and much fewer alleles from common ancestry. The pure southern red spruce populations may become critically endangered under projected climate change conditions as their ecological niche may disappear.

Polyoxygenated cyclohexene derivatives and other constituents of Uvaria rufa stem.

Six undescribed compounds, uvarirufols D and E, (+)-uvarigranol B, (-)-uvarigranol E, 6-acetoxy-5-hydroxy-7-methoxyflavanone and cherrevenaphthalene D, along with twelve known compounds, including polyoxygenated cyclohexenes, flavonoids, and lignans, were isolated from the methanol extract of Uvaria rufa stems. Their structures were elucidated by spectroscopic analyses and the absolute configurations were determined using electronic circular dichroism. Several isolates were evaluated for cytotoxic, antitubercular and anti-inflammatory potentials. (-)-6-Acetylzeylenol showed moderate inhibitory activity against Mycobacterium tuberculosis, with MIC value of 47.10 µg/mL. Cherrevenaphthalene D exhibited weak antimycobacterial activity and potent inhibitory effect on lipopolysaccharide-induced nitric oxide (NO) production in RAW 264.7 cells (EC50 = 8.54 µM). 8-Hydroxy-5,7-dimethoxyflavanone displayed moderate level of NO inhibition (EC50 = 43.62 µM) with little cytotoxicity. The polyoxygenated cyclohexenes and lignans were inactive against HCT 116 and 22Rv1 cancer cells (IC50 > 100 µM).

Developing a career versus careering through your professional life.

Vet Jeremy Johnson's career journey went from large animal 'grunt', through a world of pharmaceuticals, to embracing consultancy and then becoming director of new SQP training and registration body Vetpol.

Valproate-induced reversible cognitive decline presenting as dementia and associated clinical features: A literature review.

BACKGROUND/AIM: Valproate (VPA) is an effective broad-spectrum anti-seizure medication. Both VPA induced encephalopathy and reversible cognitive decline (VIRCD) have been reported as rare side effects. While the former is well-described in terms of risk factors, mechanism and management, the latter is less recognised and can be easily mistaken for neurodegenerative dementia. In this paper, we present a literature review of VIRCD, describe its clinical features and compare our findings to those in VPA-induced encephalopathy. METHODS: We used PubMed search for valproate induced (dementia OR cognitive impairment OR cognitive decline OR cognitive dysfunction). Patients included were those with normal or well-defined cognitive baseline who presented with dementia after valproate therapy, in whom cognitive decline reversed after VPA dose reduction or discontinuation. Clinical features were compared to published descriptions of VPA-induced encephalopathy. RESULTS: A total of 33 cases in 11 publications were included. Mean age was 51.2 years. Most were being treated for epilepsy on VPA with good seizure control and no encephalopathic features. VPA levels were within the usual quoted range. Mean latency after VPA initiation and symptoms was 6.87 years. Most had parkinsonian features. The most commonly reported cognitive deficits were in short-term memory and processing speed. All recovered fully on VPA discontinuation. CONCLUSION: VIRCD mimics neurodegenerative dementia but is reversible on VPA discontinuation. The absence of encephalopathic features and good seizure control in addition to the prolonged latency make it easy to miss. VIRCD should be considered in relevant patient groups, especially in the presence of extrapyramidal signs.

Tirzepatide: A Novel Glucose-Dependent Insulinotropic Polypeptide/Glucagon-Like Peptide 1 Receptor Agonist for the Treatment of Type 2 Diabetes: The First Twincretin.

Tirzepatide is a dual-action glucose-dependent insulinotropic polypeptide/glucagon-like peptide 1 (GLP-1) receptor agonist and the first drug in a new class known as twincretins. It is similar to GLP-1 receptor agonists but provides a synergistic enhancement of the incretin effect to control blood glucose levels and reduce weight. Across the SURPASS research program trials, tirzepatide lowered A1C by 1.7-2.4% from baseline. The proportion of patients using tirzepatide who achieved an A1C <7% ranged from 91 to 97%. Patients in the treatment groups averaged a weight loss of 5.44-11.34 kg (12-25 lb). Across all trials, patients on tirzepatide 15 mg lost 8.8-12.9 kg (19.4-28.44 lb) or 9.17-13.7% body weight. In the SURMOUNT-1 trial, maximum weight loss was 23.6 kg (52 lb) or 22.5% body weight. Tirzepatide is a potent new weapon in the arsenal against diabetes.

Non-covalent inhibitors of thioredoxin glutathione reductase with schistosomicidal activity in vivo.

Only praziquantel is available for treating schistosomiasis, a disease affecting more than 200 million people. Praziquantel-resistant worms have been selected for in the lab and low cure rates from mass drug administration programs suggest that resistance is evolving in the field. Thioredoxin glutathione reductase (TGR) is essential for schistosome survival and a validated drug target. TGR inhibitors identified to date are irreversible and/or covalent inhibitors with unacceptable off-target effects. In this work, we identify noncovalent TGR inhibitors with efficacy against schistosome infections in mice, meeting the criteria for lead progression indicated by WHO. Comparisons with previous in vivo studies with praziquantel suggests that these inhibitors outperform the drug of choice for schistosomiasis against juvenile worms.

Blunt Cerebrovascular Injury in Pediatric Hanging Victims.

INTRODUCTION: Incidence of blunt cerebrovascular injury (BCVI) following hanging in the pediatric population is ill-defined. Current guidelines recommend screening imaging during the initial trauma evaluation. Necessity of screening is questioned given BCVI is considered rare after hanging, especially when asymptomatic. This study aims to elucidate the incidence of BCVI in pediatric hangings and determine the value of radiographic work-up. METHODS: A retrospective cohort study was performed of pediatric hangings reported to the National Trauma Data Bank (NTDB), 2017-2019. Imaging, diagnoses, and findings suggestive of BCVI, such as Glasgow Coma Scale (GCS) ≤8, presence of cervical injury, and soft tissue injury were considered. Statistical analysis was carried out to compare incidence. RESULTS: 197 patients met study criteria, with 179 arriving in the trauma bay with signs of life. BCVI incidence was 5.6% (10 of 179). Computed Tomography Angiography (CTA) of the neck was the only reported screening modality in this data set. A CTA was completed in 46% of the cases. DISCUSSION: BCVI incidence following pediatric hanging is more common than previously thought. Less than half of patients had a CTA reported in this cohort. This may result in an underestimate. Given the potentially devastating consequences of a missed BCVI, the addition of CTA to initial work-up may be worthwhile to evaluate for cervical vascular injury, but further studies into the outcomes of children who do receive prophylactic therapy are needed.

Terpenes: Modulating anti-inflammatory signaling in inflammatory bowel disease.

Inflammatory Bowel Disease (IBD) are autoimmune diseases characterized by chronic intestinal inflammation. Considered a western disease, IBD incidence in newly developed countries is skyrocketing. Accordingly, global prevalence is steadily increasing. There are two major IBD phenotypes, ulcerative colitis (UC) and Crohn's disease (CD). UC manifests as uninterrupted inflammation localized in the colon and rectum. Meanwhile, CD presents as interrupted inflammation that can occur throughout the digestive tract. As a result, therapeutics have focused on anti-inflammatory approaches for its treatment. Unfortunately, only 50% of patients benefit from current Food and Drug Administration approved treatments, and all are associated with serious adverse effects. Thus, there is a need for safer and novel therapeutics to increase the efficacy in this population. One aspect that is critical in understanding IBD is how food and phytochemicals therein may be associated with modifying the pathogenesis of IBD. A variety of retrospective and prospective studies, and clinical trials have shown benefits of plant-rich diets on the prevention and symptomatic improvement of IBD. The Mediterranean diet is rich in vegetables, fruits, legumes, and herbs; and characterized by the abundance of anti-inflammatory phytochemicals. An understudied phytochemical class enriched in this diet is terpenes; isoprene-based molecules are widely available in Mediterranean herbs and citrus fruits. Various terpenes have been evaluated in different IBD models. However, some present contradictory or inconclusive results. Therefore, in this review we evaluated preclinical studies of terpenes modulating basic inflammatory signaling related to IBD.

Comprehension of acoustically degraded speech in Alzheimer's disease and primary progressive aphasia.

Successful communication in daily life depends on accurate decoding of speech signals that are acoustically degraded by challenging listening conditions. This process presents the brain with a demanding computational task that is vulnerable to neurodegenerative pathologies. However, despite recent intense interest in the link between hearing impairment and dementia, comprehension of acoustically degraded speech in these diseases has been little studied. Here we addressed this issue in a cohort of 19 patients with typical Alzheimer's disease and 30 patients representing the three canonical syndromes of primary progressive aphasia (non-fluent/agrammatic variant primary progressive aphasia; semantic variant primary progressive aphasia; logopenic variant primary progressive aphasia), compared to 25 healthy age-matched controls. As a paradigm for the acoustically degraded speech signals of daily life, we used noise-vocoding: synthetic division of the speech signal into frequency channels constituted from amplitude-modulated white noise, such that fewer channels convey less spectrotemporal detail thereby reducing intelligibility. We investigated the impact of noise-vocoding on recognition of spoken three-digit numbers and used psychometric modelling to ascertain the threshold number of noise-vocoding channels required for 50% intelligibility by each participant. Associations of noise-vocoded speech intelligibility threshold with general demographic, clinical and neuropsychological characteristics and regional grey matter volume (defined by voxel-based morphometry of patients' brain images) were also assessed. Mean noise-vocoded speech intelligibility threshold was significantly higher in all patient groups than healthy controls, and significantly higher in Alzheimer's disease and logopenic variant primary progressive aphasia than semantic variant primary progressive aphasia (all P < 0.05). In a receiver operating characteristic analysis, vocoded intelligibility threshold discriminated Alzheimer's disease, non-fluent variant and logopenic variant primary progressive aphasia patients very well from healthy controls. Further, this central hearing measure correlated with overall disease severity but not with peripheral hearing or clear speech perception. Neuroanatomically, after correcting for multiple voxel-wise comparisons in predefined regions of interest, impaired noise-vocoded speech comprehension across syndromes was significantly associated (P < 0.05) with atrophy of left planum temporale, angular gyrus and anterior cingulate gyrus: a cortical network that has previously been widely implicated in processing degraded speech signals. Our findings suggest that the comprehension of acoustically altered speech captures an auditory brain process relevant to daily hearing and communication in major dementia syndromes, with novel diagnostic and therapeutic implications.

Benign mesenchymal tumours of the tongue: A report of adult-type rhabdomyoma and granular cell tumour with a review of the literature.

The cytomorphological features of benign mesenchymal tumours of the tongue have rarely been reported. Herein, we present the cytomorphological features of adult-type rhabdomyoma, which occurred in the tongue of a female patient, and granular cell tumour (GCT), which occurred in the tongue of a male patient; both patients were in their mid-50s. The cytological features of the adult-type rhabdomyoma case included large polygonal to ovoid cells with abundant and granular cytoplasm with predominantly peripherally located, uniform, round to oval nuclei and small nucleoli. Cross-striation and crystalline intracytoplasmic structures were not seen. The cytological features of the GCT case included large cells with abundant granular pale cytoplasm, small round nuclei and small distinct nucleoli. The cytological differential diagnoses of these tumours overlap; thus, the cytological findings of the different entities included in their differential diagnoses are discussed.

Evolutionary constraint and innovation across hundreds of placental mammals.

Zoonomia is the largest comparative genomics resource for mammals produced to date. By aligning genomes for 240 species, we identify bases that, when mutated, are likely to affect fitness and alter disease risk. At least 332 million bases (~10.7%) in the human genome are unusually conserved across species (evolutionarily constrained) relative to neutrally evolving repeats, and 4552 ultraconserved elements are nearly perfectly conserved. Of 101 million significantly constrained single bases, 80% are outside protein-coding exons and half have no functional annotations in the Encyclopedia of DNA Elements (ENCODE) resource. Changes in genes and regulatory elements are associated with exceptional mammalian traits, such as hibernation, that could inform therapeutic development. Earth's vast and imperiled biodiversity offers distinctive power for identifying genetic variants that affect genome function and organismal phenotypes.