Probable pulmonary embolism with repeat administration of prothrombin complex concentrate in a factor Xa inhibitor patient.

WHAT IS KNOWN AND OBJECTIVE: Prothrombin complex concentrate (PCC) is a plasma-derived concentrate used to replenish clotting factors. There are limited recommendations for treating coagulopathy induced by direct oral anticoagulants (DOAC). Data are limited regarding both total dose and repeated dosing with this population. CASE SUMMARY: We describe a case of an adult patient anticoagulated with apixaban who received two 35 unit/kg doses of PCC resulting in suspected pulmonary embolism. WHAT IS NEW AND CONCLUSION: Treatment of DOAC-induced bleeding remains an "off-label" indication for PCC. Additional doses should be given with caution if given at all and patients monitored closely.

Therapeutic opportunities in polyglutamine disease.

Polyglutamine diseases comprise a class of familial neurodegenerative disorders caused by expression of proteins containing expanded polyglutamine tracts. Great progress has been made in elucidating the molecular mechanisms contributing to polyglutamine pathology, and in identifying potential drug targets. Although much remains to be learned, these advances provide an opportunity for rational approaches to target-based drug discovery.

Alveolar rhabdomyosarcoma originating between the fourth and fifth metatarsal--case report and literature review.

We report a case of alveolar rhabdomyosarcoma arising between the fourth and fifth metatarsal. A 13-year-old boy presented to outpatients with a history of pain and swelling in the lateral aspect of his left forefoot. Plain radiographs and MRI showed a soft tissue mass displacing the fourth metatarsal. Percutaneous biopsy revealed an alveolar rhabdomyosarcoma. Staging scans showed advanced metastatic disease. The patient was treated with chemotherapy. This highly malignant lesion remains challenging to diagnose, and difficult to treat successfully.

Structure of pressinoic acid: the cyclic moiety of vasopressin.

Arginine vasopressin consists of a 20-membered, disulfide-linked macrocyclic ring system called pressinoic acid to which is attached a COOH-terminal tripeptide. The molecular conformation of pressinoic acid has been determined from single crystal x-ray diffraction data. The 20-membered macrocyclic ring, stabilized by two intramolecular hydrogen bonds, has a type I beta-bend centered on Gln4 and Asn5 and a highly distorted type II' bend centered on Phe3 and Gln4. In vasopressin the Asn5 side chain extends away from the macrocyclic ring system and hydrogen bonds to the terminal tripeptide, but in pressinoic acid the Asn5 side chain lies over the molecule and forms a strong hydrogen bond to the nitrogen of Tyr2. The absence of pressor activity in pressinoic acid may be a result of both the loss of the COOH-terminal tripeptide and the incorrect orientation of the Asn5 side chain. Whether this class of hormones has pressor or oxytocic activity is determined by the orientation of the Tyr2 side chain, that is, whether it is extended away from or over the ring system, respectively. In pressinoic acid, the Tyr2 side chain is in the expected "pressor conformation," that is, extended away from the ring system, and is stabilized through a hydrophobic interaction with the Phe3 side chain. Thus, the conformation of the pressinoic acid molecule partly explains the activity of vasopressin-like hormones.

Mauritian Endemic Medicinal Plant Extracts Induce G2/M Phase Cell Cycle Arrest and Growth Inhibition of Oesophageal Squamous Cell Carcinoma in Vitro.

Terrestrial plants have contributed massively to the development of modern oncologic drugs. Despite the wide acceptance of Mauritian endemic flowering plants in traditional medicine, scientific evidence of their chemotherapeutic potential is lacking. This study aimed to evaluate the in vitro tumor cytotoxicity of leaf extracts from five Mauritian endemic medicinal plants, namely Acalypha integrifolia Willd (Euphorbiaceae), Labourdonnaisia glauca Bojer (Sapotaceae), Dombeya acutangula Cav. subsp. rosea Friedmann (Malvaceae), Gaertnera psychotrioides (DC.) Baker (Rubiaceae), and Eugenia tinifolia Lam (Myrtaceae). The cytotoxicities of the extracts were determined against six human cancer cell lines, including cervical adenocarcinoma, colorectal carcinoma, oesophageal adenocarcinoma, and oesophageal squamous cell carcinoma. The potent extracts were further investigated using cell cycle analysis and reverse phase protein array (RPPA) analysis. The antioxidant properties and polyphenolic profile of the potent extracts were also evaluated. Gas chromatography mass spectrometry (GC-MS) analyses revealed the presence of (+)-catechin and gallocatechin in E. tinifolia and L. glauca, while gallic acid was detected in A. integrifolia. L. glauca, A. integrifolia, and E. tinifolia were highly selective towards human oesophageal squamous cell carcinoma (KYSE-30) cells. L. glauca and E. tinifolia arrested KYSE- 30 cells in the G2/M phase, in a concentration-dependent manner. RPPA analysis indicated that the extracts may partly exert their tumor growth-inhibitory activity by upregulating the intracellular level of 5'AMP-activated kinase (AMPK). The findings highlight the potent antiproliferative activity of three Mauritian endemic leaf extracts against oesophageal squamous cell carcinoma and calls for further investigation into their chemotherapeutic application.

Readmission Rates for One Versus Two-Midnight Length of Stay for Primary Total Knee Arthroplasty: Analysis of the Michigan Arthroplasty Registry Collaborative Quality Initiative (MARCQI) Database.

BACKGROUND: The length of stay (LOS) in the hospital for total knee arthroplasty (TKA) has been declining over recent decades. The purpose of this study was to determine if patients with an LOS for TKA that includes only 1 midnight have an increased odds of 90-day readmission compared with those with a 2-midnight LOS. We also sought to identify any predictors of 90-day hospital readmission among those readmitted during our period of analysis. METHODS: A retrospective review of the Michigan Arthroplasty Registry Collaborative Quality Initiative (MARCQI) database was performed to identify patients with a 1-midnight or 2-midnight LOS for TKA during a 5-year period. The primary end point of this study was inpatient readmission within the 90-day postoperative period. A multiple logistic regression model and propensity score matching were used to compare the odds of 90-day readmission between 1-midnight and 2-midnight LOS. The secondary end points of this study were 90-day complications. RESULTS: There were 96,250 TKA procedures identified in the database, and 46,709 met our inclusion criteria for LOS. No difference in 90-day-readmission odds between patients with a 1-midnight LOS and those with a 2-midnight LOS for primary TKA was identified. Male sex, single marital status, age of ≥80 years, type-I diabetes, previous smoking, narcotic use prior to surgery, and a higher American Society of Anesthesiologists (ASA) scores increased the odds of 90-day readmission. Patients in the age group of ≥50 to <65 years, those with a higher preoperative hemoglobin level, and those with a positive social history of alcohol use were found to have decreased odds of readmission. CONCLUSIONS: We found no association between the LOS for primary TKA (1 midnight compared with 2 midnights) and the 90-day readmission risk. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

Systematic and large-scale two-hybrid screens.

The increasing rate at which complete genome sequences become available necessitates rapid and robust methods for investigating the functions of their encoded proteins. Efforts have been made to study protein function by systematically screening large sets of proteins using the two-hybrid method. Analyses of the complete proteomes of baceriophage T7, the mammalian viruses hepatitis C and vaccinia, as well as of several protein complexes including RNA splicing proteins and RNA polymerase III from yeast, have been undertaken. Saccharomyces cerevisiae has been studied extensively by two-hybrid methods, with more than 2500 protein-protein interactions described. Systematic studies on metazoan proteomes are, however, still in their infancy.

Ca2+-dependent conformational changes in bovine GCAP-2.

GCAP-2, a mammalian photoreceptor-specific protein, is a Ca2+-dependent regulator of the retinal membrane guanylyl cyclases (Ret-GCs). Sensing the fall in intracellular free Ca2+ after photo-excitation, GCAP-2 stimulates the activity of Ret-GC leading to cGMP production. Like other members of the recoverin superfamily, GCAP-2 is a small N-myristoylated protein containing four EF-hand consensus motifs. In this study, we demonstrate that like recoverin and neurocalcin, GCAP-2 alters its conformation in response to Ca2+-binding as measured by a Ca2+-dependent change in its far UV CD spectrum. Differences in the conformation of the Ca2+-bound and Ca2+-free forms of GCAP-2 were also observed by examining their relative susceptibility to V8 protease. In contrast to recoverin, we do not observe proteolytic cleavage of the myristoylated N-terminus of Ca2+-bound GCAP-2. NMR spectra also show that, in contrast to recoverin, the chemical environment of the N-terminus of GCAP-2 is not dramatically altered by Ca2+ binding. Despite the similarity of GCAP-2 and recoverin, the structural consequences of Ca2+-binding for these two proteins are significantly dissimilar.

The effects of ascorbic acid and flavonoids on the occurrence of symptoms normally associated with the common cold.

A controlled study was made of the effects of natural orange juice, synthetic orange juice, and placebo in the prevention of the common cold; both natural and synthetic orange juices contained 80 mg of ascorbic acid daily. Three-hundred sixty-two healthy normal young adult volunteers, ages 17 to 25 years, were studied for 72 days with 97% of participants completing the trial. There was a 14 to 21% reduction in total symptoms due to the common cold in the supplemented groups that was statistically significant (P less than 0.05). Ascorbic acid supplementation also increased the number of "episode-free" subjects. However, the clinical usefulness of the results does not support prophylactic ascorbic acid supplements in the well-nourished adult. The results in this study with both natural and synthetic orange juice of physiological content of ascorbic acid, are similar to those obtained using a "megadose" of ascorbic acid.

Quercetin, flavonoids and the life-span of mice.

A dietary supplement of 0.1% quercetin significantly reduced the life span of mice. The effect was predominantly on the 'shorter living' males. A blackcurrant juice extract, containing a mixture of flavonoids in addition to quercetin, prolonged significantly the life span of the 'older dying' females. The significance of these results vis-a-vis aging mechanisms and the dietary intake of quercetin is discussed.

Evaluation of muscle force prediction models of the lumbar trunk using surface electromyography.

Optimization-based models for prediction of muscle forces in the lumbar region of the torso are used to estimate the forces acting on spinal motion segments, especially for asymmetric tasks. The objectives of this study were to determine (a) which of four torso model formulations best predicted the electromyographic data, (b) the difference in muscular contribution to spinal compression force for the four models, and (c) the effect of using the lowest possible muscle stress bound in the model formulation. An approach for the investigation of competing optimization model formulations was developed and was illustrated with electromyographic data from static asymmetric loading conditions. This method is based on (a) the choice of experimental conditions in which models predict decidedly different muscle forces, and (b) the ability to ensure that the experimental conditions are such that the minimum number of assumptions about the force-electromyogram relationship must be made in order to choose between competing model predictions. Of the four models analyzed, only the formulation with an objective function that was the sum of cubed muscle stresses predicted the electromyographic data acceptably. The muscular contribution to spinal compression force predicted by these models differed by as much as 160% for some experimental conditions. The use of the lowest possible muscle stress bound does not appear to predict muscle forces that are in agreement with electromyographic data.

Food intake, dietary supplements and survival time of scorbutic guinea pigs.

Manual presentation of a liquid scorbutogenic diet permitted a more complete characterisation of the terminal stages of scurvy in guinea pigs. A bioflavonoid preparation from orange peel, previously shown both to increase the tissue concentrations of ascorbic acid and to stimulate the growth of hypovitaminotic C guinea pigs, had no influence on the survival time of scorbutic guinea pigs. Tetrahydrofolic acid, reported to possess 40% of the activity of ascorbic acid in the protocollagen proline-hydroxylase system, also failed significantly to prolong the survival period. This latter finding could indicate that ascorbic acid has essential biochemical functions in addition to its involvement in the hydroxylation of proline and lysine.

Biomechanical effect of medial advancement of the supraspinatus tendon. A study in cadavera.

During the repair of some rotator-cuff tears, the torn tendon cannot be freed up adequately to permit reattachment at its original anatomical site of insertion. An option is to advance the site of insertion medially and reattach the tendon to a trough in the sulcus or to the humeral head. The biomechanical effects of such medial advancement on the moment arm of the supraspinatus muscle during glenohumeral elevation were studied in ten fresh-frozen shoulders from cadavera. Medial advancement of the site of insertion of the supraspinatus tendon was simulated by the placement of suture anchors in the sulcus of the proximal part of the humerus at points three, ten, and seventeen millimeters medial to the junction of the supraspinatus tendon and the bone. These distances were chosen not because they represent clinical options but because the large range allowed biomechanical study of medial advancement. Nylon lines were attached to the suture anchors and were passed back through an eyehook at the midpoint of the supraspinatus muscle. The excursion of each line was measured as the humerus was elevated, and the moment arm was estimated from the joint angle and excursion data with use of the principle of virtual work. Three and ten millimeters of medial advancement of the tendon (attachment in the sulcus) had a minimum (non-significant) effect on the moment arm during elevation compared with the value determined for the intact condition. However, seventeen millimeters of medial advancement was found to reduce the moment arm significantly (p < 0.05).

Effect of optimization criterion on spinal force estimates during asymmetric lifting.

Optimization-based muscle force prediction models of the lumbar region are used in research and ergonomic practice, usually as a subroutine of a job analysis software package. Various optimization criteria have been put forward for use in rationally selecting a set of muscle forces to satisfy moment equilibrium, including the sum of cubed muscle contraction intensities and a double linear programming procedure for minimizing the spinal compression force and maximum muscle contraction intensity. A laboratory study was conducted to determine whether these two model formulations produce significantly different estimates of spinal forces for a dynamic asymmetric lift. Although statistically significant differences were found between the predictions of the two models, the difference in peak spinal compression force was only 1.1%.

The effect of strict muscle stress limits on abdominal muscle force predictions for combined torsion and extension loadings.

The objective of this study was to determine to what extent the central nervous system activates torso muscles so as to equalize the largest muscle stresses. Two optimization models that treat large muscle stresses differently were formulated. One model minimized spinal compression force subject to the lowest possible muscle stress limit, and the other model minimized the sum of cubed muscle stresses. Experimental conditions were determined for which the two models made different muscle force predictions. Specifically, the models predicted different rectus abdominis activity levels for tasks involving torsion and extension moment loadings. Surface electromyography was used to evaluate the model predictions. Applied loads were chosen to assure that the rectus abdominis EMG exceeded 30% MVC. Analysis of variance indicated that rectus abdominis activity was not affected by torsion loading at the p < 0.05 level of significance in a statistical design having 90% power, which was consistent with the predictions of the model that minimized the sum of cubed muscle stresses. Thus, it was concluded that equalization of the largest muscles stress was not the paramount objective of the central nervous system in the tasks studied.

Evaluating the effect of co-contraction in optimization models.

The effect of co-contraction of antagonist muscles on spinal compression force is estimated using Karush-Kuhn-Tucker (K-K-T) multipliers. Co-contraction is modelled as an incremental increase in the lower bounds on the allowable muscle forces in an optimization model formation. The K-K-T multipliers associated with each lower bound provide an estimate of the partial derivate of the optimal objective function value with respect to a change in the lower bound. A model whose objective function is spinal compression force is analyzed to estimate the effect of co-contraction on spinal compression force. While the effect depends on the specific muscle and task under consideration, the marginal effect of co-contraction on spinal compression force can be as high as 5.52 N additional spinal compression force for every additional N of muscle force. Paradoxically, the co-contraction may slightly decrease predicted spinal compression in special circumstances.

Comparison of two methods for computing abduction moment arms of the rotator cuff.

Biomechanical models of the shoulder mechanism require estimates of muscle moment arm magnitude. Some shoulder models have estimated muscle moment arms by assuming an idealized minimum distance path from the origin to insertion that passes around the bony geometry. Alternatively, the principle of virtual work can be used to estimate moment arms from tendon excursion and joint-angle data. The purpose of this study was to determine if these two methods give different estimates of abduction moment arms for the supraspinatus, infraspinatus, and subscapularis muscles. Muscle moment arms were estimated for these muscles on ten fresh frozen cadaver specimens. The results showed a significant difference between the two estimation methods. Average differences were 3.1 mm (10.6%), 3.9 mm (43.9%), and 7.2 mm (70.3%) for the supraspinatus, subscapularis, and infraspinatus muscles, respectively. These results suggest that shoulder models based on the origin-insertion method may give higher rotator cuff muscle force estimates than methods using the slope of the tendon excursion vs joint angle relationship.

Torso loading via a harness method activates trunk muscles less than a hand loading method.

There is a need for data comparing muscle activity under equivalent moments at the torso using different loading methods. In torso biomechanics, it is often necessary to apply moments to people and then measure or predict the muscle activity in response to the external load. Alternative methods exist to generate moments including applying forces by a chest harness and loads held in the hands. The limitation of previous research has been to use only one of the loading methods, generally harness loading, assuming it produces muscle activity equal to when loads are held in the hands. The objective of the this study was to test if equivalent moments at L3/L4 applied to subjects through two loading methods resulted in the same muscle activity. Subjects maintained a static posture while attempting a combination of flexion/extension, lateral bending, and torsion to counter the external loads applied via hand and harness loading methods. Hand and harness loading did not result in equal muscle activity as measured by electromyographic techniques. The left and right latissimus dorsi had increases in activity (16-25%) when loads were held with the hands instead of applied via the harness. Increased activity for hand loading was also found for the left and right rectus abdominis (13-17%) and left external oblique (24%). The left and right erector spinae and right external oblique exhibited the same activity for both loading methods. The current findings indicate that studies of torso loading using a shoulder harness to create torso moments may be lowering activity of some torso muscles.