Variation in partial direct costs of treating clinical mastitis among 37 Wisconsin dairy farms.

The objective of this observational study was to describe variations in partial direct costs of clinical mastitis (CM) treatments among 37 dairy herds using data obtained from herd management records. Animal health and drug purchase records were retrospectively collected from 37 Wisconsin dairy herds for a period of 1 yr. Each farm was visited to verify case definitions, recording accuracy, and detection criteria of CM cases. Descriptive statistics were used to summarize cost of drugs and milk discard. Differences in costs among protocols, intramammary (IMM) products, parities, days in milk, and recurrence were analyzed using ANOVA. Of 20,625 cases of CM, 31% did not receive antimicrobial treatment. The average cost of drugs and milk discard (including cases that were not treated) was $192.36 ± 8.90 (mean ± SE) per case and ranged among farms from $118.13 to $337.25. For CM cases treated only with IMM antimicrobials, milk discard accounted for 87% of total costs and was highly influenced by duration of therapy. Differences in costs were observed among parities, recurrence, and stage of lactation at case detection. Eight different treatment protocols were observed, but 64% of cases were treated using only IMM antimicrobials. Treatment costs varied among protocols; however, cases treated using both IMM and injectable antimicrobials as well as supportive therapy had the greatest costs as they were also treated for the longest duration. Ceftiofur was used for 82% of cases that received IMM antimicrobials while ampicillin was used for 51% of cases treated using injectable antimicrobials. With the exception of ceftiofur and pirlimycin IMM products, many IMM products were given for durations that exceeded the maximum labeled duration. For cases treated using only IMM therapy, as compared with observed costs, we estimated that partial direct costs could be reduced by $65.20 per case if the minimum labeled durations were used. Overall, partial direct costs per case varied among herds, cow factors, and treatment protocols and were highly influenced by the duration of therapy.

Quantification of antimicrobial usage in adult cows and preweaned calves on 40 large Wisconsin dairy farms using dose-based and mass-based metrics.

Use of antimicrobials in animal agriculture is under increasing scrutiny, but the quantity of antimicrobials used on large US dairy farms has not been evaluated using data from large farms and different metrics. This study investigated total antimicrobial usage (AMU) in adult dairy cows and preweaned calves (PWC) and contrasted 2 metrics used for measurement of AMU. Wisconsin dairy farms were eligible if they had >250 lactating cows, maintained computerized animal health records, and were willing to allow researchers access to treatment records. Animal health data for a 1-yr period was retrospectively collected from computerized records, and a farm visit was performed to verify case definitions and recording accuracy. Both dose-based (animal daily doses; ADD) and mass-based (total mg of antimicrobials per kg of body weight; BW) metrics were calculated at the herd, cow, and PWC levels. Descriptive statistics for AMU were examined for both age groups. Mean AMU was compared among active ingredients and route of usage using ANOVA models that included farm as a random variable. At enrollment, farms (n = 40) contained approximately 52,639 cows (mean: 1,316 ± 169; 95% CI: 975, 1657) and 6,281 PWC (mean: 180 ± 33; 95% CI: 112, 247). When estimated using ADD, total herd AMU was 17.2 ADD per 1,000 animal-days (95% CI: 14.9, 19.5), with 83% of total herd-level AMU in adult cows. When estimated using the mass-based metric, total herd AMU was 13.6 mg of antimicrobial per kilogram of animal BW (95% CI: 10.3, 17.0), with 86% of total AMU used in adult cows. For cows, 78% of total ADD (15.8 ADD per 1,000 cow-d) was administered as intramammary (IMM) preparations. In contrast, when AMU was estimated using a mass-based metric, IMM preparations represented only 24% of total AMU (12.1 mg of antimicrobial/kg of cow BW). For cows, ceftiofur was the primary antimicrobial used and accounted for 53% of total ADD, with 80% attributed to IMM and 20% attributed to injectable treatments. When estimated using a mass-based metric, ampicillin was the predominant antimicrobial used in cows and accounted for 33% of total antimicrobial mass per kilogram of BW. When AMU was estimated for PWC using ADD, injectable antimicrobials represented 79% of total usage (28.3 ADD per 1,000 PWC-d). In contrast, when AMU was estimated for PWC using a mass-based metric, injectable products represented 42% of total AMU, even though more farms administered antimicrobials using this route. When AMU in PWC was summarized using ADD, penicillin represented 32% of AMU, and there were no significant differences in ADD among ampicillin, oxytetracycline or enrofloxacin. When a mass-based metric was used to estimate AMU in PWC, oral products (sulfadimethoxine and trimethoprim-sulfa) represented more than half of the total AMU given to this group. Overall, these results showed that choice of metric and inclusion of different age groups can substantially influence interpretation of AMU on dairy farms.

Modified Mouse Model of Clostridioides difficile Infection as a Platform for Probiotic Efficacy Studies.

Probiotics may represent a promising approach for reducing Clostridioides (Clostridium) difficile infections (CDIs). A clinical trial conducted by our group demonstrated that CDI patients undergoing adjunctive treatment with Lactobacillus and Bifidobacterium probiotics had a reduction in diarrheal duration and compositional changes in their stool microbiomes. Here, we modified a CDI mouse model to represent clinical outcomes observed in patients and employed this model to identify evidence for the prevention of primary CDI and relapse with the same probiotic. Mice (n = 80) were administered 0.25 mg/ml cefoperazone over 5 days and subsequently challenged with 102C. difficile VPI 10463 spores. A subset of mice (n = 40) were administered 108 CFU of probiotics daily alongside cefoperazone pretreatment and until experimental endpoints were reached. Clinical scoring was performed daily on mice and used to evaluate CDI onset and severity. Moderate CDI in mice was defined by survival beyond day 3 postinfection, while mice with severe CDI were those who succumbed to infection prior to day 3 postinfection. Sequencing and analysis of 16S rRNA from stool content were performed to determine compositional alterations to the microbiota. Using total clinical scores, we identified an association between probiotic treatment and delayed onset of primary CDI and relapse by approximately 12 to 24 h (P < 0.001). The stool microbiome of mice with moderate CDI receiving probiotic treatment was significantly enriched with Lachnospiraceae during primary CDI (P < 0.05). The outcomes observed present an opportunity to use this modified CDI mouse model to examine the efficacy of nonantibiotic options for CDI management.

Oral probiotic combination of Lactobacillus and Bifidobacterium alters the gastrointestinal microbiota during antibiotic treatment for Clostridium difficile infection.

Perturbations in the gastrointestinal microbiome caused by antibiotics are a major risk factor for Clostridium difficile infection (CDI). Probiotics are often recommended to mitigate CDI symptoms; however, there exists only limited evidence showing probiotic efficacy for CDI. Here, we examined changes to the GI microbiota in a study population where probiotic treatment was associated with significantly reduced duration of CDI diarrhea. Subjects being treated with standard of care antibiotics for a primary episode of CDI were randomized to probiotic treatment or placebo for 4 weeks. Probiotic treatment consisted of a daily multi-strain capsule (Lactobacillus acidophilus NCFM, ATCC 700396; Lactobacillus paracasei Lpc-37, ATCC SD5275; Bifidobacterium lactis Bi-07, ATCC SC5220; Bifidobacterium lactis B1-04, ATCC SD5219) containing 1.7 x 1010 CFUs. Stool was collected and analyzed using 16S rRNA sequencing. Microbiome analysis revealed apparent taxonomic differences between treatments and timepoints. Subjects administered probiotics had reduced Verrucomicrobiaceae at week 8 compared to controls. Bacteroides were significantly reduced between weeks 0 to 4 in probiotic treated subjects. Ruminococcus (family Lachnospiraceae), tended to be more abundant at week 8 than week 4 within the placebo group and at week 8 than week 0 within the probiotic group. Similar to these results, previous studies have associated these taxa with probiotic use and with mitigation of CDI symptoms. Compositional prediction of microbial community function revealed that subjects in the placebo group had microbiomes enriched with the iron complex transport system, while probiotic treated subjects had microbiomes enriched with the antibiotic transport system. Results indicate that probiotic use may impact the microbiome function in the face of a CDI; yet, more sensitive methods with higher resolution are warranted to better elucidate the roles associated with these changes. Continuing studies are needed to better understand probiotic effects on microbiome structure and function and the resulting impacts on CDI.

Staphylococcus aureus in the nose and throat of Iowan families.

The study objective was to determine the prevalence of Staphylococcus aureus colonisation in the nares and oropharynx of healthy persons and identify any risk factors associated with such S. aureus colonisation. In total 263 participants (177 adults and 86 minors) comprising 95 families were enrolled in a year-long prospective cohort study from one urban and one rural county in eastern Iowa, USA, through local newspaper advertisements and email lists and through the Keokuk Rural Health Study. Potential risk factors including demographic factors, medical history, farming and healthcare exposure were assessed. Among the participants, 25.4% of adults and 36.1% minors carried S. aureus in their nares and 37.9% of adults carried it in their oropharynx. The overall prevalence was 44.1% among adults and 36.1% for minors. Having at least one positive environmental site for S. aureus in the family home was associated with colonisation (prevalence ratio: 1.34, 95% CI: 1.07-1.66). The sensitivity of the oropharyngeal cultures was greater than that of the nares cultures (86.1% compared with 58.2%, respectively). In conclusion, the nares and oropharynx are both important colonisation sites for healthy community members and the presence of S. aureus in the home environment is associated with an increased probability of colonisation.

Prevalence and molecular characterization of Staphylococcus aureus from human stool samples.

Background: To determine the prevalence of intestinal S. aureus colonization of patients at a large teaching hospital and determine the molecular characteristics of the identified strains. The second objective of this research was to determine risk factors associated with S. aureus intestinal colonization. Methods: A cross-sectional study of 781 specimens from inpatients and outpatients at the University of Iowa Hospitals and Clinics Clinical Microbiology Laboratory was conducted. S. aureus was identified using traditional culture methodologies. Methicillin-resistance was determined via PCR of the mecA gene. PVL PCR, spa typing, and antimicrobial sensitivity testing were also done. A nested case-control study was done on a subset of patients with all colonized patients defined as cases and non-colonized controls. Medical record abstractions were done to identify risk factors for intestinal colonization in the nested study. Results: Out of 625 patients included in the final study, 58 were positive for S. aureus (9.3%). One isolate was positive for the PVL gene. A high number of isolates were resistant to multiple antibiotics including oxacillin (43.1%), erythromycin (51.7%), and levofloxacin (41.4%). All isolates were susceptible to vancomycin, daptomycin, linezolid, and quinupristin-dalfopristin. In the nested study, having a disease or condition of the gastrointestinal tract significantly increased the odds of intestinal colonization (OR: 1.96, 95% CI: 1.04-3.7; aOR: 13.9, 95% CI: 1.67-115.7). No other variables were significantly associated with increased odds of colonization. Conclusions: S. aureus was identified from the stool of patients at the University of Iowa Hospitals and Clinics, with a large number of those isolates being resistant to antibiotics and may serve a reservoir for subsequent infections as well as asymptomatic transmission.

Noninvasive coronary artery imaging in the diagnosis and management of patients with ischemic heart disease.

The inherent limitations of x-ray coronary angiography have led to the development for both noninvasive and minimally invasive techniques for imaging the coronary arteries to assist in the diagnosis and management of patients with ischemic heart disease. Significant advances in transesophageal echocardiography, electron beam computed tomography, and magnetic resonance imaging now permit imaging of the proximal to mid-coronary arteries. Moreover, results of initial studies demonstrate the promise of these methods to detect coronary artery stenoses. In addition, each of these methods provides biochemical or physiologic data about the stenoses that are not obtainable through x-ray angiography. Quantification of coronary calcification via electron beam computed tomography has shown promise as a surrogate marker of coronary atherosclerosis. Transesophageal echocardiography and magnetic resonance imaging appear useful in evaluating the physiologic significance of angiographically detectable coronary artery stenoses via assessment of coronary blood flow. However, it should be noted that significant improvements in technology or acquisition parameters must occur before these techniques can be used on a routine clinical basis for coronary artery imaging. The relative merits and ultimate clinical potential of each of these techniques are discussed in this article.

Apparent lack of beta 3-adrenoceptors and of insulin regulation of glucose transport in brown adipose tissue of guinea pigs.

Norepinephrine-induced thermogenesis was substantial in adipocytes from brown adipose tissue (BAT) of cold-acclimated guinea pigs but absent in adipocytes from BAT of warm-acclimated guinea pigs. There was no thermogenic response to any beta 3-adrenergic agonist (CL-316,243, ZD-7114, BRL-28410, CGP-12177). The receptor was characterized as a beta 1-adrenoceptor. Adrenergic agonists stimulated adenylate cyclase in membranes from BAT of both warm- and cold-acclimated guinea pigs also via a beta 1-adrenoceptor; beta 3-adrenergic agonists had no effect. Glucose transport by brown adipocytes from warm-acclimated guinea pigs was not stimulated by either norepinephrine or insulin. Cold acclimation induced the appearance of stimulation of glucose transport by norepinephrine in association with the appearance of a large capacity for thermogenesis, but there was little improvement in response to insulin. GLUT4 was present in membranes from BAT of both warm- and cold-acclimated guinea pigs. Insulin is known to have an antilipolytic effect on both BAT and white adipose tissue of guinea pigs. Thus there is a selective lack of insulin-regulated glucose transport that is not improved by cold acclimation. Guinea pigs may have a mutated component of the translocation mechanism for GLUT4. beta 3-Adrenoceptors appear to be absent in brown adipocytes of adult guinea pigs, as in white adipocytes of guinea pigs, yet are known to be present in the gut. Tissue-specific expression of beta 3-adrenergic receptors in guinea pigs may differ from that in rats, in which receptors are expressed in the adipose tissues and gut.

ATPase-inhibitor proteins of brown-adipose-tissue mitochondria from warm- and cold-acclimated rats.

1. A group of male Sprague-Dawley rats (5-6 weeks old) was cold-acclimated at 4 degrees C for 4 weeks. Warm-acclimated controls remained at 24 degrees C. Total protein content of brown adipose tissue (BAT) increased more than 3-fold and total uncoupling protein (UCP) content increased more than 6-fold upon cold-acclimation. The concentration of UCP in isolated BAT mitochondria almost doubled. 2. Specific ATPase activity of the non-thermogenic BAT mitochondria (from warm-acclimated controls) was low and increased about 6-fold on addition of 1 microM-Ca2+, which raised free Ca2+ levels (measured by Fura-2) in the incubation media from 1.32 +/- 0.28 microM (mean +/- S.E.M.) to 2.29 +/- 0.39 microM [at which the Ca(2+)-binding ATPase-inhibitor protein (CaBI) is inactivated]. Correspondingly, the specific ATP synthetase activity of the non-thermogenic BAT mitochondria was high and was decreased by 74% by addition of 1 microM-Ca2+. 3. In contrast, specific ATPase activity of thermogenic BAT mitochondria (from cold-acclimated rats) was 5 times that of the control group, and addition of Ca2+ had only a small stimulatory response. Correspondingly, the specific ATP synthetase activity of the thermogenic BAT mitochondria was low, and the decrease by Ca2+ was small, albeit significant. 4. Extracts of BAT mitochondria from both groups of animals contained significant amounts of the ATPase-inhibitor protein of Pullman and Monroy (PMI) as well as of CaBI, as shown by gel electrophoresis. Kinetic studies of inhibition of mitochondrial ATPase activity showed that PMI activity was unaltered in extracts from the thermogenic BAT mitochondria, whereas CaBI activity was slightly but significantly increased. 5. The presence of active ATPase-inhibitor proteins in BAT mitochondria was shown for the first time. We conclude that uncoupling of oxidative phosphorylation occurs in thermogenic BAT mitochondria, even in the presence of the ATPase-inhibitor proteins.

Effects of cold acclimation and fasting on thyroxine 5'-deiodinase in brown adipose tissue of ob/ob mice.

Gradual acclimation to mild cold for 6 weeks increases the total activity of thyroxine 5'-deiodinase in brown adipose tissue (BAT) of genetically obese (ob/ob) mice to a level greater than that in similarly acclimated lean mice. This increase is largely due to the growth of the BAT in the ob/ob mouse, because specific activity of the enzyme is only slightly increased. In similarly cold-acclimated lean mice, the specific activity of thyroxine 5'-deiodinase was not altered. BAT mitochondrial GDP binding increased to the same high level in the gradually cold-acclimated ob/ob mouse as in cold-acclimated lean mice. We conclude that the growth and maintenance of BAT in the cold-acclimated ob/ob mouse, as in the cold-acclimated lean mouse, does not require greatly increased activity of thyroxine 5'-deiodinase. Fasting for 48 hr did not alter thyroxine 5'-deiodinase activity of BAT in either lean or ob/ob mice. The fasting-induced increase in activity seen by others in lean mice is probably due to thermoregulatory stimulation of BAT occasioned by the low environmental temperature at which the fasting occurred.

Thyroid hormone regulates type I deiodinase messenger RNA in rat liver.

Conversion of the prohormone T4 to the active hormone T3 is catalyzed by 5'-deiodinases, enzymes that have not been purified. Previous studies have shown that modulating thyroid status results in changes in type I deiodinase activity in the rat liver. We have quantitated type I deiodinase mRNA in liver by an expression assay using Xenopus laevis oocytes. We report here that changes in enzyme activity correlate closely with changes in levels of the mRNA for this enzyme, indicating that thyroid hormone regulates type I deiodinase at a pretranslational step. Using the oocyte system to express size-fractionated mRNA, we have also determined that the mRNA coding for this protein is between 1.9-2.4 kilobases in length. It has been proposed that protein disulfide isomerase (PDI) is closely related to the rat type I 5'-deiodinase. Our results indicate that this is not the case, since injection of in vitro transcribed PDI mRNA into oocytes did not result in expression of deiodinase activity, and the deiodinase mRNA could be physically separated from the 2.8-kilobase mRNA species hybridizing to rat PDI cRNA by size fractionation.

Adrenergic effects on thyroxine 5'-deiodinase in brown adipose tissue of lean and ob/ob mice.

Genetically obese, ob/ob, mice have an impaired capacity to increase the level of thyroxine 5'-deiodinase (T5'D) in their brown adipose tissue (BAT) when they are exposed to cold. Yet they are able to secrete norepinephrine (NE) from the nerves of their BAT in response to cold and are apparently refractory to this action of NE. The principal objective was to find out whether injected NE could increase T5'D in BAT of the ob/ob mouse. A secondary objective was to elucidate the nature of the adrenergic receptor(s) involved in this response in lean and ob/ob mice. Injection of NE increased T5'D in BAT of lean mice within 3 h. It also increased T5'D in BAT of ob/ob mice but to a lesser extent. Basal T5'D activity in BAT of ob/ob mice was greater than that seen in BAT of lean mice because of the greater size of the tissue. Neither isopropylnorepinephrine nor phenylephrine alone could increase T5'D activity, but a combination increased it almost as well as did NE, although to a lesser extent in ob/ob mice than in lean mice. Both a beta-adrenergic antagonist (propranolol) and an alpha 1-adrenergic antagonist (prazosin) could inhibit the effect of NE. The acute effect of NE on metabolic rate of intact mice also involves an action of both beta- and alpha 1-adrenergic receptors. The beta-adrenergic component appears to be defective in the ob/ob mouse.

Thyroxine 5'-deiodinase in brown adipose tissue of the cynomolgus monkey Macaca fascicularis.

Brown adipose tissue was identified in axillary, interscapular, subscapular, and cervical fat deposits of male and female cynomolgus monkeys (Macaca fascicularis) by histological and immunological techniques. Histology included staining of mitochondria with a Novelli stain and identification of mitochondria-rich multilocular cells. Immunological detection involved separation of homogenate proteins by sodium dodecyl sulphate--polyacrylamide gel chromatography, blotting on to nitrocellulose membranes, and identification of the specific uncoupling protein, unique to brown adipose tissue, with an antiserum to purified hamster uncoupling protein followed by detection with 125I-labelled protein A. The activity of thyroxine 5'-deiodinase in monkey brown adipose tissue homogenates was much higher than that seen previously in brown adipose tissue of rats, mice, and hamsters. This is the first demonstration of the presence of this enzyme in brown adipose tissue of a primate species.

Defective regulation of thyroxine 5'-deiodinase in brown adipose tissue of ob/ob mice.

Genetically obese (ob/ob) and lean (+/?) mice were exposed to a cold (14 degrees C) environment for 1, 3, 6, 12, 16, or 24 h or remained in a warm (28 degrees C) environment. In ob/ob mice the increase in brown adipose tissue (BAT) thermogenesis (mitochondrial GDP binding) was low and the increase in thyroxine 5'-deiodinase (T5'D) was delayed; there was a reduced increase in serum 3,5,3'-triiodothyronine (T3) level and these mice became hypothermic. Content of uncoupling protein (UCP) was low in BAT of obese mice and no cold-induced increase occurred. Adrenalectomy of obese mice before exposure to cold (14 degrees C) improved defective thermogenic response of BAT and thermoregulation, restored to normal the increases in T5'D activity and serum T3 level, and promoted an exaggerated increase in UCP content, detectable after only 6 h. Adrenalectomy of cold-exposed lean mice did not alter thermoregulation, the increase in BAT T5'D activity, or the increase in serum T3 but enhanced the thermogenic response and allowed a higher UCP content in BAT of cold-exposed mice. We conclude that suppression of the cold-induced increase in T5'D activity in BAT can be added to the other known corticosterone-dependent anomalies of the ob/ob mouse. We speculate that lack of the cold-induced increase in T5'D in BAT of the ob/ob mouse prevents the normal participation of T3 in the trophic response of BAT to cold and underlies the abnormality in this response.

Studies of 5'-deiodinase activity in rats differing in hepatic lipogenic activity.

Studies of the relationship of hepatic 5'-deiodinase activity to hepatic lipogenic capacity were conducted. Rats of the Zucker, BHE, and Sprague-Dawley strains were used. BHE and Sprague-Dawley rats were starved and refed a 65% glucose diet, whereas lean and obese Zucker rats were fed a stock diet; the rats were thus different in hepatic lipogenic capacity. After hepatic 5'-deiodinase activity was determined, we found that rats genetically predisposed to increased hepatic lipogenesis had less deiodinase activity than rats without this genetic feature. The role of the interaction between the thyroid hormones and glucocorticoid in the activity of hepatic deiodinase was also studied. Adrenalectomized (ADX) or intact BHE and Sprague-Dawley rats were injected with saline, thyroxine, or triiodothyronine and either saline or glucocorticoid. The normal Sprague-Dawley rats made predictable adjustments to their deiodinase activity when their hormonal status was manipulated, whereas the BHE rats responded as though these manipulations were corrections rather than additions or deletions.

Attenuated cold-induced increase in mRNA for uncoupling protein in brown adipose tissue of obese (ob/ob) mice.

The level of mRNA for uncoupling protein was measured in brown adipose tissue of young (8-10 weeks) and old (11 months) lean and ob/ob mice using a cDNA clone constructed previously. The level of poly(A)+ RNA was also measured using an oligo(dT)18 probe. Mice were kept at 28 degrees C or exposed to 14 degrees C for 12 h. The level of mRNA for uncoupling protein was normal in brown adipose tissue of younger obese mice but reduced in brown adipose tissue of old obese mice. The cold-induced absolute increase in uncoupling protein mRNA was smaller in obese mice, regardless of age. It is concluded that the known attenuation of the acute thermogenic response of brown adipose tissue of the ob/ob mouse to cold is accompanied by a similar attenuation of the initiation of the trophic response. It is likely, however, that these defects are secondary to the chronic reduction in sympathetic nervous system activity in brown adipose tissue of the ob/ob mouse, which results in a functional atrophy of the tissue.

Defective cold-induced stimulation of thyroxine 5'-deiodinase in brown adipose tissue of the genetically obese (ob/ob) mouse.

Exposure of a normal lean mouse to cold (14 degrees C) for 12 h increases the activity of thyroxine 5'-deiodinase in brown adipose tissue 26-fold. In contrast, exposure of the genetically obese, ob/ob, mouse to cold results in little more than a doubling of thyroxine 5'-deiodinase activity. The physiological significance of endogenous 3,5,3'-triiodothyronine production in brown adipose tissue is not understood. However, it seems likely that defective cold-induced stimulation of the 5'-deiodinase in brown adipose tissue of the ob/ob mouse might cause a relatively hypothyroid state of the tissue. Thyroid hormone is known to be required for a normal thermogenic response of brown adipose tissue to noradrenaline. It is suggested that the defect in the response of the 5'-deiodinase in the ob/ob mouse could contribute to the defective thermogenic response of brown adipose tissue to cold-exposure and to noradrenaline.

Metal sensitivity in patients with a hinge arthroplasty of the knee.

Fifty patients who had received a hinge arthroplasty of the knee were investigated for possible metal sensitivity. Patients were patch tested against all the metal constituents of the prosthesis. Positive patch tests were found in 32% of patients. Seventeen patients had either lossening or a persistent sterile discharge from the knee. No correlation was found between these complications and metal sensitivity. It was concluded that metal sensitivity is probably not a primary factor in the pathogenesis of complications, particularly loosening.