Examining the inorganic elemental composition of lobster phyllosoma (Panulirus ornatus) with X-ray fluorescence microscopy.

The ornate spiny rock lobster, Panulirus ornatus, is an attractive candidate for aquaculture. The larval stages of spiny lobsters, known as phyllosoma, are complex with many developmental stages. Very little is known about the inorganic element composition of phyllosoma. In this study, a novel method using synchrotron X-ray fluorescence microscopy (XFM) was applied to investigate the distributions of metals potassium (K), calcium (Ca), copper (Cu), zinc (Zn), the metalloid arsenic (As), and nonmetal bromine (Br) within individual phyllosoma at stages 3, 4, and 8 of their development. For the first time, 1 µm resolution synchrotron XFM images of whole phyllosoma as well as closer examinations of their eyes, mouths, setae, and tails were obtained. Elements accumulated in certain locations within phyllosoma, providing insight into their likely biological role for these organisms. This information may be useful for the application of dietary supplementation in the future to closed larval cycle lobster aquaculture operations.

In H pylori infection, vonoprazan plus high-dose amoxicillin was noninferior to B-quadruple therapy for eradication.

SOURCE CITATION: Qian HS, Li WJ, Dang YN, et al. Ten-day vonoprazan-amoxicillin dual therapy as a first-line treatment of Helicobacter pylori infection compared with bismuth-containing quadruple therapy. Am J Gastroenterol. 2023;118:627-634. 36729890.

High-physiological and supra-physiological 1,2-13C2 glucose focal supplementation to the traumatised human brain.

How to optimise glucose metabolism in the traumatised human brain remains unclear, including whether injured brain can metabolise additional glucose when supplied. We studied the effect of microdialysis-delivered 1,2-13C2 glucose at 4 and 8 mmol/L on brain extracellular chemistry using bedside ISCUSflex, and the fate of the 13C label in the 8 mmol/L group using high-resolution NMR of recovered microdialysates, in 20 patients. Compared with unsupplemented perfusion, 4 mmol/L glucose increased extracellular concentrations of pyruvate (17%, p = 0.04) and lactate (19%, p = 0.01), with a small increase in lactate/pyruvate ratio (5%, p = 0.007). Perfusion with 8 mmol/L glucose did not significantly influence extracellular chemistry measured with ISCUSflex, compared to unsupplemented perfusion. These extracellular chemistry changes appeared influenced by the underlying metabolic states of patients' traumatised brains, and the presence of relative neuroglycopaenia. Despite abundant 13C glucose supplementation, NMR revealed only 16.7% 13C enrichment of recovered extracellular lactate; the majority being glycolytic in origin. Furthermore, no 13C enrichment of TCA cycle-derived extracellular glutamine was detected. These findings indicate that a large proportion of extracellular lactate does not originate from local glucose metabolism, and taken together with our earlier studies, suggest that extracellular lactate is an important transitional step in the brain's production of glutamine.

How to manage Graves' disease in women of childbearing potential.

The management of Graves' disease (GD) in women of childbearing potential has multiple specific complexities. Many factors are involved, which differ at the various stages from preconception, conception, first trimester, later pregnancy, postpartum and lactation, with both maternal and foetal considerations. The incidence and significance of the risks incurred from antithyroid drugs (ATDs) in pregnancy have been re-evaluated recently and must be balanced against the risks of uncontrolled hyperthyroidism during childbearing years. Contraception is advised until hyperthyroidism is controlled. ATD cessation should be considered in those who are well controlled on low dose therapy before conception and in early pregnancy. Advice on iodine supplementation does not generally differ in those with GD. Radioiodine (RAI) is contraindicated from 6 months preconception until completion of breastfeeding. In all women who have a history of GD, monitoring of TSH receptor antibodies (TRAb) is strongly recommended during pregnancy, and if elevated, foetal monitoring and assessment of thyroid function in the neonate are required. Of note, RAI increases TRAb for up to a year, making this treatment option even less attractive in this patient group. A small amount of ATD is transferred into breast milk but low doses are safe during lactation. Routine periodic thyroid function testing is recommended in remission to detect postpartum GD recurrence. We present our approach to the Clinical Question 'How to manage GD in women of childbearing potential?'

The Assembly Mechanism and Mesoscale Architecture of Protein-Polysaccharide Complexes Formed at the Solid-liquid Interface.

Protein-polysaccharide composite materials have generated much interest due to their potential use in medical science and biotechnology. A comprehensive understanding of the assembly mechanism and the mesoscale architecture is needed for fabricating protein-polysaccharide composite materials with desired properties. In this study, complex assemblies were built on silica surfaces through a layer-by-layer (LbL) approach using bovine beta-lactoglobulin variant A (ßLgA) and pectin as model protein and polysaccharide, respectively. We demonstrated the combined use of quartz crystal microbalance with dissipation monitoring (QCM-D) and neutron reflectometry (NR) for elucidating the assembly mechanism as well as the internal architecture of the protein-polysaccharide complexes formed at the solid-liquid interface. Our results show that ßLgA and pectin interacted with each other and formed a cohesive matrix structure at the interface consisting of intertwined pectin chains that were cross-linked by ßLgA-rich domains. Although the complexes were fabricated in an LbL fashion, the complexes appeared to be relatively homogeneous with ßLgA and pectin molecules spatially distributed within the matrix structure. Our results also demonstrate that the density of ßLgA-pectin complex assemblies increased with both the overall and local charge density of pectin molecules. Therefore, the physical properties of the protein-polysaccharide matrix structure, including density and level of hydration, can be tuned by using polysaccharides with varying charge patterns, thus promoting the development of composite materials with desired properties.

Locking the Spiro Carbon in Spirobisindane Using Sulfur and Phosphorus to Form "Olympic Ring"-like Molecules.

To improve the rigidity of spirobisindane, it was intramolecularly locked by forming eight-membered rings via sulfur and phosphorus atoms to produce an interlocked polycyclic structure under mild conditions in good yields. By carefully analyzing the crystal structures, we noticed that the angle between the two benzene rings in the locked version is significantly smaller than that of the typical spirobisindane structure. Molecular modeling indicated that locking the spiro center can remarkably enhance the rigidity.

Medical and surgical treatment of thyroid eye disease.

Thyroid eye disease is an autoimmune inflammatory disease strongly associated with thyroid disease, principally Graves disease. It can range from mild disease requiring observation or symptomatic treatments only, through to sight-threatening disease requiring major drug therapy and orbital surgery. Severity is graded by the NOSPECS system and activity by the clinical activity score (CAS) to assist in treatment selection. Non-surgical management can extend from observation alone to minor therapy such as oral selenium, then glucocorticoid therapy, cyclosporin, mycophenolate, rituximab, immunoglobulin, teprotumumab, and orbital radiotherapy. High-dose intravenous methylprednisolone therapy is used in active vision-threatening disease with early use of tarsorrhaphy and orbital decompression. Inactive but moderate to severe disease may be treated by orbital decompression, strabismus and eyelid surgery. Systematic assessment and management by both an endocrinologist and ophthalmologist to achieve and maintain euthyroidism and select and sequence treatments according to activity and severity of thyroid eye disease gives the best results for quality of life and vision.

Phasic spiking in vasopressin neurons: How and Why.

The plain title might have been an almost retro sounding grumpy retort, but it has inspired a journey of sorts, and something along the way I hope you won't have come across before. An opinionated exploration of the distinctive phasic spiking patterns of magnocellular vasopressin neurons of the supraoptic and paraventricular nuclei of the hypothalamus. A mostly life essential population of neurons that signal the kidneys to regulate water loss in response to signals that encode plasma volume and osmotic pressure, as well as regulating blood pressure, and possibly metabolism and social behaviour. The viewpoint of a modeller shorn of any explicit maths.

The Antidepressant-Like and Analgesic Effects of Kratom Alkaloids are accompanied by Changes in Low Frequency Oscillations but not ΔFosB Accumulation.

Mitragyna speciosa ("kratom"), employed as a traditional medicine to improve mood and relieve pain, has shown increased use in Europe and North America. Here, the dose-dependent effects of a purified alkaloid kratom extract on neuronal oscillatory systems function, analgesia, and antidepressant-like behaviour were evaluated and kratom-induced changes in ΔFosB expression determined. Male rats were administered a low or high dose of kratom (containing 0.5 or 1 mg/kg of mitragynine, respectively) for seven days. Acute or repeated low dose kratom suppressed ventral tegmental area (VTA) theta oscillatory power whereas acute or repeated high dose kratom increased delta power, and reduced theta power, in the nucleus accumbens (NAc), prefrontal cortex (PFC), cingulate cortex (Cg) and VTA. The repeated administration of low dose kratom additionally elevated delta power in PFC, decreased theta power in NAc and PFC, and suppressed beta and low gamma power in Cg. Suppressed high gamma power in NAc and PFC was seen selectively following repeated high dose kratom. Both doses of kratom elevated NAc-PFC, VTA-NAc, and VTA-Cg coherence. Low dose kratom had antidepressant-like properties whereas both doses produced analgesia. No kratom-induced changes in ΔFosB expression were evident. These results support a role for kratom as having both antidepressant and analgesic properties that are accompanied by specific changes in neuronal circuit function. However, the absence of drug-induced changes in ΔFosB expression suggest that the drug may circumvent this cellular signaling pathway, a pathway known for its significant role in addiction.

Immediate effects of cervical mobilisations on neck muscle activity during active neck movements in patients with non-specific neck pain. A double blind placebo controlled trial.

BACKGROUND: Cervical mobilisations are used to treat people with neck pain but their mechanisms of action are unclear. One theorised reason for induced analgesia is effect on neck muscle activity. OBJECTIVES: To assess the effects of cervical mobilisations on muscle activity during active neck movements and whether changes in muscle activity are associated with changes in symptoms. DESIGN: Double-blind randomised placebo controlled trial. SETTING: Primary care. PARTICIPANTS: 40 patients (aged 19 to 80 years, 24 female) with non-specific neck pain. INTERVENTIONS: One session of cervical mobilisations or motionless manual contact (placebo). MAIN OUTCOME MEASURES: sternocleidomastoid (SCM), scalene (SCA), upper trapezius (UT) and erector spinae (ES) surface electromyography (SEMG) during active neck flexion, extension, side flexion and rotation was measured immediately before and after the intervention. Patients were classified as responders according to change in symptoms assessed using the Global Rating of Change Scale (GROC). RESULTS: Compared with placebo, patients receiving mobilisation showed an increase in contralateral UT and ES SEMG during rotation and contralateral and ipsilateral SCM, SCA and UT during side flexion (P<0.05), however changes were mostly associated with an increase in range and speed of movement. The only association with GROC was increased (5%) SEMG in the contralateral SCM during side flexion in the mobilisation group (P=0.013). CONCLUSION: Cervical mobilisations caused increased neck SEMG, mostly due to increased movement range and speed. Change in muscle activity is unlikely to be a major mechanism of action of cervical mobilisations in symptomatic improvement with physiological neck movements. (ClinicalTrials.gov record number: 2016/066). CLINICAL TRIALS REGISTRY: ClinicalTrials.gov record number: 2016/066.

Phosphorus spectroscopy in acute TBI demonstrates metabolic changes that relate to outcome in the presence of normal structural MRI.

Metabolic dysfunction is a key pathophysiological process in the acute phase of traumatic brain injury (TBI). Although changes in brain glucose metabolism and extracellular lactate/pyruvate ratio are well known, it was hitherto unknown whether these translate to downstream changes in ATP metabolism and intracellular pH. We have performed the first clinical voxel-based in vivo phosphorus magnetic resonance spectroscopy (31P MRS) in 13 acute-phase major TBI patients versus 10 healthy controls (HCs), at 3T, focusing on eight central 2.5 × 2.5 × 2.5 cm3 voxels per subject. PCr/γATP ratio (a measure of energy status) in TBI patients was significantly higher (median = 1.09) than that of HCs (median = 0.93) (p < 0.0001), due to changes in both PCr and ATP. There was no significant difference in PCr/γATP between TBI patients with favourable and unfavourable outcome. Cerebral intracellular pH of TBI patients was significantly higher (median = 7.04) than that of HCs (median = 7.00) (p = 0.04). Alkalosis was limited to patients with unfavourable outcome (median = 7.07) (p < 0.0001). These changes persisted after excluding voxels with > 5% radiologically visible injury. This is the first clinical demonstration of brain alkalosis and elevated PCr/γATP ratio acutely after major TBI. 31P MRS has potential for non-invasively assessing brain injury in the absence of structural injury, predicting outcome and monitoring therapy response.

The spiking and secretory activity of oxytocin neurones in response to osmotic stimulation: a computational model.

KEY POINTS: A quantitative model of oxytocin neurones that combines a spiking model, a model of stimulus-secretion coupling and a model of plasma clearance of oxytocin was tested. To test the model, a variety of sources of published data were used that relate either the electrical activity of oxytocin cells or the secretion of oxytocin to experimentally induced changes in plasma osmotic pressure. To use these data to test the model, the experimental challenges involved were computationally simulated. The model predictions closely matched the reported outcomes of the different experiments. ABSTRACT: Magnocellular vasopressin and oxytocin neurones in the rat hypothalamus project to the posterior pituitary, where they secrete their products into the bloodstream. In rodents, both vasopressin and oxytocin magnocellular neurones are osmoresponsive, and their increased spiking activity is mainly a consequence of an increased synaptic input from osmoresponsive neurons in regions adjacent to the anterior wall of the third ventricle. Osmotically stimulated vasopressin secretion promotes antidiuresis while oxytocin secretion promotes natriuresis. In this work we tested a previously published computational model of the spiking and secretion activity of oxytocin cells against published evidence of changes in spiking activity and plasma oxytocin concentration in response to different osmotic challenges. We show that integrating this oxytocin model with a simple model of the osmoresponsive inputs to oxytocin cells achieves a strikingly close match to diverse sources of data. Comparing model predictions with published data using bicuculline to block inhibitory GABA inputs supports the conclusion that inhibitory inputs and excitatory inputs are co-activated by osmotic stimuli. Finally, we studied how the gain of osmotically stimulated oxytocin release changes in the presence of a hypovolaemic stimulus, showing that this is best explained by an inhibition of an osmotically regulated inhibitory drive to the magnocellular neurones.

Reporting preclinical anesthesia study (REPEAT): Evaluating the quality of reporting in the preclinical anesthesiology literature.

Poor reporting quality may contribute to irreproducibility of results and failed 'bench-to-bedside' translation. Consequently, guidelines have been developed to improve the complete and transparent reporting of in vivo preclinical studies. To examine the impact of such guidelines on core methodological and analytical reporting items in the preclinical anesthesiology literature, we sampled a cohort of studies. Preclinical in vivo studies published in Anesthesiology, Anesthesia & Analgesia, Anaesthesia, and the British Journal of Anaesthesia (2008-2009, 2014-2016) were identified. Data was extracted independently and in duplicate. Reporting completeness was assessed using the National Institutes of Health Principles and Guidelines for Reporting Preclinical Research. Risk ratios were used for comparative analyses. Of 7615 screened articles, 604 met our inclusion criteria and included experiments reporting on 52 490 animals. The most common topic of investigation was pain and analgesia (30%), rodents were most frequently used (77%), and studies were most commonly conducted in the United States (36%). Use of preclinical reporting guidelines was listed in 10% of applicable articles. A minority of studies fully reported on replicates (0.3%), randomization (10%), blinding (12%), sample-size estimation (3%), and inclusion/exclusion criteria (5%). Statistics were well reported (81%). Comparative analysis demonstrated few differences in reporting rigor between journals, including those that endorsed reporting guidelines. Principal items of study design were infrequently reported, with few differences between journals. Methods to improve implementation and adherence to community-based reporting guidelines may be necessary to increase transparent and consistent reporting in the preclinical anesthesiology literature.

Models in neuroendocrinology.

The neuroendocrine systems of the hypothalamus are critical for survival and reproduction, and are highly conserved throughout vertebrate evolution. Their roles in controlling body metabolism, growth and body composition, stress, electrolyte balance and reproduction have been intensively studied, and have yielded a rich crop of original and challenging insights into neuronal function, insights that circumscribe a vision of the brain that is quite different from conventional views. Despite the diverse physiological roles of pituitary hormones, most are secreted in a pulsatile pattern, but arising through a variety of mechanisms. An important exception is vasopressin which uses bursting neural activity, but produces a graded secretion response to osmotic pressure, a sustained robust linear response constructed from noisy, nonlinear components. Neuroendocrine systems have many features such as multiple temporal scales and nonlinearity that make their underlying mechanisms hard to understand without mathematical modelling. The models presented here cover the wide range of temporal scales involved in these systems, including models of single cell electrical activity and calcium dynamics, receptor signalling, gene expression, coordinated activity of neuronal networks, whole-organism hormone dynamics and feedback loops, and the menstrual cycle. Many interesting theoretical approaches have been applied to these systems, but important problems remain, at the core the question of what is the true advantage of pulsatility.

Reliability of a Method to Measure Neck Surface Electromyography, Kinematics, and Pain Occurrence in Participants With Neck Pain.

OBJECTIVE: To investigate the reliability of a novel method to measure neck surface electromyography (SEMG), kinematics, and pain during active movements in participants with neck pain. METHODS: This test-retest study evaluated 23 participants with chronic neck pain. Each was measured twice within a single session. Three-dimensional kinematics and SEMG were recorded in 10° increments during forward and side flexion, extension, and rotation of the neck. Neck position during pain occurrence was also measured. RESULTS: Intraclass correlation coefficients were >0.80 for 96% and 100% of SEMG and kinematic data, respectively. The percentage of standard error of the measurement (SEM) values were <25% for 91% of all SEMG measures; most were <15%, and some were <10%. For ranges of motion in the primary plane, percentage of SEM values were all <6% (SEM 1°-3°). Intraclass correlation coefficients for neck position during pain occurrence were all >0.60, except for right rotation (0.48) (SEM values 2°-8°). Pain occurred approximately 59% to 75% into the total range of motion and persisted to its end. CONCLUSIONS: This methodology showed good reliability. It may be suitable for neck pain subclassification to evaluate the effects of treatment on pain, kinematics, and muscle activity during functional neck movements. The point of pain occurrence suggests increasing mechanical load on tissues may be one of the causative factors for movement-associated neck pain.

The effect of succinate on brain NADH/NAD+ redox state and high energy phosphate metabolism in acute traumatic brain injury.

A key pathophysiological process and therapeutic target in the critical early post-injury period of traumatic brain injury (TBI) is cell mitochondrial dysfunction; characterised by elevation of brain lactate/pyruvate (L/P) ratio in the absence of hypoxia. We previously showed that succinate can improve brain extracellular chemistry in acute TBI, but it was not clear if this translates to a change in downstream energy metabolism. We studied the effect of microdialysis-delivered succinate on brain energy state (phosphocreatine/ATP ratio (PCr/ATP)) with 31P MRS at 3T, and tissue NADH/NAD+ redox state using microdialysis (L/P ratio) in eight patients with acute major TBI (mean 7 days). Succinate perfusion was associated with increased extracellular pyruvate (+26%, p < 0.0001) and decreased L/P ratio (-13%, p < 0.0001) in patients overall (baseline-vs-supplementation over time), but no clear-cut change in 31P MRS PCr/ATP existed in our cohort (p > 0.4, supplemented-voxel-vs-contralateral voxel). However, the percentage decrease in L/P ratio for each patient following succinate perfusion correlated significantly with their percentage increase in PCr/ATP ratio (Spearman's rank correlation, r = -0.86, p = 0.024). Our findings support the interpretation that L/P ratio is linked to brain energy state, and that succinate may support brain energy metabolism in select TBI patients suffering from mitochondrial dysfunction.

A Predictive, Quantitative Model of Spiking Activity and Stimulus-Secretion Coupling in Oxytocin Neurons.

Oxytocin neurons of the rat hypothalamus project to the posterior pituitary, where they secrete their products into the bloodstream. The pattern and quantity of that release depends on the afferent inputs to the neurons, on their intrinsic membrane properties, and on nonlinear interactions between spiking activity and exocytosis: A given number of spikes will trigger more secretion when they arrive close together. Here we present a quantitative computational model of oxytocin neurons that can replicate the results of a wide variety of published experiments. The spiking model mimics electrophysiological data of oxytocin cells responding to cholecystokinin (CCK), a peptide produced in the gut after food intake. The secretion model matches results from in vitro experiments on stimulus-secretion coupling in the posterior pituitary. We mimic the plasma clearance of oxytocin with a two-compartment model, replicating the dynamics observed experimentally after infusion and injection of oxytocin. Combining these models allows us to infer, from measurements of oxytocin in plasma, the spiking activity of the oxytocin neurons that produced that secretion. We have tested these inferences with experimental data on oxytocin secretion and spiking activity in response to intravenous injections of CCK. We show how intrinsic mechanisms of the oxytocin neurons determine this relationship: In particular, we show that the presence of an afterhyperpolarization (AHP) in oxytocin neurons dramatically reduces the variability of their spiking activity and even more markedly reduces the variability of oxytocin secretion. The AHP thus acts as a filter, protecting the final product of oxytocin cells from noisy fluctuations.

Clinical guidance for radioiodine refractory differentiated thyroid cancer.

Prognosis from differentiated thyroid cancer is worse when the disease becomes refractory to radioiodine. Until recently, treatment options have been limited to local therapies such as surgery and radiotherapy, but the recent availability of systemic therapies now provides some potential for disease control. Multitargeted kinase inhibitors (TKIs) including lenvatinib and sorafenib have been shown to improve progression-free survival in phase III clinical trials, but are also associated with a spectrum of adverse effects. Other TKIs have been utilized as "redifferentiation" agents, increasing sodium iodide symporter expression in metastases and thus restoring radioiodine avidity. Some patients whose disease progresses on initial TKI therapy will still respond to a different TKI and clinical trials currently in progress will clarify the best options for such patients. As these drugs are not inexpensive, care needs to be taken to minimize not only biological but also financial toxicity. In this review, we examine the basic biology of radioiodine refractory disease and discuss optimal treatment approaches, with specific focus on choice and timing of TKI treatment. This clinical field remains fluid, and directions for future research include exploring biomarkers and considering adjuvant TKI use in certain patient groups.

Drosophila divalent metal ion transporter Malvolio is required in dopaminergic neurons for feeding decisions.

Members of the natural resistance-associated macrophage protein (NRAMP) family are evolutionarily conserved metal ion transporters that play an essential role in regulating intracellular divalent cation homeostasis in both prokaryotes and eukaryotes. Malvolio (Mvl), the sole NRAMP family member in insects, plays a role in food choice behaviors in Drosophila and other species. However, the specific physiological and cellular processes that require the action of Mvl for appropriate feeding decisions remain elusive. Here, we show that normal food choice requires Mvl function specifically in the dopaminergic system, and can be rescued by supplementing food with manganese. Collectively, our data indicate that the action of the Mvl transporter affects food choice behavior via the regulation of dopaminergic innervation of the mushroom bodies, a principle brain region associated with decision-making in insects. Our studies suggest that the homeostatic regulation of the intraneuronal levels of divalent cations plays an important role in the development and function of the dopaminergic system and associated behaviors.