HEART Score and Stress Test Emergency Department Bayesian Decision Scheme: Results from the Acute Care Diagnostic Collaboration.

BACKGROUND: Accurate identification of patients at risk of major adverse cardiac events (MACE) places a substantial burden on emergency physicians (EPs). Bayesian nomogram for risk stratification in low- to intermediate-risk cardiovascular patients has not been investigated previously. OBJECTIVE: The objective of this study was to develop a comparative diagnostic model using Bayesian statistics for exercise treadmill test (ETT) and stress echocardiogram (ECHO) to calculate post-test diagnostic risk of MACE using HEART (history, electrocardiogram, age, risk factors, and troponin) risk score as predictor of pretest probability. METHODS: Stratification was made by applying HEART scores for the prediction of MACE. Likelihood ratios (LR) were calculated using pooled sensitivity and specificity of ETT and ECHO from the American College of Cardiology Foundation/American Heart Association systematic review. Post-test probabilities were obtained after inserting HEART score and LR into Bayesian nomogram. Analysis of variance was used to assess statistical association. RESULTS: Positive LR (LR+) for ETT was 4.56 and negative LR (LR-) was 0.27; for ECHO, LR+ 5.65 and LR- 0.15. Bayesian statistical modeling post-test probabilities for LR+ and low HEART risk yielded a post-test probability for ETT of 7.75% and 9.09% for ECHO; intermediate risk gave 47.62% and 52.63%, respectively. For LR-, low HEART risk post-test probability for ETT was 0.46% and for ECHO 0.26%; intermediate risk probabilities were 4.48% and 2.49%, respectively. LR- was statistically significant in ruling out MACE with ECHO (p < 0.001), but no significant differences were seen for LR+ (p = 0.64). CONCLUSIONS: This Bayesian analysis demonstrated slight superiority of stress ECHO over ETT in low- and intermediate-risk patients in ruling out MACE.

Can Achilles tendinosis be treated effectively with lidocaine and glucose infiltrations, and if so, is the effect lasting? A longitudinal, observational on 27 consecutive patients.

OBJECTIVE: Our aim was to add to the small but growing body of evidence on the effectiveness of ultrasound-guided Achilles intratendinous hyperosmolar dextrose prolotherapy and introduce a novel, preceding step of paratenon hydrodissection with lidocaine in patients with chronic Achilles tendinosis resistant to rehabilitation therapy. METHODS: We conducted a longitudinal, observational study on 27 consecutive patients diagnosed with Achilles tendinosis, in whom conservative treatment, ie, physiotherapy or shock wave therapy, had failed. A 2% lidocaine paratenon anesthesia and hydrodissection was followed by ultrasound-guided, intratendinous injections of 25% glucose every 5 weeks. Visual analogue scales (VAS) were used for pain assessment at rest, for activities of daily living, and after moderate exercise at the begining and at the end of the treatment. Moreover, tendon thickness and vascularisation were recorded at baseline and final treatment consultation. Effectiveness was estimated from scoring and relative pain reduction using a 95% CI. The non-parametric Wilcoxon test and a general linear model for repeated measures were applied. Statistical significance was established as p < 0.05. RESULTS: A median of 5 (1-11) injection consultations per patient were required. Pain scores decreased significantly in all three conditions (p < 0.001). Relative reductions were 75% in pain at rest (95% CI;61-93%), 69% in pain with daily living activities (95% CI; 55-83%), and 70% in pain after moderate exercise (95% CI; 57-84%). Tendon neo-vascularisation was significantly reduced (p < 0.001). We did not observe significant changes in tendon thickness (p = 0.083). CONCLUSIONS: Achilles tendinosis treatment with paratenon lidocaine hydrodissection and subsequent prolotherapy with hyperosmolar glucose solution is safe, effective, inexpensive, and virtually painless with results maintained over time.

[Heterotopic ossification in SARS-CoV-2: Scintigraphic and radiological images]. / Osificación heterotópica en paciente con SARS-CoV-2: imágenes gammagráficas y radiológicas.

Patients with severe COVID-19 can develop painful range-of-motion restrictions of large joints due to heterotopic ossification. We present the case of a patient who developed hip pain after prolonged admission for severe COVID-19 pneumonia. Conventional radiography, computed tomography and bone scan showed extensive heterotopic ossification in the hips. It is probable that both local and systemic factors contribute to the development of heterotopic ossifications and it is necessary to rule out this entity when these patients reported joint pain. Early diagnosis is important to provide non-pharmacological interventions such as mild passive mobilization and anti-inflammatory medication and in refractory cases surgical resection of the ectopic bone is consider.

Global DNA methylation: a common early event in oral cancer cases with exposure to environmental carcinogens or viral agents.

INTRODUCTION: Two separate molecular pathways have been proposed for the early carcinogenic events observed in the oral cavity and pharynx: one is associated with chemical etiological factors such as smoking and drinking, and the other one is associated with HPV insertion. OBJECTIVE: A proof-of-principle study was performed to ascertain if global DNA methylation could be used to distinguish between the early molecular changes in premalignant oral lesions. METHODS: Personal histories of tobacco and alcohol use were obtained by questionnaire. HPV insertion in tumor tissue was detected by polymerase chain reaction (PCR). Global DNA methylation levels were obtained using HPLC for fraction separation and mass spectrometry for quantification. Predictive simulations were performed to explore potential associations between different etiological factors and the global DNA methylation index. Significance of results was ascertained using Pearson's Chi-squared test. RESULTS: The global methylation index was found to be 4.28 (95% CI, 4.1, 4.4) in an oral cancer case series. Pearson's chi squared test showed no statistically significant difference between cases that had smoking (p = 0.21), drinking (p = 0.31) or HPV insertion (p = 0.34) as etiologic risk factors, when compared to cases that did not. An inverse significant association between smoking and DNA methylation was observed. As the smoking effect increases, the global methylation index decreases, In addition, no associations between the probability of DNA methylation and drinking, or DNA methylation and HPV insertion were observed in simulations. CONCLUSIONS: The global DNA methylation index was shown to vary for oral cancer cases with different etiologies. Smoking was inversely correlated with DNA methylation levels when generalized linear model simulations were performed. Future studies should look at global DNA methylation alterations associated to the progression from normal to premalignant oral epithelium tissue in a cohort of smokers and nonsmokers.

Trypanosoma cruzi: Cardiac mitochondrial alterations produced by different strains in the acute phase of the infection.

The parasite Trypanosoma cruzi is the causative agent of Chagas disease. T. cruzi invasion and replication in cardiomyocytes induce cellular injuries and cytotoxic reactions, with the production of inflammatory cytokines and nitric oxide, both source of reactive oxygen species. The myocyte response to oxidative stress involves the progression of cellular changes primarily targeting mitochondria. We studied the cardiac mitochondrial structure and the enzymatic activity of citrate synthase and respiratory chain CI-CIV complexes, in Albino Swiss mice infected with T. cruzi, Tulahuen strain and SGO Z12 isolate, in two periods of the acute infection. Changes in the mitochondrial structure were detected in both infected groups, reaching values of 71% for Tulahuen and 88% for SGO Z12 infected mice, 30 days post infection. The citrate synthase activity was different according to the evolution of the infection and the parasite strain, but the respiratory chain alterations were similar with either strain.

Comparación de tres técnicas de tornillo endomedular mínimamente invasivo para fracturas de falange proximal. Estudio biomecánico / Comparison of three different minimally invasive intramedullary screw for proximal phalanx fractures. A biomechanical study

Antecedentes y objetivo: Las fracturas de falange proximal (FP) son las fracturas más frecuentes de la mano. En los últimos años, se ha descrito el uso de tornillos endomedulares sin cabeza (TESC) para las fracturas inestables transversas u oblicuas de la FP. A pesar de que tanto la técnica anterógrada como retrógrada con TESC han mostrado buenos resultados, no se ha publicado ningún estudio comparativo de su uso en fracturas de FP. Nuestro objetivo es determinar la estabilidad que se obtiene con el uso de TESC retrógrados y anterógrados en un modelo en cadáver de fractura transversa proximal de FP, a dos niveles diferentes. Material y métodos: Realizamos un estudio biomecánico en 30 modelos de fractura de FP de cadáver fresco-congelado. La osteotomía se realizó a los 9 mm desde la articulación metacarpofalángica (MCF) en 15 especímenes, y a una distancia de 15 mm en los otros 15. A su vez, en cada grupo, cinco osteotomías se estabilizaron con un TESC anterógrado intraarticular, cinco mediante un TESC anterógrado transarticular y cinco con un TESC retrógrado. Resultados: La fijación con TESC anterógrado en osteotomías realizadas a los 9 mm (tanto con la técnica transarticular como intraarticular, 62,74 N y 70,86 N, respectivamente) fue más estable que la fijación con TESC retrógrado (32,72 N) (p 0,022). Por otra parte, la fijación con TESC retrógrado fue más estable en el modelo de fractura más distal (90,52 N retrógrado vs. 57,64 N transarticular vs. 42,92 N intraarticular (p = 0,20). Conclusiones: La fijación con TESC retrógrado ofrece más estabilidad en fracturas más distales, mientras que las técnicas anterógradas son más estables en fracturas proximales.(AU)

Background and objective: Phalangeal fractures are the most common hand fractures. In the last years, intramedullary compression screw (IMHCS) for instable transverse or short oblique proximal P1 fractures have been described. Although both anterograde (intraarticular or trans-articular) and retrograde IMHCS techniques have shown good results, no comparison between anterograde and retrograde screw in P1 fractures has been published. We sought to determine stability with retrograde IMHCS and anterograde IMHCS, both trans-articular and intra-articular technique, in a cadaveric transverse proximal P1 fracture model, at two different levels. Material and methods: We performed a biomechanical study in 30 fresh-frozen human cadaveric P1 fracture model. Fracture was performed at 9-mm from the metacarpo-phalangeal (MCP) joint in 15 specimens, whereas it was done at 15 mm in the other 15. In turn, in each group, five fractures were stabilized with an anterograde intra-articular IMHCS, five with anterograde trans-articular IMHCS and other five with retrograde IMHCS. Results: Anterograde IMHCS fixation in 9-mm P1 fractures (both trans- and intra-articular technique, 62.74 N and 70.86 N, respectively) was found to be more stable than retrograde IMHCS one (32.72 N) (p = 0.022). Otherwise, retrograde IMHCS fixation was found to be more stable in more distal P1 fractures (90.52 N retrograde vs. 57.64 N trans-articular vs. 42.92 N intra-articular; p = 0.20). Conclusions: Anterograde IMHCS fixation in proximal transverse P1 bone cut in a cadaveric model provides more stability than retrograde IMHCS, while retrograde screw provides more stability when the bone cut is located more distal.(AU)

Binding of [3H]narciclasine to eukaryotic ribosomes. A study on a structure-activity relationship.

[3H]Narciclasine is a specific inhibitor of peptide bond formation on eukaryotic ribosomes and binds to 60-S ribosomal subunits. Binding of [3H]-narciclasine to yeast ribosomes is inhibited by many other inhibitors of peptide bond formation including anisomycin, several sequiterpene antibiotics (trichodermin, trichothecin, fusarenon X and verrucarin A) several Cephalotaxus alkaloids (harringtonine, homoharringtonine and isoharringtonine), several Amaryllidaceae alkaloids (pretazettine, haemanthamine, lycorine, pseudolycorine and dihydrolycorine) and the narciclasine derivatives trans-dihydronarciclasine, trans-dihydronarciclasine acetonide and isonarciclasine. Binding is also inhibited, although to a very small extent, by methylnarciclasine and cisdihydronarciclasine. In contrast, no inhibition of [3H]narciclasine binding was observed in the presence of certain other inhibitors of peptide bond formation including blasticidin S, gougerotin, sparsomycin and puromycin.

The mathematics of SELEX against complex targets.

We have developed a computer model for the simulation of simultaneous SELEX against multiple targets. The model assumes equilibrium behavior for the formation of binary ligand:target complexes, and that there is no ligand:ligand or target:target interaction. Target concentrations, ligand concentrations, and affinity distributions of the initial ligand pool for each individual target may be set by the user. We have used this program to gain an understanding of how the presence of multiple targets affects the selection process. In most cases, we find that SELEX is capable of generating different ligands for the different targets in a heterogeneous mixture, regardless of large variations in target concentrations and ligand:target affinities. A low relative partitioning efficiency (the efficiency with which ligands complexed with a target are separated from free ligands) for a target in a mixture gives a greatly reduced rate of selection of high-affinity ligands to that target. The ratio of each high-affinity ligand to its individual target within a pool of ligands selected for binding against a mixture of targets is approximately proportional to the concentration of the target multiplied by the ligand:target partitioning efficiency.

Expression of proliferation-associated nuclear autoantigens, p330d/CENP-F and PCNA, in differentiation and in drug-induced growth inhibition using two-parameter flow cytometry.

p330d/CENP-F is a recently described nuclear autoantigen that was detected in PHA-stimulated but not in resting peripheral lymphocytes. This protein accumulates in the nucleus during S-phase and reaches maximum levels during the G2 and M phases of the cell cycles. We compared the expression of p330d/CENP-F and proliferating cell nuclear antigen (PCNA) during the induction of terminal myeloid differentiation of HL-60 tumour cells. HL-60 cells were induced to differentiate with retinoic acid (RA), dimethyl sulfoxide (DMSO), and 3-nitrobenzothiazolo [3,2-]quinolinium (NBQ), and collected at different intervals. Control and treated cells were analyzed by two-parameter flow cytometry using propidium iodide and antibodies to p330d/CENP-F and PCNA. The percentage of p330d/CENP-F and PCNA positive cells was found to be proportional to the percentage of proliferating cells. After two cell cycles (65 h), the percentage of p330d/CENP-F and PCNA positive cells was reduced proportionately to the number of cells that had differentiated. Reduction in the expression of both antigens was completed after 120 h when 80% to 85% of the cells were arrested in G1 and displayed the mature phenotype. The expression of p330d/CENP-F and PCNA was also assessed in the growth inhibition of HT-29 cells induced by various concentrations of camptothecin (CPT), etoposide (VP-16), and aphidicolin (APH). There was a dose-dependent displacement of cells to late S-phase by CPT while VP-16 induced cells to accumulate in G2+M, and as expected these effects caused a strong increase in the cellular levels of both antigens. The arrest of cells in G1 by APH led to a significant decrease in their expression. The dramatic reduction in p330d/CENP-F levels during differentiation, and the correlation of its expression with the cell cycle effects of the cytotoxic drugs are consistent with the behaviour expected for a proliferation marker.

Biotin supplementation affects lymphocyte carboxylases and plasma biotin in severe protein-energy malnutrition.

We studied the effect of a supplement of biotin (10 mg/d) or a placebo under double-blind conditions on plasma biotin concentrations and lymphocyte propionyl CoA carboxylase (PCC) and pyruvate carboxylase (PC) in 22 children with severe protein-energy malnutrition (PEM) (5 with kwashiorkor, 10 with marasmus, and 7 "sugar babies"). There were significant differences between the malnourished and control subjects only for PCC, although not among the three PEM types. Six of the patients had both PC and PCC activities below the lowest of the normal control subjects; there was no correlation between biotin concentrations and carboxylase activities in individual patients. In response to biotin supplementation, the greatest change in lymphocyte carboxylase activities was detected in patients who had abnormally decreased initial carboxylase activities, but the response was not related to initial plasma biotin concentration. These results indicate that these enzyme deficiencies are the result of a nutritionally determined biotin deficiency, that carboxylases and especially PCC are better indicators of the biotin status in individual patients than is the plasma biotin concentration, and that in some malnourished patients biotin deficiency may be rate-limiting in their nutritional homeostasis.

Endothelial injury. Association with elevations of serum bile acid and cholesterol concentration in biliary-obstructed rats.

An association between atherosclerosis, biliary obstruction and hyperlipidemia has been reported in the literature. In previous study from this laboratory, ultrastructural evidence of coronary artery endothelial damage was obtained in rats following ligation-induced biliary obstruction. In the present investigation, serum bile acids, total cholesterol and alkaline phosphatase levels were studied in association with similarly induced biliary obstruction and related to electron-microscopic observations of coronary artery endothelium. The results disclosed marked elevation of all serum parameters in as short a time as 24 hr following ligation compared with shamoperated controls. Animals exhibiting increases of serum bile acids and cholesterol also revealed severe configurational changes of endothelial cells which manifesed as buckling, detachment from the underlying internal elastic lamina, and vacuole formation. The role of elevated circulating bile acids and hypercholesterolemia as possible factors in producing arterial injury through membrane interaction is discussed. These observations suggest that biliary obstruction, even of short duration, may act as a potentially atherogenic mechanism in the experimental animal.

Patients surviving 10 years of hemodialysis.

Experience with 37 patients surviving 10 years of hemodialysis therapy was reviewed. These patients were compared with 103 patients who began hemodialysis between 1967 and 1971 and who subsequently died. Males had an excess risk of death. Patients with polycystic kidneys survived longer. There was more uncontrolled hypertension among a control group than in 10-year survivors. In survivors, the hematocrit level increased over time and averaged 30.4 percent at 10 years. Over 10 years, many complications arose including parathyroidectomy (24), pericarditis (13), gastrointestinal bleeding (11), myocardial infarction (10), septicemia (eight), and active tuberculosis (six). Despite complications, most patients are now stable. Between their eighth and 10th years they required an average of only one hospitalization with a mean stay of 9.7 days. Eighteen patients were not hospitalized. Excluding housewives, 67 percent of patients between ages 20 and 59 years are employed full-time and 10 percent part-time. Patients surviving 10 years are not progressively deteriorating and may look to the future with cautious optimism.

Nitroglycerin and nitroprusside increase coronary blood flow in dogs by a mechanism independent of prostaglandin release.

The hypothesis that local release of vasodilator prostaglandins mediates, in part, the decrease in coronary resistance after nitroglycerin (NG) administration was tested. NG (60 micrograms/min) and nitroprusside (NP) (30 micrograms/min) were infused for 10 minutes into the left circumflex coronary artery of 9 open-chest, chloralose-anesthetized dogs before and after blockade of prostaglandin synthesis with indomethacin (5 mg/kg). Also, to eliminate the effects of reflex tachycardia on the responses to NG and NP, these experiments were repeated in 6 dogs with heart rate held constant by pacing. NG infusion into dogs without pacing resulted in a maximal increase in coronary blood flow of 55% and after 8 minutes of infusion an increase of 20%, from a baseline of 57 ml/min. NP infusion resulted in a maximal increase in blood flow of 89% and after 8 minutes an increase of 71%, from a baseline of 64 ml/min. In dogs with heart rate held constant, NG infusion caused a maximal increase in coronary artery blood flow of 132% and after 8 minutes of infusion an increase of 18%, from a baseline of 48 ml/min; NP infusion resulted in increase from 51 ml/min of 132% and 62%, respectively. In neither group of dogs did indomethacin significantly change the increases in coronary blood flow or decreases in coronary resistance to NG or NP. Thus, both NG and NP, when infused into the coronary artery of dogs, cause increases in coronary blood flow and decreases in coronary resistance by a mechanism which is independent of prostaglandin release.

Effects of the antitumor drugs 3-nitrobenzothiazolo[3,2-alpha]quinolinium and fagaronine on nucleic acid and protein synthesis.

3-Nitrobenzothiazolo[3,2-alpha]quinolinium perchlorate (NBQ) has been shown to be active against in vivo experimental tumors of P388 and Ehrlich ascites cells. Furthermore, it has been established that NBQ binds to DNA by intercalation. In this work we describe its effects on DNA, RNA and protein syntheses both in KB cells and in cell-free synthesizing systems. Fagaronine, an alkaloid structurally related to NBQ, was studied also in an attempt to establish the basis for future studies on structure-activity relationships. Both NBQ and fagaronine inhibited DNA, RNA and protein syntheses in KB cells, with essentially equal effectiveness. Exposure of KB cells to NBQ for 2 hr caused irreversible inhibition of DNA, RNA and protein syntheses. Studies in cell-free systems showed that NBQ strongly inhibited Escherichia coli DNA polymerase I, whereas RNA polymerase activities were moderately affected. Furthermore, both drugs inhibited protein synthesis in cell-free systems derived from rabbit reticulocytes and Saccharomyces cerevisiae. Our results indicate that NBQ and fagaronine exert their cytotoxic activity by at least two independent mechanisms: inhibition of DNA activity by binding to this molecule, and inhibition of protein synthesis probably by interacting with the ribosomal system.

Interaction between a 3-nitrobenzothiazolo (3,2-a) quinolinium antitumour drug and deoxyribonucleic acid.

The interaction of 3-nitrobenzothiazolo (3,2-a) quinolinium (NBQ) perchlorate with DNA was studied by u.v.-visible and fluorescence spectrophotometry as well as by hydrodynamic methods. On binding to DNA, the absorption spectrum underwent bathochromic and hypochromic shifts, and the fluorescence was quenched. Binding parameters, determined from spectrophotometric measurements by Scatchard analysis according to an excluded-site model, indicated a binding constant of 2.4 X 10(5)M-1 for calf thymus DNA at ionic strength 0.01. The interaction was markedly suppressed by increasing the salt concentration. Binding to the GC-rich DNA of Micrococcus lysodeikticus was weaker than the binding to calf thymus DNA at ionic strength 0.01 NBQ increased the viscosity of sonicated rod-like DNA fragments, producing a calculated increment in length of 2.4 A/bound drug molecule. It removed and reversed the supercoiling of closed circular duplex plasmid pBR322 DNA by virtue of a helix-unwinding angle estimated as approximately 13 degrees/bound ligand molecule. We conclude that the binding of NBQ to DNA occurs by a mechanism of intercalation, which probably accounts for its reported antitumor activity.

Myeloid differentiation of HL-60 cells induced by anti-tumor drug 3-nitrobenzothiazolo[3,2-a]quinolinium.

Drugs which elicit cell differentiation might have an important role in the treatment of leukemias and other neoplasias. Various chemotherapeutic agents promote leukemic cell differentiation. The HL-60 cell line is a useful model to study in vitro myeloid differentiation. Sublethal concentrations of 3-nitrobenzothiazolo[3,2-a]quinolinium (NBQ), an antitopoisomerase II drug, were given to HL-60 cells from one to five days to evaluate its capacity to induce differentiation. NBQ-induced HL-60 cells reduced nitroblue tetrazolium (NBT), increased MY-4 receptors, increased phagocytic activity and displayed the granulocytic morphology. Flow cytometric DNA analysis of NBQ-induced cells revealed an arrest in the G1 phase a reduction in the relative percentage of cells in S and G2+M phases. Our results suggest that NBQ induces an S-phase specific differentiation of HL-60 cells comparable to that previously described with dimethyl sulfoxide and retinoic acid. NBQ and its analogs, as differentiation inducers, may have potential utility as a novel therapeutic modality for leukemias.