The cost of implanting a cemented versus cementless total knee arthroplasty.

AIMS: The aim of this study was to compare the actual cost of a cemented and cementless total knee arthroplasty (TKA) procedure. MATERIALS AND METHODS: The cost of operative time, implants, cement, and cementing accessories were included in the overall cost of the TKA procedure. Operative time was determined from a previously published study comparing cemented and cementless implants of the same design. The cost of operative time, implants, cement, and cementing accessories was determined from market and institutional data. RESULTS: Mean operative time for cemented TKA was 11.6 minutes longer for cemented TKA than cementless TKA (93.7 minutes (sd 16.7) vs 82.1 minutes (sd 16.6); p = 0.001). Using a conservative published standard of $36 per minute for operating theatre time cost, the total time cost was $418 higher for cementing TKA. The cost of cement and accessories ranged from $170 to $625. Overall, the calculated cost of cemented TKA is $588 to $1043, depending on technique. The general increased charge for cementless TKA implants over cemented TKA implants was $366. CONCLUSION: The overall procedural cost of implanting a cementless TKA is less than implanting a cemented TKA. Cost alone should not be a barrier to using cementless TKA. Cite this article: Bone Joint J 2019;101-B(7 Supple C):61-63.

South Pole Telescope optics.

The South Pole Telescope is a 10 m diameter, wide-field, offset Gregorian telescope with a 966-pixel, millimeter-wave, bolometer array receiver. The telescope has an unusual optical system with a cold stop around the secondary. The design emphasizes low scattering and low background loading. All the optical components except the primary are cold, and the entire beam from prime focus to the detectors is surrounded by cold absorber.

Blocking probe as a potential tool for detection of single nucleotide DNA mutations: design and performance.

Developing strategies to detect single nucleotide DNA mutations associated with treatment decisions in cancer patients from liquid biopsies is a rapidly emerging area of personalized medicine that requires high specificity. Here we report how to design an easy enzyme-free approach that could create a platform for detection of L858R mutation of EGFR that is a predictive biomarker of tyrosine kinase treatment in many cancers. This approach includes the addition of blocking probes with the antisense ssDNA at different blocking positions and different concentrations such as to avoid re-annealing with the respective sense ssDNA. The successful blocking strategy was corroborated by fluorescence spectroscopy in solution using two distinct FRET pairs and quartz crystal microbalance with dissipation (QCM-D) measurements under comparable experimental conditions, as the hybridization rate-limiting step in both methods is the nucleation process. The efficiency of hybridization of each blocking probe was strongly dependent on its position particularly when the analyte possesses a secondary hairpin-structure. We tested the performance of blocking probes in combination with gold nanoparticles; the obtained results were in agreement with those of QCM-D. These findings could facilitate the development of better biosensors, especially those using probes containing secondary structure.

The alpha adrenoceptor antagonist properties of idazoxan in normal subjects.

The imidazoline derivative idazoxan, which has been shown to be a potent, selective alpha 2-adrenoceptor antagonist, was injected intravenously to eight men with normotension. There was a transient small increase in blood pressure and a decrease in heart rate within 20 min of injection, with a slight increase in plasma norepinephrine levels. These effects are consistent with antagonism of prejunctional alpha 2-adrenoceptors. In response to infusions of the relatively selective alpha 2-adrenoceptor agonist alpha-methylnorepinephrine, the pressor dose-response curve shifted to the right with idazoxan. These data provide evidence for receptors with alpha 2-adrenoceptor characteristics on resistance vessels in man. In vitro platelet aggregation studies provide further evidence of selective alpha 2-adrenoceptor antagonism by idazoxan, with greater potency and affinity than alpha-yohimbine. These observations are consistent with both pre- and postjunctional peripheral alpha 2-adrenoceptors in man and provide further support that idazoxan is a selective alpha 2-adrenoceptor antagonist.

Antibody and interleukin-12 treatment in murine models of encephalitogenic flavivirus (St. Louis encephalitis, tick-borne encephalitis) and alphavirus (Venezuelan equine encephalitis) infection.

Early and sustained treatment with interleukin-12 (IL-12) ameliorated disease in a mouse model of infection with the encephalitogenic flavivirus, St. Louis encephalitis virus (SLEV, Japanese encephalitis serogroup). However, this effect was not reproduced in murine infections with either the flavivirus tick-bore encephalitis virus (TBEV) or the alphavirus Venezuelan equine encephalitis virus (VEEV). IL-12 exacerbated TBEV disease when used in conjunction with monoclonal antibody (mAb), suggesting an enhancement of immunopathology, and was without clinical effects in VEEV infection. These data confirm the need to fully understand the pathogenesis of viral infection before cytokine intervention may be employed as a broad-spectrum antiviral therapy.

Repetitively negative changing T waves at 24-h electrocardiographic monitors in patients with the chronic fatigue syndrome. Left ventricular dysfunction in a cohort.

This study surveys the occurrence of repetitively negative to flat T waves, alternating with normal upright T waves in 24-h electrocardiographic recordings from a subspecialty infectious diseases outpatient practice during the years 1982 to 1990. Patients with normal resting electrocardiogram in the assayed leads, but with repetitively inverted to isoelectric abnormal T waves at Holter monitors, were considered to have abnormal readings. A total of 300 patients had undergone a 24-h Holter monitor. This group included 24 individuals with chronic fatigue syndrome (CFS). This population was restricted to individuals 50 years old or younger, and the patients with CFS are compared with the patients without CFS. One of the more striking differences between the two groups was the difference in abnormal Holter readings. The patients with CFS all had abnormal Holter readings, while 22.4 percent patients without CFS had abnormal readings (p < 0.01). We further report the occurrence of mild left ventricular dysfunction in 8 of 60 patients in continuing studies of this population with CFS, younger than 50 years old, and with no risk factors for coronary artery disease. All 60 patients with CFS showed repetitively flat to inverted T waves alternating with normal T waves. Stress multiple gated acquisitions (MUGAs) (labeled erythrocytes with stannous pyrophosphate) were abnormal in eight patients with CFS. Although resting ejection fractions (EFs) were normal (mean, 60 percent), with increasing work loads (Kilopon meters [Kpms]), gross left ventricular dysfunction occurred. The fatigue of patients with CFS may be related to subtle cardiac dysfunction occurring at work loads common to ordinary living.

The urinary excretion of bacterial amino-acid metabolites by rats fed saccharin in the diet.

Administration of a diet containing 7.5% saccharin to adult male rats for 40 days caused a three- to four-fold increase in the daily excretion of indican and rho-cresol. Indican is formed from indole which is a microbial metabolite of tryptophan, whilst rho-cresol is formed by the gut flora from tyrosine. The excretion of phenol, which is also a microbial metabolite of tyrosine, was abolished by saccharin administration for 40 days. Analysis of urines collected at 13, 18 and 24 months during a two-generation cancer bioassay showed that these changes occur throughout the life of saccharin-treated rats. These data indicate that saccharin changes the metabolism of amino acids by the gut flora, leading to an increased formation of products known to have promoting or co-carcinogenic properties.

Clinical pharmacological studies with the vasodilator endralazine in normotensive subjects and essential hypertensives.

Endralazine is a peripherally-acting vasodilator with chemical and pharmacological similarities to hydralazine. In both normotensive volunteers and essential hypertensives, single oral doses of 10 mg endralazine (in combination with a beta-adrenoceptor antagonist) led to substantial falls in blood pressure, with no significant additional orthostatic effect. Maintenance treatment of hypertensive patients with the addition of 5 or 10 mg B.D. endralazine significantly improved blood pressure control: the mean supine blood pressure improved from 197/107 mmHg, on baseline treatment with a thiazide and beta blocker, to 160/86 after one week and 161/91 mmHg after one year with endralazine as third drug therapy. Apart from facial flushing and mild headache following the early doses, no significant side-effects were observed or reported. In the long term, there was no weight gain to suggest fluid retention and in all patients treated with endralazine for at least one year the anti-nuclear factor remained negative. Following acute administration the terminal elimination half-life of endralazine was approximately 2.5 h and the oral bioavailability was 75%. During chronic dosing with endralazine the terminal elimination half-life significantly increased to a mean of 7.5 h, but there was no accumulation of drug. There were no significant differences related to acetylator phenotype either for the dosage, the pharmacokinetics or the hypotensive effect.

Abnormal left ventricular myocardial dynamics in eleven patients with chronic fatigue syndrome.

Eleven patients diagnosed with chronic fatigue syndrome were found to have abnormal left ventricular myocardial dynamics as indicated on MUGA studies. Among the abnormalities noted were abnormal wall motion at rest and stress, dilatation of the left ventricle, and segmental wall motion abnormalities.

Reciprocal expression of the endocytic protein HIP1R and its repressor FOXP1 predicts outcome in R-CHOP-treated diffuse large B-cell lymphoma patients.

We previously identified autoantibodies to the endocytic-associated protein Huntingtin-interacting protein 1-related (HIP1R) in diffuse large B-cell lymphoma (DLBCL) patients. HIP1R regulates internalization of cell surface receptors via endocytosis, a process relevant to many therapeutic strategies including CD20 targeting with rituximab. In this study, we characterized HIP1R expression patterns, investigated a mechanism of transcriptional regulation and its clinical relevance in DLBCL patients treated with immunochemotherapy (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone, R-CHOP). HIP1R was preferentially expressed in germinal center B-cell-like DLBCL (P<0.0001) and inversely correlated with the activated B-cell-like DLBCL (ABC-DLBCL) associated transcription factor, Forkhead box P1 (FOXP1). HIP1R was confirmed as a direct FOXP1 target gene in ABC-DLBCL by FOXP1-targeted silencing and chromatin immunoprecipitation. Lower HIP1R protein expression (≤ 10% tumoral positivity) significantly correlated with inferior overall survival (OS, P=0.0003) and progression-free survival (PFS, P=0.0148) in R-CHOP-treated DLBCL patients (n=157). Reciprocal expression with ≥ 70% FOXP1 positivity defined FOXP1(hi)/HIP1R(lo) patients with particularly poor outcome (OS, P=0.0001; PFS, P=0.0016). In an independent R-CHOP-treated DLBCL (n=233) microarray data set, patients with transcript expression in lower quartile HIP1R and FOXP1(hi)/HIP1R(lo) subgroups exhibited worse OS, P=0.0044 and P=0.0004, respectively. HIP1R repression by FOXP1 is strongly associated with poor outcome, thus further understanding of FOXP1-HIP1R and/or endocytic signaling pathways might give rise to novel therapeutic options for DLBCL.

Role of microRNAs and microRNA machinery in the pathogenesis of diffuse large B-cell lymphoma.

Deregulation of microRNA (miRNA) expression has been documented in diffuse large B-cell lymphoma (DLBCL). However, the impact of miRNAs and their machinery in DLBCL is not fully determined. Here, we assessed the role of miRNA expression and their processing genes in DLBCL development. Using microarray and RT-qPCR approaches, we quantified global miRNAs and core components of miRNA-processing genes expression in 75 DLBCLs (56 de novo and 19 transformed) and 10 lymph nodes (LN). Differential miRNA signatures were identified between DLBCLs and LNs, or between the de novo and transformed DLBCLs. We also identified subsets of miRNAs associated with germinal center B-cell phenotype, BCL6 and IRF4 expression, and clinical staging. In addition, we showed a significant over-expression of TARBP2 in de novo DLBCLs as compared with LNs, and decreased expression of DROSHA, DICER, TARBP2 and PACT in transformed as compared with de novo cases. Interestingly, cases with high TARBP2 and DROSHA expression had a poorer chemotherapy response. We further showed that TARBP2 can regulate miRNA-processing efficiency in DLBCLs, and its expression inhibition decreases cell growth and increases apoptosis in DLBCL cell lines. Our findings provide new insights for the understanding of miRNAs and its machinery in DLBCL.

Different dietary patterns in relation to age and the consequences for intake of food chemicals.

This paper principally addresses the question of whether exposure to food additives/contaminants is likely to be higher in children than adults. Food consumption surveys conducted in the United Kingdom indicated that 99% of infants were receiving some solid food at 6 months of age (mean age of introduction 13 weeks), mainly 'family' foods not specifically produced for infants. On a body weight basis, young children, age 1 1/2-4 1/2 years, were shown to consume more than adults most notably of dairy products, puddings and confectionery (up to five times adult intakes) and of soft drinks (up to 16 times adult values). Two examples of risk assessments are given, for chlorinated dibenzodioxins and saccharin, where the intake was highest in children, in some cases exceeding the Provisional Tolerable Weekly Intake or Acceptable Daily Intake, respectively. The necessary risk management measures taken are discussed.

The effect of saccharin ingestion on the excretion of microbial amino acid metabolites in rat and man.

Low dietary levels of sodium saccharin (0-2%) fed to male rats for 6 weeks produced a dose-related increase in the urinary excretion of p-cresol, a major microbial metabolite of tyrosine. Some animals fed higher levels of saccharin (5-7.5%) for 6 weeks excreted increased amounts of p-cresol, but many excreted negligible amounts so that the overall dose-response relationship was bell shaped. After 20 weeks of exposure, all rats in the higher dose groups showed increased p-cresol excretion and by 26 weeks the 7.5% saccharin group showed a 36-fold increase over animals fed the 0% saccharin diet. The urinary excretion of phenol, another microbial amino acid metabolite, was constant in animals fed dietary levels of saccharin below 2% for 6 weeks, but was virtually abolished at higher levels. The excretion of indican (formed from indole, a microbial metabolite of tryptophan) was increased by saccharin in a dose-related fashion at all time points, but showed only a 3-fold increase at 7.5% compared with the 0% group. p-Cresol may therefore prove more sensitive than indican as an indicator of altered microbial metabolism due to saccharin. In a separate study the effect of 7.5% saccharin on p-cresol and indican excretion was shown to be largely reversible and the excretion of phenol increased rapidly when saccharin was withdrawn from the diet. Chronic saccharin administration to man at high doses (1 g/day for 4 weeks) had no perceptible effect on the excretion of these three metabolites.

Antigenic profile of Ixodes ricinus: effect of developmental stage, feeding time and the response of different host species.

Antigens recognized by host species in response to ectoparasite infestation have been widely reported. Although differences in the immune responses of different host species have been described, only a very few of these studies compare the range of antigens recognized by different host species in response to infestation. We used Western blot analysis to investigate antigenic responses of different host species that were repeatedly infested with Ixodes ricinus ticks. Antigenic profiles of larval and nymphal whole tick homogenates were compared with the respective salivary gland extract (SGE) samples using sera from rabbits repeatedly infested with either adults, nymphs or larvae. SGE samples were also analysed using sera from hamsters infested with adults, nymphs or larvae. Sera from BALB/C mice, Apodemus flavicollis (yellow-necked mouse) or Clethrionomys glareolus (bank vole) repeatedly infested with larvae were used to compare the antigenic profiles of SGE and larval homogenate samples. We also investigated different sources of tick antigens, using rabbit sera, by comparing midgut extracts from female adult ticks and SGE from unfed ticks and from ticks throughout the 6-day feeding period with whole tick homogenates of female and male adults, nymphs and larvae. The pattern of antigenic tick-molecules recognized by infested host species varies with the period of feeding, developmental stage and the particular host species parasitized.

The approach adopted in the UK for the estimation of the intake of food additives.

The UK has developed considerable experience in the estimating additive intake over the past 20 years. The earliest approach involved collecting large amounts of detailed information on additive concentrations and aimed to provide accurate estimates of intake for all additives in a given class. This has been replaced in recent times by a hierarchical approach which is applied to selected additives following an initial prioritization. Initial intake estimates are made using readily available data and conservative assumptions about additive occurrence and food consumption. More refined calculations are not necessary if the initial estimate shows that intake is well below the Acceptable Daily Intake. Once the level of intake has been established, it is only necessary to repeat the estimation if market information shows that there have been substantial changes in additive usage or food consumption. A similar approach is recommended for adoption across the European Union.

The effect of increased caffeine intake on the metabolism and pharmacokinetics of theophylline in man.

The metabolism and pharmacokinetics of intravenously administered theophylline (100 mg) have been investigated in three healthy male volunteers who consumed 6 bottles/day of a cola beverage, in addition to their usual intake of methylxanthines, for 7 days prior to and during the study. Five urinary metabolites were detected in addition to unchanged theophylline, that is 3-methylxanthine, 1,3-dimethyluric acid, 1-methyluric acid, and two minor unknown metabolites. The elimination of theophylline, 1,3-dimethyluric acid, 1-methyluric acid, and the two unknowns was described by first-order kinetics, whereas that of 3-methylxanthine was described by Michaelis-Menten kinetics. The results have been compared with those previously obtained in the same volunteers while consuming their usual intake of methylxanthine-containing foods and beverages, and this shows that the addition of extra methylxanthines to the diet does not influence the disposition of theophylline. This is in marked contrast to the effect of deprivation of dietary methylxanthines on theophylline metabolism. The results are discussed in terms of the influence of methylxanthines on theophylline metabolism, and of its possible dose-dependency.

Ixodes ticks: serum species sensitivity of anticomplement activity.

Ixodid ticks feed for extended periods of up to 2 weeks or more. To complete engorgement, they must overcome their host's innate immune mechanisms of which the complement system is a major component. Using in vitro assays, salivary gland extracts of the ixodid ticks, Ixodes ricinus, I. hexagonus, and I. uriae, were shown to inhibit activity of the alternative pathway of complement. The ability of the different Ixodes species to inhibit complement activity varied with the animal species used as a complement serum source. Serum species sensitivity correlates to the reported host range of the tick species tested.

Microbial amino acid metabolites and bladder cancer: no evidence of promoting activity in man.

1. Indole, p-cresol and phenol are microbial amino acid metabolites which show co-carcinogenic or promoting activity in animal studies. Their involvement in the development of human bladder cancer has been determined by measuring the urinary excretion of indican (indoxyl sulphate) and conjugated phenols. 2. Thirty-two patients (22 males, 10 females) with histologically confirmed carcinoma of the urinary bladder and a similar number of age and sex matched controls took part in the study. The excretion of indican, p-cresol and phenol showed wide interindividual variability, but did not differ significantly between the two groups. 3. The findings indicate that these endogenous metabolites do not contribute significantly to the development of human bladder cancer.

Specific inhibition of aldosterone responses to endogenous and exogenous angiotensin II by somatostatin.

Aldosterone and renin responses to head-up tilt (60 degrees for 1 h) and angiotensin II infusions (2,5 and 10 ng/kg/min) 1 h later were compared in six normal subjects during infusions of somatostatin (3 micrograms/kg/min) or saline. The infusions were performed on separate days two weeks apart. The increase in aldosterone due to exogenous angiotensin II and orthostasis were significantly attenuated by somatostatin. Neither the increase in plasma renin activity (PRA) nor the angiotensin II mediated suppression of PRA were affected by somatostatin. These findings are consistent with the recent observation that somatostatin suppresses aldosterone release in response to angiotensin II in rat adrenal cells in culture and they indicate a possible role for somatostatin in the regulation of aldosterone secretion.