Articular spacers in two-stage revision arthroplasty for prosthetic joint infection of the hip and the knee.

Use of articular antibiotic-eluting cement spacers during two-stage revision arthroplasty for prosthetic joint infection (PJI) is a long-established and proven adjunctive technique during first-stage surgery. Articular spacers come in many forms, either static or dynamic. The authors present an instructional review of current evidence regarding their use. A total of 45 studies (for spacer use in PJI involving either hip or knee) were analysed for data regarding eradication rate, functional outcomes, mechanical complications and the impact on second-stage surgery. A large number of case series and retrospective cohort studies were retrieved, with only a small number of prospective studies (2). High levels of infection eradication were commonly reported (>80%). Outcome scores were commonly reported as indicating good-to-excellent function and pain levels. Second-stage procedures were often not required when dynamic spacers were used. Static spacers were associated with more mechanical complications in both the hip and the knee. In the hip, dynamic spacers were more commonly associated with instability compared to static spacers. Consideration should be given to the use of dual-mobility or constrained definitive acetabular components in these cases at second-stage surgery. The use of antibiotic-eluting polymethylmethacrylate articular spacers in two-stage revision for PJI of hip and knee arthroplasty achieves a high rate of infection eradication. Dynamic spacers may confer a variety of benefits compared to static spacers, with a similar rate of infection eradication.

Risk Factors for Revision of Polished Taper-Slip Cemented Stems for Periprosthetic Femoral Fracture After Primary Total Hip Replacement: A Registry-Based Cohort Study from the National Joint Registry for England, Wales, Northern Ireland and the Isle of Man.

BACKGROUND: Total hip replacement (THR) with a cemented polished taper-slip (PTS) femoral stem has excellent long-term results but is associated with a higher postoperative periprosthetic femoral fracture (PFF) risk compared with composite beam stems. This study aimed to identify risk factors associated with PFF revision following THR with PTS stems. METHODS: In a retrospective cohort study, 299,019 primary THRs using PTS stems from the National Joint Registry for England, Wales, Northern Ireland and the Isle of Man (NJR) were included, with a median follow-up of 5.2 years (interquartile range [IQR], 3.1 to 8.2 years). The adjusted hazard ratio (HR) of PFF revision was estimated for each variable using multivariable Cox survival regression analysis. RESULTS: Of 299,019 THR cases, 1,055 underwent revision for PFF at a median time of 3.1 years (IQR, 1.0 to 6.1 years). The mean age (and standard deviation) was 72 ± 9.7 years, 64.3% (192,365 patients) were female, and 82.6% (247,126 patients) had an American Society of Anesthesiologists (ASA) class of 1 or 2. Variables associated with increased PFF were increasing age (HR, 1.02 per year), intraoperative fracture (HR, 2.57 [95% confidence interval (CI), 1.42 to 4.66]), ovaloid (HR, 1.96 [95% CI, 1.22 to 3.16]) and round cross-sectional shapes (HR, 9.58 [95% CI, 2.29 to 40.12]), increasing stem offset (HR, 1.07 per millimeter), increasing head size (HR, 1.04 per millimeter), THR performed from 2012 to 2016 (HR, 1.45 [95% CI, 1.18 to 1.78]), cobalt-chromium stem material (HR, 6.7 [95% CI, 3.0 to 15.4]), and cobalt-chromium stems with low-viscosity cement (HR, 22.88 [95% CI, 9.90 to 52.85]). Variables associated with a decreased risk of PFF revision were female sex (HR, 0.52 [95% CI, 0.45 to 0.59]), increasing stem length (HR, 0.97 per millimeter), and a ceramic-on-polyethylene bearing (HR, 0.55 [95% CI, 0.36 to 0.85]). CONCLUSIONS: Increased risk of PFF revision was associated with PTS stems that are short, have high offset, are used with large femoral heads, are made of cobalt-chromium, or have ovaloid or round cross-sectional shapes. Large increases in PFF risk were associated with cobalt-chromium stems used with low-viscosity cement. Further study is required to confirm causation. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

Vascular endothelial growth factor as a marker of tumor endothelium.

Vascular endothelial growth factor (VEGF) is an angiogenic growth factor that is a primary stimulant of the vascularization of solid tumors. VEGF production is induced by oncogenic gene mutations in the tumor cells and by hypoxic conditions inside the tumor mass. Hypoxia and the locally increased concentration of VEGF lead to an up-regulation of VEGF receptor expression on tumor endothelial cells. Therefore, in the tumor microenvironment, there is an up-regulation of both VEGF and its receptor, leading to a high concentration of occupied receptor on tumor vascular endothelium. The VEGF:receptor complex presents an attractive target for the specific delivery of drugs or other effectors to tumor endothelium. In the present study, several hybridomas that secrete monoclonal antibodies against the VEGF:receptor (Flk-1) complex or against VEGF itself have been raised. Three of the antibodies (3E7, GV39M, and 11B5) bind with high affinity to the VEGF:Flk-1 complex in ELISA and to tumor endothelium in frozen sections of human tumors, rodent tumors, and human tumor xenografts. 3E7 and GV39M localize selectively to tumor endothelium after i.v. injection into mice bearing human tumor xenografts. Additionally, one antibody (2C3) was raised that blocks the interaction between VEGF and KDR/Flk-1. 2C3 inhibits VEGF-mediated growth of endothelial cells in vitro and localizes strongly to connective tissue in tumors after injection into mice bearing human tumor xenografts. These findings suggest that 3E7, GV39M, and 2C3 are candidates for targeting and imaging the vasculature or connective tissue of tumors.

Up-regulation of endoglin on vascular endothelial cells in human solid tumors: implications for diagnosis and therapy.

We have characterized a murine IgM monoclonal antibody, TEC-11, that recognizes endoglin and may be suitable for targeting cytotoxic agents to human tumor vasculature. TEC-11 strongly stains endothelial cells in a broad range of solid human tumors while staining endothelial cells in the majority of normal, healthy adult tissues relatively weakly. Human umbilical vein endothelial cells (HUVECs) in sections of the umbilical vein react weakly with TEC-11, whereas proliferating HUVECs in tissue culture react strongly and uniformly. HUVEC cultures grown to confluence and then rested contain two subpopulations having high and low levels of endoglin expression. Flow cytometry revealed that a significant proportion of cells with high endoglin expression are cycling, having markedly increased levels of cellular protein, RNA, and DNA by comparison to low endoglin-expressing cells, which appear to be noncycling. Taken together, the increased binding of TEC-11 to tumor vasculature and to dividing as opposed to noncycling HUVECs in vitro suggests that endoglin is an endothelial cell proliferation-associated marker. An immunotoxin [TEC-11.deglycosylated ricin A chain (dgA)] composed of TEC-11 and dgA was 3000-fold more potent at inhibiting protein synthesis in proliferating HUVEC cultures than in confluent cultures. The confluent cells were no more sensitive to TEC-11.dgA than they were to an isotype-matched immunotoxin of irrelevant specificity. These findings suggest that TEC-11.dgA might have therapeutic value in the treatment of solid tumors in humans by selectively killing dividing endothelial cells which are prevalent in such tumors.

Bioactive conformation of 1-arylpiperazines at central serotonin receptors.

A number of 1-arylpiperazines have been characterized as direct-acting serotonin agonists. Conformational parameters of this class that may affect receptor recognition and binding have been examined through the analysis of X-ray data and synthesis of rigid analogues. Radioligand binding studies indicate that 2,3,4,4a,5,6-hexahydro-9-(trifluoromethyl)-1H-pyrazino[1,2-a]quinoline, an arylpiperazine that mimics the X-ray conformation of the serotonin agonist 1-(6-chloropyrazin-2-yl)piperazine, exhibits high affinity for serotonin receptors, suggesting that the two rings of 1-arylpiperazines are relatively coplanar in the bioactive conformation.

Trichloroacetamidines, a new class of positive inotropic agents.

A series of trichloroacetamidine derivatives, obtained by addition of amines to trichloroacetonitrile, was evaluated for positive inotropic activity on isolated cat heart papillary muscles. Increased contractility, not antagonized by beta-adrenergic blockade with sotalol or reserpine pretreatment, was observed in this assay with a variety of N-substituted trichloroacetamidine derivatives. More extensive pharmacological studies with the 3-indolylmethyl analogue 2 showed that this amidine in dogs, 5 mg/kg iv, produced a positive inotropic effect more pronounced than that of ouabain, 50 microgram/kg iv. Several of the trichloroacetamidines were found to be inhibitors of guinea pig kidney and calf heart Na-K-dependent ATPase and to have specificity for these enzymes different from that of ouabain. Bacterial mutagenic activity was observed with three members, 2,3, and 12, of the series.

Synthesis and antihypertensive activity of some ester progenitors of methyldopa.

A variety of esters of methyldopa was synthesized with the objective of obtaining derivatives that would be more efficiently absorbed from the gastrointestinal tract than the free amino acid and would undergo conversion to methyldopa readily in the blood or target tissues. Two of the esters, alpha-pivaloyloxyethyl (4u) and alpha-succinimidoethyl (4w), were found to be more potent antihypertensive agents than methyldopa in animal models and were selected for further study in man. The amino esters were prepared by three different methods, including direct esterification of methyldopa without the use of N- or O-protecting groups.

Pyridinylpiperazines, a new class of selective alpha 2-adrenoceptor antagonists.

A series of 1-(2-pyridinyl)piperazine derivatives was synthesized and evaluated for adrenergic activity. In vitro activity was assessed through the antagonism of clonidine's effect in the rat, isolated, field-stimulated vas deferens and by the displacement of [3H]clonidine from membrane binding sites of calf cerebral cortex. Antagonism of clonidine-induced mydriasis in the rat was used as an in vivo assay. Several members of the series proved to be potent, selective alpha 2-adrenoceptor antagonists. 1-(3-Fluoro-2-pyridinyl)piperazine was more potent than either yohimbine or rauwolscine in displacement of [3H]clonidine and had a higher affinity for this binding site (alpha 2) than for the [3H]prazosin site (alpha 1). In vivo, the 3-F derivative was more potent than the reference standards in reversing clonidine-induced mydriasis. None of the members of this series was more selective or potent than rauwolscine in antagonizing clonidine in the rat vas deferens.

Synthesis and receptor binding studies relevant to the neuroleptic activities of some 1-methyl-4-piperidylidene-9-substituted-pyrrolo[2,1-b][3]benzazepine derivatives.

The synthesis of a series of 1-methyl-4-(9-substituted-11H-pyrrolo[2,1-b]benzazepin-11-ylidene)piperidines (4a-f) and 1-methyl-4-(9-substituted-6,11-dihydro-5H-pyrrolo[2,1-b][3]benzazepin-11-ylidene)piperidines (4g-l) is described. As with th e 3-substituted cyproheptadine compounds 1b-e, atropisomerism exists in 4b-f, but unlike the enantiomers of 1b-e, the pyrrolobenzazepine enantiomers racemize at room temperature. Thus, the bromo compound (+)-4b has a half-life of 128 +/- 1 min at 25 degrees C, while the chloro compound (-)-4c has a half-life of 114 +/- 9 min at 25 degrees C. Compounds 4a-l have been examined for receptor binding affinities in assays that have been recognized as predictive for antipsychotic activity. The displacement of specifically bound tritiated ligands, comprising the dopamine antagonist [3H]spiperone, the dopamine agonist [3H]apomorphine, the muscarinic cholinergic antagonist [3H]quinuclidinyl benzilate (QNB), the alpha-adrenergic antagonist [3H]prazosin, the alpha-adrenergic agonist [3H]clonidine, the serotonin-1 binding agent [3H]serotonin, and the mixed serotonin agonist-antagonist [3H]lysergic acid diethylamide (LSD), by 4a-l has been measured utilizing membrane preparations of mammalian brain. Certain of the features of the receptor binding of these compounds have been shown to be common to several of the receptor sites. Data from these binding studies have been compared to corresponding data previously obtained for a series of chiral 3-substituted cyproheptadine analogues, and the receptor binding data of the two classes of compounds are discussed with respect to their molecular geometries.

Monoclonal antibodies produced against antigenic determinants present in complex mixtures of proteins.

This overview provides information concerning the production of monoclonal antibodies (MAbs) against specific antigenic determinants present in complex mixtures of proteins. We review five specific techniques for the production of these antibodies (Abs): (a) So-called "shotgun," non-selective approach; (b) cascade procedure; (c) lymphocyte "panning"; (d) cyclophosphamide elimination of unwanted Ab producers; and finally (e) use of polyclonal antisera to extinguish unwanted antibody production. We discuss the relative advantages and disadvantages of these various procedures, and suggest alternative strategies by which specific MAbs might be generated.

Effects of heart rate and pulmonary artery pressure on Doppler pulmonary artery acceleration time in experimental acute pulmonary hypertension.

Chronic pulmonary hypertension in humans is characterized by shortening of the pulmonary artery acceleration time as measured by Doppler echocardiography, such that the higher the pulmonary artery pressure, the shorter the pulmonary acceleration time. Increases in heart rate are also known to produce decreases in the pulmonary artery acceleration time. To explore the relationship between mean pulmonary artery pressure, heart rate, and Doppler pulmonary artery acceleration time, experimental acute pulmonary hypertension was created in nine Duroc swine, either by infusion of Sephadex beads with embolization of the pulmonary arterial circulation or by partially occluding the main pulmonary artery 8 to 10 cm distal to the pulmonic valve. Pulmonary artery Doppler flow velocity recordings and invasive pressure measurements were made at baseline and at paced atrial rates ranging from 60 to 160 beats per minute, in 20-beat increments. The results in this acute animal model reveal that increases in heart rate produced significant decreases in Doppler pulmonary artery acceleration time at mean pressures below 25 mm Hg. However, with mean pulmonary artery pressures greater than 25 mm Hg, both heart rate and increases in pulmonary artery pressure had no significant effect on acceleration time.

The effect of a short burst of exercise on activity values of enzymes in sera of healthy young men.

We report the effect of exercise on the activity values of five enzymes in sera as studied in four healthy male volunteers. The underlying purpose of this present study was to produce an increase in the activity values in the sera of selected enzymes found in muscle. Then by observing the decay rate of these enzymes, we computed the inter-individual differences in clearance rates serum half-life) of these enzymes. Blood specimens were collected just prior to exercise, 1 h after excerise, and on eight additional times up to 93 h after exercise. All specimens were assayed on one occasion for activity values of creatine kinase, asparate aminotransferase, alanine aminotransferase, alkaline phosphatase, and lactate dehydrogenase. We found increases in the three muscle enzymes with average increases being: creatine kinase, +116%; asparate aminotransferase, +41%; and lactate dehydrogenase, +32%; all of which remained above baseline values for 53 h or longer. In the case of creatine kinase, a monoexponential decay curve depicted the data (from the 19-h specimen to the 67-h specimen). The calculated "apparent serum half-life" for creatine kinase varied from 38 h to 118 h in the subjects tested.

Aluminum toxicity in relation to kidney disorders.

Aluminum toxicity in patients with chronic renal failure has been related to renal osteodystrophy and dialysis encephalopathy (DES). The toxicity is associated with renal osteodystrophy in two ways. One association is the iatrogenic effect of excessive use of aluminum hydroxide gels resulting in hypophosphatemia which interferes with bone mineralization. The second association may involve deposition of aluminum in bone owing to aluminum being absorbed during hemodialysis. Evidence for this second association has been gathered from epidemiological studies of hemodialysis centers and their practices of using either tap water high in aluminum in the dialysate, or aluminum-free deionized water. In patients with DES, aluminum accumulation in the brain has been clearly shown to come from either the ingestion of aluminum containing phosphate-binding gels, aluminum in the dialysate, or a combination of the two. The outbreak of the DES also has been well-correlated with the sudden elevation of aluminum in tap water owing to the use of large amounts of aluminum in water treatment plants. Whether aluminum itself or a combination of aluminum and other factors causes DES is not understood at this time.

Aluminum distribution in serum following hemodialysis.

Aluminum is a toxic metal and has been implicated as the causative agent in the dialysis encephalopathy syndrome. In the study reported here, the transfer of aluminum to the blood from dialysis fluid during hemodialysis was demonstrated even when deionized water was used in the preparation of the dialysate. Studies were carried out on the binding of aluminum to serum proteins and other constituents in patients on long-term hemodialysis. Five major aluminum peaks were observed on chromatographic separation; four were associated with proteins and one large peak was probably associated with a low molecular weight species. The size of the latter peak was enhanced by increasing the aluminum content of the eluting buffer. It is postulated that this low molecular weight species might be the neurotoxic form of aluminum.

Prophylactic ephedrine and hypotension associated with spinal anesthesia for cesarean delivery.

Hypotension commonly accompanies induction of spinal anesthesia for cesarean section. To determine whether intravenous ephedrine prophylaxis would benefit prehydrated obstetrical patients presenting for elective cesarean section, we studied 30 patients randomly assigned to one of three experimental groups. All patients were preloaded with crystalloid (15 ml/kg), given spinal anesthesia and positioned with left uterine displacement (LUD). During induction, all patients received a 2 ml intravenous bolus and intravenous infusion of the study drug or placebo. The control group (n=10) received a saline bolus and saline infusion, the bolus group (n=10) received an ephedrine bolus (10 mg) and a saline infusion and the infusion group (n=10) received a saline bolus and a two-stage ephedrine infusion (20 mg over 12 min). After induction of anesthesia, systolic blood pressure decreased in the first 5 min in all groups. Hypotension occurred in 6/10 control patients, 5/10 bolus patients and 5/10 infusion patients. The amount of supplemental ephedrine required to treat hypotension did not differ among groups. Although the efficacy of ephedrine prophylaxis for hypotension associated with spinal anesthesia for elective cesarean section cannot be established by the small number of patients studied, this practice does not appear to be clinically relevant at the doses studied.