Remote ischaemic conditioning: defining critical criteria for success-report from the 11th Hatter Cardiovascular Workshop.

The Hatter Cardiovascular Institute biennial workshop, originally scheduled for April 2020 but postponed for 2 years due to the Covid pandemic, was organised to debate and discuss the future of Remote Ischaemic Conditioning (RIC). This evolved from the large multicentre CONDI-2-ERIC-PPCI outcome study which demonstrated no additional benefit when using RIC in the setting of ST-elevation myocardial infarction (STEMI). The workshop discussed how conditioning has led to a significant and fundamental understanding of the mechanisms preventing cell death following ischaemia and reperfusion, and the key target cyto-protective pathways recruited by protective interventions, such as RIC. However, the obvious need to translate this protection to the clinical setting has not materialised largely due to the disconnect between preclinical and clinical studies. Discussion points included how to adapt preclinical animal studies to mirror the patient presenting with an acute myocardial infarction, as well as how to refine patient selection in clinical studies to account for co-morbidities and ongoing therapy. These latter scenarios can modify cytoprotective signalling and need to be taken into account to allow for a more robust outcome when powered appropriately. The workshop also discussed the potential for RIC in other disease settings including ischaemic stroke, cardio-oncology and COVID-19. The workshop, therefore, put forward specific classifications which could help identify so-called responders vs. non-responders in both the preclinical and clinical settings.

Resolvin D2 promotes host defense in a 2 - hit model of sepsis with secondary lung infection.

In the development of sepsis, there is early, massive inflammation which can lead to multiple organ failure. Later there is an immunosuppressed phase where the host is susceptible to secondary infections or is unable to clear existing infection. Specialized Pro-resolving Mediators (SPMs) are endogenously produced lipids which resolve infection by decreasing bacteria load and reducing systemic inflammatory response. There has been little work studying if SPMs given late, can promote host defense. We examined if an SPM, Resolvin D2 (RvD2) could promote host defense in a 2-hit mouse model of cecal ligation and puncture (CLP) sepsis and secondary Pseudomonas aeruginosa lung infection. RvD2 given 48 h after mild CLP (1st hit), increased gene expression of Toll-like receptor-2 (TLR-2) and alveolar macrophage/monocyte phagocytic ability compared to CLP mice given saline vehicle. In this model, RvD2 did not affect plasma IL-6 or IL-10. These effects induced by RvD2, lowered lung bacterial load and decreased mortality after the secondary infection of Pseudomonas aeruginosa (2nd hit). Splenic T-cell numbers were also increased in RvD2 treated mice compared to saline vehicle treated animals. The results suggest that RvD2 promoted mechanisms of host defense in a 2-hit model sepsis and secondary lung infection.

Lipoxin A4 promotes reduction and antibiotic efficacy against Pseudomonas aeruginosa biofilm.

Pseudomonas aeruginosa (P. aeruginosa) is an opportunistic bacterium commonly found in wound infections and airways of cystic fibrosis patients. P. aeruginosa readily forms biofilms which can reduce the efficacy of antibiotics used to eradicate the pathogen. We have previously shown that a Specialized Pro-resolving Mediator (SPM), Lipoxin A4 (LxA4) is a quorum sensing inhibitor which can reduce P. aeruginosa virulence. In this study, we examined the direct actions of LxA4 and RvD2 on P. aeruginosa biofilm formation and virulence gene expression. The influence of LxA4 on antibiotic efficacy and the combined effects on biofilm formation were also investigated. LxA4 and RvD2 reduced P. aeruginosa biofilm formation and virulence gene expression. LxA4 increased ciprofloxacin inhibition on biofilm formation but did not affect ciprofloxacin's action on non-adherent bacteria. On the other hand, LxA4 increased bacterial killing action of imipenem but did not affect imipenem's action on biofilm. We also found that LxA4 can increase ciprofloxacin's bacterial killing ability in established biofilm. Together these results suggest that LxA4 has direct effects on P. aeruginosa biofilm formation and can increase antibiotic efficacy directly.

Morphological development of Pleurochrysis carterae coccoliths examined by cryo-electron tomography.

Coccolithophores are single-celled marine algae that produce calcified scales called coccoliths. Each scale is composed of anvil-shaped single crystals of calcite that are mechanically interlocked, constituting a remarkable example of the multi-level construction of mineralized structures. Coccolith formation starts with the nucleation of rhombohedral crystals on an organic substrate called base plate. The crystals then grow preferentially along specific directions to generate the mature structure, which is then transported to the outside of the cells. Here, we extracted forming coccoliths from Pleurochrysis carterae cells and used cryo-electron tomography to characterize, in their native, hydrated state, the three-dimensional morphology and arrangement of the crystals. Comparing the crystal morphology across three different stages of coccolith formation, we show that competition for space between adjacent crystals contributes significantly to regulation of morphology by constraining growth in certain directions. We further demonstrate that crystals within a coccolith ring develop at different rates and that each crystalline unit rests directly in contact with the base plate and overgrow the rim of the organic substrate during development.

Three-dimensional architecture and surface functionality of coccolith base plates.

Coccolithophores are marine phytoplankton that are among the most prolific calcifiers widespread in Earth's oceans, playing a crucial role in the carbon cycle and in the transport of organic matter to the deep sea. These organisms produce highly complex mineralized scales that are composed of hierarchical assemblies of nano-crystals of calcium carbonate in the form of calcite. Coccolith formation in vivo occurs within compartmentalized mineralisation vesicles derived from the Golgi body, which contain coccolith-associated polysaccharides ('CAPs') providing polymorph selection and mediating crystal growth kinetics, and oval organic mineralisation templates, also known as base plates, which promote heterogenous nucleation and further mechanical interlocking of calcite single crystals. Although the function of coccolith base plates in controlling crystal nucleation have been widely studied, their 3D spatial organization and the chemical functional groups present on the crystal nucleation sites, which are two crucial features impacting biomineralization, remain unsolved. Utilising cryo-electron tomography we show that base plates derived from an exemplary coccolithophore Pleurochrysis carterae (Pcar) in their native hydrated state have a complex 3-layered structure. We further demonstrate, for the first time, the edge and rim of the base plate - where the crystals nucleate - are rich in primary amine functionalities that provide binding targets for negatively charged complexes composed of synthetic macromolecules and Ca2+ ions. Our results indicate that electrostatic interactions between the negatively charged biogenic CAPs and the positively charged rim of the base plate are sufficient to mediate the transport of Ca2+ cations to the mineralization sites.

9th Hatter Biannual Meeting: position document on ischaemia/reperfusion injury, conditioning and the ten commandments of cardioprotection.

In the 30 years since the original description of ischaemic preconditioning, understanding of the pathophysiology of ischaemia/reperfusion injury and concepts of cardioprotection have been revolutionised. In the same period of time, management of patients with coronary artery disease has also been transformed: coronary artery and valve surgery are now deemed routine with generally excellent outcomes, and the management of acute coronary syndromes has seen decade on decade reductions in cardiovascular mortality. Nonetheless, despite these improvements, cardiovascular disease and ischaemic heart disease in particular, remain the leading cause of death and a significant cause of long-term morbidity (with a concomitant increase in the incidence of heart failure) worldwide. The need for effective cardioprotective strategies has never been so pressing. However, despite unequivocal evidence of the existence of ischaemia/reperfusion in animal models providing a robust rationale for study in man, recent phase 3 clinical trials studying a variety of cardioprotective strategies in cardiac surgery and acute ST-elevation myocardial infarction have provided mixed results. The investigators meeting at the Hatter Cardiovascular Institute workshop describe the challenge of translating strong pre-clinical data into effective clinical intervention strategies in patients in whom effective medical therapy is already altering the pathophysiology of ischaemia/reperfusion injury-and lay out a clearly defined framework for future basic and clinical research to improve the chances of successful translation of strong pre-clinical interventions in man.

Heterogeneity of the growth phenotype and birth size in acid-labile subunit (ALS) deficiency.

PURPOSE: The IGFALS gene encodes the acid-labile subunit (ALS) protein, which regulates circulating IGF-1. Human IGFALS mutations cause growth hormone insensitivity (GHI) associated with ALS, IGF-1 and IGFBP-3 deficiencies and mild to moderate postnatal growth impairment (height SDS -2 to -4). Prenatal growth impairment is not a recognised feature of this disorder, but heterozygous carriers may show an intermediate phenotype. METHODS: We report a family of five subjects, including three children born small for gestational age, who were investigated for IGFALS gene mutations. RESULTS: The proband, an 8.7 years female with pre- and postnatal growth failure (BW SDS -3.04, Ht SDS -3.86) and biochemical features of GHI, had a homozygous mutation of IGFALS, c.401T>A; p.L134Q. Her 6.1 years brother (BW SDS -2.11, Ht SDS -2.0) had the same homozygous IGFALS mutation. Both parents [adult height SDS -1.76 (father) and -1.82 (mother)] and her 2.7 years sister (BW SDS -2.60, Ht SDS -2.04) were heterozygous for the IGFALS mutation. CONCLUSION: Significant phenotypic heterogeneity was observed between family members, in particular varying degrees of prenatal growth retardation were present in the three siblings, which may have contributed to the variation in the postnatal growth phenotype.

Impact of diatomaceous biofilms on the frictional drag of fouling-release coatings.

Skin-friction results are presented for fouling-release (FR) hull coatings in the unexposed, clean condition and after dynamic exposure to diatomaceous biofilms for 3 and 6 months. The experiments were conducted in a fully developed turbulent channel flow facility spanning a wide Reynolds number range. The results show that the clean FR coatings tested were hydraulically smooth over much of the Reynolds number range. Biofilms, however, resulted in an increase in skin-friction of up to 70%. The roughness functions for the biofilm-covered surfaces did not display universal behavior, but instead varied with the percentage coverage by the biofilm. The effect of the biofilm was observed to scale with its mean thickness and the square root of the percentage coverage. A new effective roughness length scale (keff) for biofilms based on these parameters is proposed. Boundary layer similarity-law scaling is used to predict the impact of these biofilms on the required shaft power for a mid-sized naval surface combatant at cruising speed. The increase in power is estimated to be between 1.5% and 10.1% depending on the biofilm thickness and percentage coverage.

Impact of broiler processing scalding and chilling profiles on carcass and breast meat yield.

The effect of scalding and chilling procedures was evaluated on carcass and breast meat weight and yield in broilers. On 4 separate weeks (trials), broilers were subjected to feed withdrawal, weighed, and then stunned and bled in 4 sequential batches (n = 16 broilers/batch, 64 broilers/trial). In addition, breast skin was collected before scalding, after scalding, and after defeathering for proximate analysis. Each batch of 16 carcasses was subjected to either hard (60.0°C for 1.5 min) or soft (52.8°C for 3 min) immersion scalding. Following defeathering and evisceration, 8 carcasses/batch were air-chilled (0.5°C, 120 min, 86% RH) and 8 carcasses/batch were immersion water-chilled (water and ice 0.5°C, 40 min). Carcasses were reweighed individually following evisceration and following chilling. Breast meat was removed from the carcass and weighed within 4 h postmortem. There were significant (P < 0.05) differences among the trials for all weights and yields; however, postfeed withdrawal shackle weight and postscald-defeathered eviscerated weights did not differ between the scalding and chilling treatments. During air-chilling all carcasses lost weight, resulting in postchill carcass yield of 73.0% for soft-scalded and 71.3% for hard-scalded carcasses, a difference of 1.7%. During water-chilling all carcasses gained weight, resulting in heavier postchill carcass weights (2,031 g) than for air-chilled carcasses (1,899 g). Postchill carcass yields were correspondingly higher for water-chilled carcasses, 78.2% for soft-scalded and 76.1% for hard-scalded carcasses, a difference of 2.1%. Only in trials 1 and 4 was breast meat yield significantly lower for hard-scalded, air-chilled carcasses (16.1 and 17.5%) than the other treatments. Proximate analysis of skin sampled after scalding or defeathering did not differ significantly in moisture (P = 0.2530) or lipid (P = 0.6412) content compared with skin sampled before scalding. Skin protein content was significantly higher (P < 0.05) for prescald and soft-scalded skin samples than for hard-scalded or soft or hard-scalded skin samples after defeathering. The hard-scalding method used in this experiment did not result in increased skin lipid loss either before or after defeathering.

Effects of a metabotropic glutamate receptor 5 positive allosteric modulator, CDPPB, on spatial learning task performance in rodents.

Metabotropic glutamate receptor 5 (mGlu5) has been implicated in a variety of learning and memory processes and is important for avoidance learning. The present studies used an mGlu5 receptor positive allosteric modulator, 3-cyano-N-(1,3 diphenyl-1H-hyrazol-5-yl)benzamide (CDPPB), to characterize the importance of mGlu5 receptors in aversively- and appetitively-motivated spatial learning tasks (tasks in which the instrumental contingency involves discriminative cues that differ in spatial location). C57Bl/6 male mice were initially trained in the Barnes maze in the absence of drug. Subsequently, CDPPB (30mg/kg, i.p.), administered 20min prior to each of 3 daily reversal learning training sessions in the Barnes maze, significantly enhanced performance compared to vehicle-treated controls and had a significant effect on search strategy. Mice treated with CDPPB also displayed significantly less perseverative behavior than control-treated animals. In a second experiment, male Sprague-Dawley rats were trained in an appetitively-motivated, delayed alternation version of a T-maze. 30mg/kg CDPPB (s.c.), delivered 20min prior to each of 5 daily training sessions, enhanced the delay rats were able to withstand between the sample and choice portions of each T-maze trial. The present results emphasize the role of mGlu5 receptors in spatial learning tasks and support previous studies which report mGlu5 positive allosteric modulators can enhance learning in some tasks and may have potential as nootropic drugs.

Remote cerebellar haemorrhage after lumbar spine surgery: case report.

Remote cerebellar haemorrhage (RCH) is a well-described complication of supratentorial surgical procedures with an incidence ranging between 0.2 and 4.9 %, but is a rare complication of spinal surgery. We report a case of RCH in a 65-year-old woman who showed sudden mental deterioration 48 h after lumbar spinal surgery, which was complicated by incidental dural tearing with minimal CSF loss. Brain CT scan revealed hypodense areas compatible with acute infarction involving mostly the left cerebellar hemisphere. No cerebral bleeding was observed. MRI was also performed revealing small cerebellar areas of acute infarction mainly relating the vermis and the left postero-inferior cerebellar hemisphere with haemorrhagic transformation and mass effect in the posterior fossa producing acute hydrocephalus. Haematoma removal was initially attempted by means of a suboccipital craniotomy. An external ventricular derivation was placed in a second procedure 24 h later due to the persistence of ventricular dilatation. At discharge the patient was only showing a slight dysmetria with the fine motor skills of hands and fingers. All cases of RCH after spinal surgery reported in the literature are invariably associated to iatrogenic dural tearing; although CSF loss seems to play the key role in the pathogenesis of this rare complication, the exact pathophysiology of this condition still remains undetermined.

The protective role of dynamic stabilization on the adjacent disc to a rigid instrumented level. An in vitro biomechanical analysis.

OBJECTIVES: To assess the changes of intradiscal pressure at the bridged and at the adjacent levels to a lumbar two-level hybrid instrumentation. INTRODUCTION: The elimination of motion produced by spinal fusion may have potential consequences beyond the index level overloading the juxtaposed spinal motion segments and leading to the appearance of degenerative changes. Degeneration of the segments adjacent to instrumented levels has become a topic of increasing interest in the literature over the last years. In order to prevent degenerative disc changes at the adjacent segments to a fused level, a broad scope of techniques have been developed, one of them is hybrid constructs. METHODS: In 6 human cadaveric lumbosacral specimens, pressure transducers quantified intradiscal pressure changes at three levels (L3-L4, L4-L5 and L5-S1) under axial compression (0-750 N), anterior flexion (+12°) and extension (-12°) in three different situations of spinal stability: intact, L5-S1 rigid rod pedicle screw instrumentation and L4-S1 two-level hybrid instrumentation (rigid at L5-S1 and dynamic at L4-L5). RESULTS: Once the L5-S1 segment had implanted the rigid instrumentation system (Diapason), the intradiscal pressure at this level decreased by 65 % while the intradiscal pressure at the disc above (L4-L5) increased 20 %. After augmenting the L5-S1 posterior construct with a dynamic stabilization device (Dynesys) at the superior adjacent level, the intradiscal pressure at this level, L4-L5, decreased by 50 % whereas intradiscal pressure at its adjacent level, L3-L4, only experienced a slight increase of 10 %. CONCLUSIONS: The raise of intradiscal pressure at the adjacent segment to a rigid instrumented segment can be reduced when the rigid construct is augmented with a dynamic stabilization device. Hybrid constructs might have a possible protecting role preventing the occurrence of degenerative disc changes at the adjacent segment to a rigid instrumented level. Augmentation with a dynamic stabilization device might protect the disc above a rigid rod pedicle screw construct.

Parsonage-Turner Syndrome After COVID-19 Vaccination in a Child.

Parsonage-Turner syndrome (PTS) is a peripheral neuropathy involving the brachial plexus very rare in childhood. To date, no cases of PTS after COVID-19 vaccination have been reported in children. We report a case of a 15-year-old boy affected by PTS after the second dose of the BNT162b2 (Comirnaty, Pfizer-BioNTech) COVID-19 vaccine.

Sagittal imbalance influences outcome of vertebroplasty in patients with osteoporotic vertebral compression fracture. / Influencia del desequilibrio sagital en el resultado clínico de la vertebroplastia en pacientes con fractura por compresión vertebral osteoporótica.

BACKGROUND AND OBJECTIVES: The correlation between sagittal balance of the spine and clinical outcome after vertebroplasty (VP) in patients with osteoporotic vertebral compression fractures (OVCF) is poorly investigated. We analysed the clinical outcome of patients with OVCF undergoing VP taking into account sagittal balance. MATERIAL AND METHOD: The primary endpoint was the change in axial back pain, disability and health-related quality-of-life using Visual Analogue Scale (VAS), Oswestry Disability Index (ODI) and SF-36, respectively, in correlation to the parameters that define sagittal balance (SVA). Radiographic assessment included full spine standing lateral films. Imaging and clinical data were collected pre- and post-procedure at 1, 3 and 12 months. RESULTS: 51 patients were included presenting a total of 113 OVCF. 30 patients (60.7%) had multiple OVCF. Comparing the evolution of VAS and ODI throughout the follow-up it does not seem that there are significant differences in their behaviour between the SVA>50mm and the SVA<50mm groups (p>0.05). On the contrary, pre-VP SF-36 scores showed worst results in the SVA>50mm group in the physical functioning (PF) section (p<0.05) and in the physical component score (PCS) (p<0.05). These differences were maintained until 3 months of follow-up in the case of the PCS and until the end of follow-up in the case of the PF (p<0.05). CONCLUSIONS: Patients with a SVA>50mm showed a slower recovery of their quality-of-life after VP for OVCF, but without significant differences with respect to pain or disability, when compared patients with SVA<50mm.

[Translated article] Sagittal imbalance influences outcome of vertebroplasty in patients with osteoporotic vertebral compression fracture.

BACKGROUND AND OBJECTIVES: The correlation between sagittal balance of the spine and clinical outcome after vertebroplasty (VP) in patients with osteoporotic vertebral compression fractures (OVCF) is poorly investigated. We analysed the clinical outcome of patients with OVCF undergoing VP taking into account sagittal balance. METHODS: The primary endpoint was the change in axial back pain; disability and health-related quality of life using VAS, ODI and SF-36 respectively in correlation to the parameters that define sagittal balance (SVA). Radiographic assessment included full spine standing lateral films. Imaging and clinical data were collected pre and post procedure at 1, 3 and 12 months. RESULTS: Fifty-one patients were included presenting a total of 113 OVCF. Thirty patients (60.7%) had multiple OVCF. Comparing the evolution of VAS and ODI throughout the follow-up it does not seem that there are significant differences in their behaviour between the SVA>50mm and the SVA<50mm groups (p>0.05). On the contrary, preVP SF-36 scores showed worst results in the SVA>50mm group in the physical functioning section (PF) (p<0.05) and in the physical component score (PCS) (p<0.05). These differences were maintained until 3 months of follow-up in the case of the PCS and until the end of follow-up in the case of the PF (p<0.05). CONCLUSIONS: Patients with a SVA>50mm showed a slower recovery of their quality of life after VP for OVCF, but without significant differences with respect to pain or disability, when compared with patients with SVA<50mm.

Functional interaction of mGlu5 and NMDA receptors in aversive learning in rats.

Metabotropic glutamate receptor 5 (mGlu5) has been implicated in a variety of learning processes and is important for inhibitory avoidance and conditioned taste aversion learning. MGlu5 receptors are physically connected with NMDA receptors and they interact with, and modulate, the function of one another in several brain regions. The present studies used systemic co-administration of an mGlu5 receptor positive allosteric modulator, 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (CDPPB) and an NMDA receptor antagonist dizocilpine maleate (MK-801) to characterize the interactions of these receptors in two aversive learning tasks. Male Sprague-Dawley rats were trained in a single-trial step-down inhibitory avoidance or conditioned taste aversion task. CDPPB (3 or 10mg/kg, s.c.), delivered by itself prior to the conditioning trial, did not have any effect on performance in either task 48 h after training. However, CDPPB (at 3mg/kg) attenuated the MK-801 (0.2mg/kg, i.p.) induced learning deficit in both tasks. CDPPB also reduced MK-801-induced hyperactivity. These results underlie the importance of mGlu5 and NMDA receptor interactions in modulating memory processing, and are consistent with findings showing the efficacy of positive allosteric modulators of mGlu5 receptors in reversing the negative effects of NMDA receptor antagonists on other behaviors such as stereotypy, sensorimotor gating, or working, spatial and recognition memory.

Coccolith crystals: Pure calcite or organic-mineral composite structures?

The localization of organic material within biominerals is central to developing biomineral formation mechanisms. Coccoliths, morphologically sophisticated calcite platelets of intracellularly calcifying coccolithophores, are not only eco-physiologically important, but also influence biogeochemical cycles through mass production. Despite their importance and over a century of research, the formation mechanism of coccoliths is still poorly understood. Crucial unsolved questions include the localization of organic material within coccoliths. In extracellular calcifiers the discovery of an organics-containing nano-structure within seemingly single crystals has led to the formulation of a two-step crystallization mechanism. Coccoliths are traditionally thought of as being formed by a different mechanism, but it is unclear whether coccolith crystals possess a nano-structure. Here we review the evidence for and against such a nano-structure. Current SXPD analyses suggest a nano-structure of some kind, while imaging methods (SEM, TEM, AFM) provide evidence against it. We suggest directions for future research which should help solve this puzzle. STATEMENT OF SIGNIFICANCE: Coccolithophores, unicellular calcifying algae, are important primary producers and contribute significantly to pelagic calcium carbonate export. Their calcite platelets, the coccoliths, are amongst the most sophisticated biomineral structures. Understanding the crystallization mechanism of coccolith crystals is not only central to coccolithophore cell biology but also lies at the heart of biomineralization research more generally. The crystallization mechanism of coccoliths has remained largely elusive, not least because it is still an open question whether the micron sized coccolith crystals are pure calcite, or contain organic material. Here we review the state of the art and suggest a way to solve this central problem.

Cardiac T2* magnetic resonance for prediction of cardiac complications in thalassemia major.

BACKGROUND: The goal of this study was to determine the predictive value of cardiac T2* magnetic resonance for heart failure and arrhythmia in thalassemia major. METHODS AND RESULTS: We analyzed cardiac and liver T2* magnetic resonance and serum ferritin in 652 thalassemia major patients from 21 UK centers with 1442 magnetic resonance scans. The relative risk for heart failure with cardiac T2* values <10 ms (compared with >10 ms) was 160 (95% confidence interval, 39 to 653). Heart failure occurred in 47% of patients within 1 year of a cardiac T2* <6 ms with a relative risk of 270 (95% confidence interval, 64 to 1129). The area under the receiver-operating characteristic curve for predicting heart failure was significantly greater for cardiac T2* (0.948) than for liver T2* (0.589; P<0.001) or serum ferritin (0.629; P<0.001). Cardiac T2* was <10 ms in 98% of scans in patients who developed heart failure. The relative risk for arrhythmia with cardiac T2* values <20 ms (compared with >20 ms) was 4.6 (95% confidence interval, 2.66 to 7.95). Arrhythmia occurred in 14% of patients within 1 year of a cardiac T2* of <6 ms. The area under the receiver-operating characteristic curve for predicting arrhythmia was significantly greater for cardiac T2* (0.747) than for liver T2* (0.514; P<0.001) or serum ferritin (0.518; P<0.001). The cardiac T2* was <20 ms in 83% of scans in patients who developed arrhythmia. CONCLUSIONS: Cardiac T2* magnetic resonance identifies patients at high risk of heart failure and arrhythmia from myocardial siderosis in thalassemia major and is superior to serum ferritin and liver iron. Using cardiac T2* for the early identification and treatment of patients at risk is a logical means of reducing the high burden of cardiac mortality in myocardial siderosis. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00520559.

Evidence for homologous actions of pro-opiocortin products.

alpha-Melanocyte-stimulating hormone (alpha-MSH), a modified fragment of adrenocorticotropic hormone, derives from the same biosynthetic route as beta-endorphin and is stored by the same arcuate neurons. Microinjection of alpha-melanocyte-stimulating hormone and several related peptides into the periaqueductal gray matter significantly reduced responsiveness to pain and had a behavioral profile similar to that produced by beta-endorphin.

Nonopiate effects of dynorphin and des-Tyr-dynorphin.

Intracerebroventricular administration of dynorphin produced potent and long-lasting effects on motor function and the electroencephalogram in rats. In addition, local iontophoretic or pressure ejection of dynorphin consistently inhibited hippocampal unit activity. None of these effects were significantly affected by naloxone even at high doses. Moreover, a fragment of dynorphin that failed to displace any of a number of tritiated narcotics from rat brain homogenates produced similar effects on these physiological measures in vivo. On the basis of a variety of criteria for "opiate action," the results suggest that a second biologically active site within the dynorphin sequence is capable of quite potent but nonopiate effects.