The unexpected evolution of myocardial injury while infected with the coronavirus: A COVID-19 case report.

Background: A novel virus breakout in December 2019, with diverse clinical manifestations, initially identified as infecting the respiratory system, has spread rapidly around the world, with adverse effects which have caused acute myocardial injury and chronic damage to the cardiovascular system in some individuals. Aim: To present a clinical case with the manifestation of COVID-19 suspected to be either a mild case of either myocarditis or pericarditis. This case highlights a relatively atypical presentation of COVID-19 and the value of a coordinated approach to the unexpected sequences of patient recovery patterns that may require further specialist referral and intervention. Findings: A ribonucleic acid (RNA) viral infection was confirmed by a polymerase chain reaction with reverse transcription (RT-PCR) and the patient was diagnosed with coronavirus disease 2019 (COVID-19). The presenting symptoms failed to resolve and the patient was admitted to the accident and emergency (A&E) department. Upon the second visit to the A&E department at 27 days postinfection, an electrocardiograph (ECG) was conducted revealing T wave inversion. Implications: A coordinated approach is needed to combat the infection, develop cardiac-protective strategies and direct supportive measures.

The Isokinetic Rugby Union Physical Work Evaluation (RUPWE) protocol: Can Rugby Union Players meet the physical work demands of the game?

Background: To protect the lumbar spine from excessive forces, rugby union players need to demonstrate the work ability of the trunk extensors and flexors to meet the physical demands. Aim: To measure and evaluate whether rugby union players were able to meet the imposed physical work demand, considering limitations, tolerances and resistance to fatigue, using isokinetic dynamometry for trunk extensors (TE) and trunk flexors (TF). Methods: Fifty-five male players, between the ages of 18 and 23 years, participated in the study. All participants completed a PAR-Q (pre-activity risk) questionnaire before the isokinetic testing. Their height was between 1.80 ± 0.67 m and body mass was 86.0 ± 17.5 kg. Participants were subjected to a newly designed protocol using the Biodex Isokinetic System 3 Dynamometer, called the Rugby Union Physical Work Evaluation (RUPWE). Results: There was a significant difference between the forwards' trunk extensor peak torque to body weight 488% ± 119% and the trunk flexor peak torque to body weight 289% ± 73%. Furthermore, there was a large effect size between trunk extensor and trunk flexor muscle performance for the forwards (d =2.0) and backs (d =1.9) for peak torque to body weight. Spearman's rank-order correlations (rs) showed a moderate negative correlation for the forwards between trunk extensor peak torque to body weight and time to peak torque, (rs = -0.4; p=0.018). There is a strong negative correlation for the backs between trunk extensor peak torque to body weight and time to peak torque, (rs = -0.6; p=0.003). Conclusion: The physical work evaluation protocol can be used as a screening tool for rugby players as it measures the extensive mechanical load placed on the lumbar region. This has the potential to evaluate their athletic performance for the demands of tackling and scrumming.

Nicotine-induced enhancement of a sensory reinforcer in adult rats: antagonist pretreatment effects.

RATIONALE AND OBJECTIVES: The reinforcement-enhancing effect (REE) of nicotine refers to the drug's ability to enhance the strength of other primary and conditioned reinforcers. The main aim was to investigate neuropharmacological mechanisms underlying nicotine's strengthening of a primary visual reinforcer (i.e., a light cue), using a subcutaneous (SC) dose previously shown to provide plasma nicotine levels associated with habitual smoking. METHODS: Adult male rats pressed an "active" lever to illuminate a brief cue light during daily 60-min sessions. Rats that showed a clear REE were tested with systemically administered pretreatment drugs followed by nicotine (0.1 mg/kg SC) or saline challenge, in within-subject counterbalanced designs. Pretreatments were mecamylamine (nicotinic, 0.1-1 mg/kg SC), SCH 39166 (D1-like dopaminergic, 0.003-0.2 mg/kg SC), naloxone (opioid, 1 and 5 mg/kg SC), prazosin (alpha1-adrenergic antagonist, 1 and 2 mg/kg IP), rimonabant (CB1 cannabinoid inverse agonist, 3 mg/kg IP), sulpiride (D2-like dopaminergic antagonist, 40 mg/kg SC), or propranolol (beta-adrenergic antagonist, 10 mg/kg IP). RESULTS: The nicotine REE was abolished by three antagonists at doses that did not impact motor output, i.e., mecamylamine (1 mg/kg), SCH 39166 (0.01 and 0.03 mg/kg), and naloxone (5 mg/kg). Prazosin and rimonabant both attenuated the nicotine REE, but rimonabant also suppressed responding more generally. The nicotine REE was not significantly altered by sulpiride or propranolol. CONCLUSIONS: In adult male rats, the reinforcement-enhancing effect of low-dose nicotine depends on nicotinic receptor stimulation and on neurotransmission via D1/D5 dopaminergic, opioid, alpha1-adrenergic, and CB1 cannabinoid receptors.

Tolerogenic dendritic cells generated with dexamethasone and vitamin D3 regulate rheumatoid arthritis CD4+ T cells partly via transforming growth factor-ß1.

Tolerogenic dendritic cells (tolDC) are a new immunotherapeutic tool for the treatment of rheumatoid arthritis (RA) and other autoimmune disorders. We have established a method to generate stable tolDC by pharmacological modulation of human monocyte-derived DC. These tolDC exert potent pro-tolerogenic actions on CD4+ T cells. Lack of interleukin (IL)-12p70 production is a key immunoregulatory attribute of tolDC but does not explain their action fully. Here we show that tolDC express transforming growth factor (TGF)-ß1 at both mRNA and protein levels, and that expression of this immunoregulatory cytokine is significantly higher in tolDC than in mature monocyte-derived DC. By inhibiting TGF-ß1 signalling we demonstrate that tolDC regulate CD4+ T cell responses in a manner that is at least partly dependent upon this cytokine. Crucially, we also show that while there is no significant difference in expression of TGF-ßRII on CD4+ T cells from RA patients and healthy controls, RA patient CD4+ T cells are measurably less responsive to TGF-ß1 than healthy control CD4+ T cells [reduced TGF-ß-induced mothers against decapentaplegic homologue (Smad)2/3 phosphorylation, forkhead box protein 3 (FoxP3) expression and suppression of (IFN)-γ secretion]. However, CD4+ T cells from RA patients can, nonetheless, be regulated efficiently by tolDC in a TGF-ß1-dependent manner. This work is important for the design and development of future studies investigating the potential use of tolDC as a novel immunotherapy for the treatment of RA.

Two step continuous method to synthesize colloidal spheroid gold nanorods.

This research investigated a two-step continuous process to synthesize colloidal suspension of spheroid gold nanorods. In the first step; gold precursor was reduced to seed-like particles in the presence of polyvinylpyrrolidone and ascorbic acid. In continuous second step; silver nitrate and alkaline sodium hydroxide produced various shape and size Au nanoparticles. The shape was manipulated through weight ratio of ascorbic acid to silver nitrate by varying silver nitrate concentration. The specific weight ratio of 1.35-1.75 grew spheroid gold nanorods of aspect ratio ∼1.85 to ∼2.2. Lower weight ratio of 0.5-1.1 formed spherical nanoparticle. The alkaline medium increased the yield of gold nanorods and reduced reaction time at room temperature. The synthesized gold nanorods retained their shape and size in ethanol. The surface plasmon resonance was red shifted by ∼5 nm due to higher refractive index of ethanol than water.

Kiss1 mutant placentas show normal structure and function in the mouse.

INTRODUCTION: Kisspeptins, encoded by the Kiss1 gene, are a set of related neuropeptides that are required for activation of the mammalian reproductive axis at puberty and to maintain fertility. In addition, kisspeptin signaling via the G-protein coupled receptor GPR54 (KISS1R) has been suggested to regulate human placental formation and correlations have been found between altered kisspeptin levels in the maternal blood and the development of pre-eclampsia. METHODS: We have used Kiss1 and Gpr54 mutant mice to investigate the role of kisspeptin signaling in the structure and function of the mouse placenta. RESULTS: Expression of Kiss1 and Gpr54 was confirmed in the mouse placenta but no differences in birth weight were found in mice that had been supported by a mutant placenta during fetal development. Stereological measurements found no differences between Kiss1 mutant and wild-type placentas. Measurement of amino-acid and glucose transport across the Kiss1 mutant placentas at E15.5 days did not reveal any functional defects. DISCUSSION: These data indicate that mouse placentas can develop a normal structure and function without kisspeptin signaling and can support normal fetal development and growth.

Glucocorticoid receptor dimerization is required for proper recovery of LPS-induced inflammation, sickness behavior and metabolism in mice.

Endogenous glucocorticoids are essential for mobilizing energy resources, restraining inflammatory responses and coordinating behavior to an immune challenge. Impaired glucocorticoid receptor (GR) function has been associated with impaired metabolic processes, enhanced inflammation and exaggerated sickness and depressive-like behaviors. To discern the molecular mechanisms underlying GR regulation of physiologic and behavioral responses to a systemic immune challenge, GR(dim) mice, in which absent GR dimerization leads to impaired GR-DNA-binding-dependent mechanisms but intact GR protein-protein interactions, were administered low-dose lipopolysaccharide (LPS). GR(dim)-LPS mice exhibited elevated and prolonged levels of plasma corticosterone (CORT), interleukin (IL)-6 and IL-10 (but not plasma tumor necrosis factor-α (TNFα)), enhanced early expression of brain TNFα, IL-1ß and IL-6 mRNA levels, and impaired later central TNFα mRNA expression. Exaggerated sickness behavior (lethargy, piloerection, ptosis) in the GR(dim)-LPS mice was associated with increased early brain proinflammatory cytokine expression and late plasma CORT levels, but decreased late brain TNFα expression. GR(dim)-LPS mice also exhibited sustained locomotor impairment in the open field, body weight loss and metabolic alterations measured by indirect calorimetry, as well as impaired thermoregulation. Taken together, these data indicate that GR dimerization-dependent DNA-binding mechanisms differentially regulate systemic and central cytokine expression in a cytokine- and time-specific manner, and are essential for the proper regulation and recovery of multiple physiologic responses to low-dose endotoxin. Moreover, these results support the concept that GR protein-protein interactions are not sufficient for glucocorticoids to exert their full anti-inflammatory effects and suggest that glucocorticoid responses limited to GR monomer-mediated transcriptional effects could predispose individuals to prolonged behavioral and metabolic sequelae of an enhanced inflammatory state.

Resolving the challenge of measuring ligand binding to membrane proteins by combining analytical ultracentrifugation and light scattering photometry.

Membrane proteins are attractive therapeutic targets, however the presence of detergents complicates biophysical binding measurements. Difficulties in determining quantitative dissociation constants for problematic membrane proteins were addressed by combining analytical ultracentrifugation and classical light scattering techniques. Validation of the algorithm used to calculate dissociation constants from sedimentation equilibrium experiments was demonstrated by analyzing binding data of the inhibitor Y-27632 to rho-kinase (ROCK). Kd's of 1.3 ± 0.7 and 52 ± 27 µM were calculated for ROCK constructs (S6-R415) and (M71-E379) respectively, consistent with previously published Ki's of 1.4 ± 0.1 and > 30 µM. Extension of the algorithm to membrane proteins required the collection of light scattering data to determine the partial specific volume, ν, for the membrane protein-detergent complex. Vitamin B12 binding to the bacterial protein btuB in octyl ß-D-glucopyranoside (ß-OG) illustrates the applicability of the method. A ν of 0.781 ml/g was determined for the btuB-ß-OG complex. Incorporating this value into the algorithm generated a Kd of 7.0 ± 1.5 µM for the vitamin B12-btuB affinity. A Kd of 9.7 ± 2.7 µM was determined by equilibrium dialysis under similar experimental conditions. Successfully applying AUC to quantifying small-molecule ligand affinities to membrane proteins represents a significant advance to the field.

A cancer research UK pharmacokinetic study of BPA-mannitol in patients with high grade glioma to optimise uptake parameters for clinical trials of BNCT.

This paper describes results to-date from a human pharmacokinetic study which began recruitment in December 2007. Results are presented for a single patient recruited in December 2007. A second patient was recruited in July 2008 but detailed data are not available at the time of writing. The trial is an open-label, non-comparative, non-therapeutic study of BPA-mannitol in patients with high-grade glioma, who will be undergoing stereotactic brain biopsy as part of the diagnostic process before definitive treatment. The study investigates the route of infusion (intra-venous (IV) or intra-carotid artery) and in each case will assess the effect of administration of mannitol as a blood-brain barrier disrupter. All cohorts will receive a 2 h infusion of BPA-mannitol, and for some cohorts an additional mannitol bolus will be administered at the beginning of this infusion. Measurements are made by inductively coupled plasma mass spectrometry (ICP-MS) of (10)B concentration in samples of blood, urine, extra-cellular fluid in normal brain (via a dialysis probe), brain tissue around tumour and tumour tissue. Additional analysis of the tumour tissue is performed using secondary ion mass spectrometry (SIMS). The first patient was part of the cohort having intra-venous infusion without mannitol bolus. No serious clinical problems were experienced and the assay results can be compared with available patient data from other BNCT centres. In particular we note that the peak (10)B concentration in blood was 28.1 mg/ml for a total BPA administration of 350 mg/kg which is very consistent with the previous experience with BPA-fructose reported by the Helsinki group.

An audit of hospital based outpatient infusions and a pilot program of community-based monoclonal antibody infusions.

INTRODUCTION: Infliximab, a chimeric monoclonal antibody to tumour necrosis factor alpha, is administered as an intravenous infusion requiring a costly hospital day case or inpatient admission. METHODS: An audit of all current therapies given by intravenous infusions in an outpatient setting in St Vincent's University Hospital (SVUH) was undertaken. Furthermore, in conjunction with TCP homecare, we established in a general practise health clinic, the first Irish community infusion centre for the administration of infliximab in August 2006. RESULTS: All outpatient departments indicated that they would favour a centralized hospital infusion unit. There were no adverse events and the mean global satisfaction improved in the community infliximab infusion pilot programme of seven patients. CONCLUSION: This study suggests efficiencies in providing centralized infusion facilities, while the community based infusion of infliximab is feasible and safe in this small cohort and identifies the community infusion unit as a viable and cost efficient alternative for administration of infliximab.

Biomarkers in systemic sclerosis.

SSc is a CTD, which may cause critical organ fibrosis. It has a highly variable clinical presentation and course. While it is more common in females, this heterogeneity has led to significant problems with classification. Biomedical (clinical) and biomolecular markers to identify diagnostic, prognostic and therapeutic response have been elusive in part as a result of difficulties with classification and also due to the rarity of the disease. Existing biomarkers have been identified largely in small cohorts and larger cross-sectional or occasional longitudinal observational cohorts. The nature of biomarkers requires well-defined clinical characteristics and/or defined clinical outcomes and this has been extremely challenging to the international SSc research community. This brief review summarizes the current level of knowledge; however, it most importantly highlights the potential now to find biomarkers through a large, multicentre, international collaborative group approach.

Soil electrical conductivity and water content affect nitrous oxide and carbon dioxide emissions in intensively managed soils.

Accumulation of soluble salts resulting from fertilizer N may affect microbial production of N(2)O and CO(2) in soils. This study was conducted to determine the effects of electrical conductivity (EC) and water content on N(2)O and CO(2) production in five soils under intensive cropping. Surface soils from maize fields were washed, repacked and brought to 60% or 90% water-filled pore space (WFPS). Salt mixtures were added to achieve an initial in situ soil EC of 0.5, 1.0, 1.5 and 2.0 dS m(-1). The soil cores were incubated at 25 degrees C for 10 d. Average CO(2) production decreased with increasing EC at both soil water contents, indicating a general reduction in microbial respiration with increasing EC. Average cumulative N(2)O production at 60% WFPS decreased from 2.0 mg N(2)O-N m(-2) at an initial EC of 0.5 dS m(-1) to 0.86 mg N(2)O-N m(-2) at 2.0 dS m(-1). At 90% WFPS, N(2)O production was 2 to 40 times greater than that at 60% WFPS and maximum N(2)O losses occurred at the highest EC level of 2.0 dS m(-1). Differences in the magnitude of gas emissions at varying WFPS were due to available substrate N and the predominance of nitrification under aerobic conditions (60% WFPS) and denitrification when oxygen was limited (90% WFPS). Differences in gas emissions at varying soil EC may be due to changes in mechanisms of adjustment to salt stress and ion toxicities by microbial communities. Direct effects of EC on microbial respiration and N(2)O emissions need to be accounted for in ecosystems models for predicting soil greenhouse gas emissions.

Results of inguinal canal repair in athletes with sports hernia.

AIMS: To evaluate the role of surgical exploration and repair of the inguinal canal in athletes suspected of having a sports hernia. METHODS: Thirty-five (34 males, 1 female) athletes with a suspected sports hernia underwent surgical exploration and inguinal hernia repair. After six months, all athletes were sent questionnaires to assess any improvement in analogue pain scores, return to sport, recurrence of symptoms and the overall result of surgery. RESULTS: Operative findings revealed a tear in the external oblique aponeurosis with or without a significant posterior bulge (n=20), a lone significant posterior bulge (n=10), a tear in the conjoint tendon with dilated superficial ring (n=3), small direct hernial sac (n=1) and lipoma of the spermatic cord (n=1). Surgery consisted of repair of external oblique tear (when present) and prolene darn or lichtenstein mesh repair of the posterior inguinal canal. Twenty-seven patients replied to the questionnaire giving a response rate of 78%; of these, 25 patients (93%: 95% CI 83-100) had returned to normal athletic activities at pre-injury level. There was a marked improvement in level of pain (median pain level=8 pre-operative vs 2 post-operative, p<0.001). Eleven patients (41%) rated the results as excellent, eleven (41%) as good and five (18%) as fair and none worse. Six patients complained of occasional discomfort related to the scar. Three patients complained of recurrence of their symptoms after 4 to 5 months following strenuous exercise. CONCLUSION: Sports hernia presents with a spectrum of surgical findings. Athletes with sports hernia should be considered for routine hernia repair, as the majority of the patients benefit from surgery. It is important to offer a structured rehabilitation programme to maximise the benefits of surgery.

Expression of salt and urea transporters in rat kidney during cisplatin-induced polyuria.

BACKGROUND: Cisplatin (CP) induced polyuria in rats is associated with a reduction in medullary hypertonicity, normally generated by the thick ascending limb (TAL) salt transporters, and the collecting duct urea transporters (UT). To investigate the molecular basis of this abnormality, we determined the protein abundance of major salt and UT isoforms in rat kidney during CP-induced polyuria. METHODS: Male Sprague-Dawley rats received either a single injection of CP (5 mg/kg, N = 6) or saline (N = 6) intraperitoneally five days before sacrifice. Urine, blood, and kidneys were collected and analyzed. RESULTS: CP-treated rats developed polyuric acute renal failure as assessed by increased blood urea nitrogen (BUN), urine volume and decreased urine osmolality. Western analysis of kidney homogenates revealed a marked reduction in band density of the bumetanide-sensitive Na-K-2Cl cotransporter in cortex (60% of control values, P < 0.05), but not in outer medulla (OM) (106% of control values). There were no differences in band densities for the renal outer medullary potassium channel (ROMK), the type III Na-H exchanger (NHE3), the alpha-subunit of Na,K-ATPase in the OM; or for UT-A1, UT-A2 or UT-A4 in outer or inner medulla. However, the band pattern of UT-A2 and UT-A4 proteins in the OM of CP-treated rats was different from the control rats, suggesting a qualitative modification of these proteins. CONCLUSIONS: Changes in the abundance of outer or inner medullary salt or urea transporters are unlikely to play a role in the CP-induced reduction in medullary hypertonicity. However, qualitative changes in UT proteins may affect their functionality and thus may have a role.

Localization of the urea transporter UT-B protein in human and rat erythrocytes and tissues.

A new polyclonal antibody to the human erythrocyte urea transporter UT-B detects a broad band between 45 and 65 kDa in human erythrocytes and between 37 and 51 kDa in rat erythrocytes. In human erythrocytes, the UT-B protein is the Kidd (Jk) antigen, and Jk(a+b+) erythrocytes express the 45- to 65-kDa band. However, in Jk null erythrocytes [Jk(a-b-)], only a faint band at 55 kDa is detected. In kidney medulla, a broad band between 41 and 54 kDa, as well as a larger band at 98 kDa, is detected. Human and rat kidney show UT-B staining in nonfenestrated endothelial cells in descending vasa recta. UT-B protein and mRNA are detected in rat brain, colon, heart, liver, lung, and testis. When kidney medulla or liver proteins are analyzed with the use of a native gel, only a single protein band is detected. UT-B protein is detected in cultured bovine endothelial cells. We conclude that UT-B protein is expressed in more rat tissues than previously reported, as well as in erythrocytes.

UT-A urea transporter protein in heart: increased abundance during uremia, hypertension, and heart failure.

Urea transporters have been cloned from kidney medulla (UT-A) and erythrocytes (UT-B). We determined whether UT-A proteins could be detected in heart and whether their abundance was altered by uremia or hypertension or in human heart failure. In normal rat heart, bands were detected at 56, 51, and 39 kDa. In uremic rats, the abundance of the 56-kDa protein increased 1.9-fold compared with pair-fed, sham-operated rats, whereas the 51- and 39-kDa proteins were unchanged. We also detected UT-A2 mRNA in hearts from control and uremic rats. Because uremia is accompanied by hypertension, the effects of hypertension per se were studied in uninephrectomized deoxycorticosterone acetate salt-treated rats, where the abundance of the 56-kDa protein increased 2-fold versus controls, and in angiotensin II-infused rats, where the abundance of the 56 kDa protein increased 1.8-fold versus controls. The 51- and 39-kDa proteins were unchanged in both hypertensive models. In human left ventricle myocardium, UT-A proteins were detected at 97, 56, and 51 kDa. In failing left ventricle (taken at transplant, New York Heart Association class IV), the abundance of the 56-kDa protein increased 1.4-fold, and the 51-kDa protein increased 4.3-fold versus nonfailing left ventricle (donor hearts). We conclude that (1) multiple UT-A proteins are detected in rat and human heart; (2) the 56-kDa protein is upregulated in rat heart in uremia or models of hypertension; and (3) the rat results can be extended to human heart, where 56- and 51-kDa proteins are increased during heart failure.

Controlled randomised crossover trial of the effects of physiotherapy on mobility in chronic multiple sclerosis.

OBJECTIVES: To determine whether physiotherapy can improve mobility in chronic multiple sclerosis and whether there is a difference between treatment at home and as a hospital outpatient? METHODS: A randomised controlled crossover trial was undertaken in patients with chronic multiple sclerosis who had difficulty walking and were referred from neurology clinics: allocation was to one of six permutations of three 8 week treatment periods separated by 8 week intervals: treatments consisted of physiotherapy at home, as an outpatient, or "no therapy". The main outcome measures were based on independent assessments at home and included mobility related disability (primary outcome: the Rivermead mobility index), gait impairments, arm function, mood, and subjective patient and carer ratings. Therapy was assessed by recording delivery, achievement of set targets, patient and carer preference, and cost. RESULTS: On the Rivermead mobility index (scale 0-15) (primary outcome) there was a highly significant (p<0.001) treatment effect of 1.4-1.5 units favouring hospital or home based therapy over no therapy: this was supported by other measures of mobility, gait, balance, and the assessor's global "mobility change" score: there was no major difference between home and hospital. Carers preferred home treatment but neither they nor patients discerned greater benefit there. Estimated costs of home physiotherapy were 25 pounds/session and those at hospital were 18 pounds (including 7 pounds patient travel costs). CONCLUSION: A course of physiotherapy is associated with improved mobility, subjective wellbeing, and improved mood in chronic multiple sclerosis compared with no treatment but benefit may only last a few weeks: there is little to choose between home and hospital based therapy but the first is more costly, mainly due to skilled staff travelling time.