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The disease RA itself is assumed to be a risk factor for the occurrence of adverse drug reactions during sulphasalazine therapy. A meta-analysis comparing treatment termination because of toxicity among RA, inflammatory bowel disease and seronegative spondylarthropathy patients was conducted. It is shown that RA itself does not appear to predispose to treatment discontinuation because of adverse reactions. Differences found in the incidence of side effects among the various disease groups can probably be explained by patient selection, particularly with respect to age, proportion treated for the first time with sulphasalazine, and dosage used. The side effect profiles in the three groups studied are not different. However, a trend towards greater haematological and hepatic toxicity in rheumatic patients is noticed. [ABSTRACT FROM PUBLISHER]

The long-term use of second-line antirheumatic drugs was prospectively studied in a consecutive sample of 245 patients with recently diagnosed rheumatoid arthritis. A survival analysis was done in which treatment termination due to side-effects and to insufficient therapeutic effect were used as index causes. Cumulative drug ‘survival’ of aurothioglucose with treatment termination due to toxicity was significantly less compared with hydroxychioroquine. With regard to lack of efficacy as index cause, the administration time of hydroxychloroquine was significantly less than that of either aurothioglucose or sulphasalazine. Treatment termination due to lack of efficacy or combined insufficient therapeutic response and toxicity proved to be influenced by the initial disease activity and by the rank order of prescription. [ABSTRACT FROM PUBLISHER]

Background: Some studies have revealed an increased risk of early aseptic loosening of cementless stems in THA when inserted through an anterior or anterolateral approach compared with a posterior approach, whereas approach does not appear to be a risk factor in others. Stem design, whether "anatomic" (that is, stems with a curved lateral profile or an obtuse angle at the proximal-lateral portion of the stem) or "shoulder" (that is, straight with a proximal shoulder), may also be associated with a differential risk of aseptic loosening in cementless THA depending on the surgical approach used, but if so, this risk is not well characterized., Questions/purposes: In this national registry study, we investigated the association between surgical approach and early aseptic loosening of (1) cementless femoral stems with a proximal angular shape (shoulder); and (2) anatomically shaped femoral stems., Methods: The Dutch Arthroplasty Registry is a nationwide population-based register recording data on primary and revision hip arthroplasty. We selected all primary THAs (n = 63,354) with a cementless femoral stem inserted through an anterior, anterolateral, or posterior approach from 2007 to 2013 with a minimal followup of 2 years. Femoral stems were classified as "anatomic," "shoulder," or "other" (that is, not classifiable as anatomic or shoulder). From the 47,372 THAs with an anatomic or shoulder stem (mean followup, 3.5 years; SD, 1.8 years), 340 (0.7%) underwent revision surgery as a result of aseptic loosening of the femoral stem, 1195 (2.5%) were revised for other reasons, and 1558 patients (3.3%) died. We used Cox proportional hazard models to determine hazard ratios for aseptic loosening of anatomic and shoulder stems for the anterolateral and anterior approaches compared with the posterior approach., Results: After controlling for relevant confounding variables such as sex, American Society of Anesthesiologists score, previous surgery, and coating and material of the femoral stem, we found that there was a stem-approach interaction. Separate analysis showed that shoulder stems had a greater likelihood of early aseptic loosening when the anterolateral approach (hazard ratio [HR], 2.28; 95% confidence interval [CI], 1.43-3.63; p < 0.001) or anterior approach (HR, 10.47; 95% CI, 2.55-43.10; p = 0.001) was used compared with the posterior approach. Separate analysis of the anatomic stems yielded no association with approach (anterolateral: HR, 1.07, 95% CI, 0.70-1.63, p = 0.77; anterior: HR, 1.31, 95% CI, 0.91-1.89, p = 0.15)., Conclusions: In THA, cementless femoral stems with a proximal shoulder are associated with early aseptic loosening when inserted through an anterior or anterolateral approach compared with a posterior approach. An anatomically shaped stem may be preferred with these approaches, although further analysis with larger registry volumes should confirm our results, in particular for shouldered stems when implanted through an anterior approach., Level of Evidence: Level III, therapeutic study.

Background: In 2012, a donor-supported proof of principle study was launched to eliminate malaria from Rusinga Island, western Kenya, using solar-powered mosquito trapping systems (SMoTS). SMoTS, which also provided power for room lighting and charging mobile telephones, were installed in houses. In view of the involvement of individual and collective benefits, as well as individual and collective maintenance solutions, this study qualitatively examined preferences of some project stakeholders towards SMoTS sustainability components to see if and how they related to social dilemma factors., Methods: The data were collected through participant observation, semi-structured interviews and focus group discussions., Results: The results show that respondents largely preferred individual solutions to various aspects of maintenance. Selective collective solutions such as table banking groups were considered positively for mobilising financial resources for maintenance, but respondents were hardly willing to contribute financially to a collective entity. Few people saw a meaningful role for a collective governing body; people preferred to rely on individual household responsibility and private service delivery for repairs and stocking spare parts. An overriding concern was that people lacked trust in other community members, leaders and/or technicians who would be employed by a governing body. Respondents also had little confidence that a governing body or saving group could effectively impose sanctions to misappropriation of funds, poor leadership, defecting group members or technicians that might abuse a salaried position., Conclusion: There seemed to be linkages between preferences towards organising various components of SMoTS sustainability and known hindrances to addressing social dilemmas. This posed considerable challenges to organising the sustainability of this innovative malaria control strategy., Trial Registration: NTR3496 .

Methotrexate is a frequently prescribed drug and is considered to be safe at a low dosage. However, serious complications may occur during treatment. In this article we describe a 78-year-old male who used low-dose methotrexate for psoriatic arthritis. He died of multi-organ failure caused by sepsis and methotrexate intoxication as a result of deteriorating renal function. The second patient was a 56-year-old male who used low-dose methotrexate for rheumatoid arthritis. This patient developed pancytopenia and methotrexate pneumonitis during treatment with methotrexate. We recommend the frequent monitoring of blood count and renal and liver function tests to detect early deterioration. Furthermore, doctors should be aware of conditions and factors predisposing to methotrexate intoxication, such as impaired kidney function and co-medication. If methotrexate intoxication is suspected, intravenous folinic acid should be administered immediately.

Multiple epidermoid cysts were observed microscopically in the testis of a New Zealand White rabbit. The cysts were lined by stratified squamous keratinizing epithelium and filled with concentric layers of keratin. Testicular epidermoid cysts have been described in men but are very rare in animals., (Copyright © 2011 Elsevier GmbH. All rights reserved.)

In this report we describe a choristoma in the lung of a female placebo rat. The lesion was observed microscopically in the central part of the left lung lobe and was characterized by a nodule consisting of well-differentiated skeletal muscle cells. The muscle fibers were haphazardly organized giving the nodule a poorly demarcated border. Choristoma is a very rare lesion., (Copyright © 2010 Elsevier GmbH. All rights reserved.)

The isolated chicken eye (ICE) test, developed at our Institute, is accepted by the OECD for identification of severe eye irritants. The OECD ICE Guideline (No. 438) encourages preservation of the treated eyes for possible histopathology of the cornea, which is believed to strengthen evidence of absence or presence of irritation and to help clarify borderline effects by assessment of the corneal Depth-of-Injury. Histopathology of the cornea in addition to the normal slit-lamp microscope assessment of corneal effects has already been performed routinely in ICE tests at our Institute, using two standard stainings (H&E and PAS). In this study, three other stainings (AZAN, EVG and Trichrome), more specific for collagen-rich membranes such as basement- and Bowman's membranes were examined with corneas exposed to four model compounds ranging from non- to severely irritating (corrosive). PAS appeared to be the superior staining method. Surprisingly, the well-known eye corrosive sodium hydroxide (NaOH, solid) did not visibly compromise the integrity of Bowman's or the basement membrane. Based on our experience, histopathology of the treated cornea is confirmative in relation to the standard assessment of eye irritation by slit-lamp observation in the ICE and in certain cases can help to evaluate borderline effects. Besides establishing the depth of injury, additional investigation of corneal limbal stem cell damage after chemical exposure might be appropriate to determine reversibility or irreversibility of eye effects., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Reactivation of tuberculosis is a severe side effect of anti-TNF treatment. Especially extrapulmonary forms of tuberculosis may occur, which are difficult to diagnose. The diagnosis may be obtained by a thorough search for Mycobacterium tuberculosis. We describe two patients who developed tuberculous peritonitis after infliximab therapy that was prescribed for treatment of rheumatoid arthritis. These cases illustrate that tuberculous peritonitis has a nonspecific clinical manifestation and that Mycobacteria can be difficult to find in ascites fluid. For this reason, tuberculostatic therapy has to be started in case of clinical suspicion. Before starting infliximab therapy, the patient must be thoroughly screened for the presence of (latent) tuberculosis.

Background: There is an overlap between the symptoms of psychopathy and autism spectrum disorders., Aim: To contribute to an adequate differential diagnosis of these disorders., Method: We reviewed the literature with the help of PubMed, using as key words: 'empathy', 'psychopathy', 'autism', 'aggression' and 'antisocial' for the period 1980-2004. We also consulted papers listed in the bibliographic references for these articles., Results: Empathic deficit is a core symptom of both disorders. In psychopathy there are signs of an emotional empathic deficit, an inability to feel along with another person (insensitivity). Research into autism spectrum disorders points to a cognitive empathic deficit, an inability to take the perspective of another person (innocence). The antisocial behaviour that can accompany both disorders might be due to the type of empathic deficit. In psychopathy the antisocial behavior often involves insensitive manipulation and exploitation ofanother person. In autism spectrum disorders there is sometimes antisocial behaviour which could be caused partly by incorrect evaluation of social situations. In both psychopathy and autism spectrum disorders dysfunctioning of the orbitoftontal cortex and the amygdala is often mentioned as a possible cause of empathic deficit., Conclusion: An accurate diagnosis of the type of empathic deficit involved could help to differentiate psychopathy from autism spectrum disorders. Good diagnostic tools are not yet available.

The effects of different dietary compounds on the formation of aberrant crypt foci (ACF) and colorectal tumours and on the expression of a selection of genes were studied in rats. Azoxymethane-treated male F344 rats were fed either a control diet or a diet containing 10% wheat bran (WB), 0.2% curcumin (CUR), 4% rutin (RUT) or 0.04% benzyl isothiocyanate (BIT) for 8 months. ACF were counted after 7, 15 and 26 weeks. Tumours were scored after 26 weeks and 8 months. We found that the WB and CUR diets inhibited the development of colorectal tumours. In contrast, the RUT and BIT diets rather enhanced (although not statistically significantly) colorectal carcinogenesis. In addition, the various compounds caused different effects on the development of ACF. In most cases the number or size of ACF was not predictive for the ultimate tumour yield. The expression of some tumour-related genes was significantly different in tumours from the control group as compared to tumours from the treated groups. It was concluded that WB and CUR, as opposed to RUT and BIT, protects against colorectal cancer and that ACF are unsuitable as biomarker for colorectal cancer. Effects of the different dietary compounds on metalloproteinase 1 (TIMP-1) expression correlated well with the effects of the dietary compounds on the ultimate tumour yield., (Copyright 2004 Elsevier Ltd.)

Purpose: A new inferior vena cava filter was evaluated in vivo to determine the percutaneous retrievability after an implantation period of up to 18 days., Materials and Methods: The inferior venae cavae of six goats were percutaneously implanted with three filters, and one animal received two filters. To assess filter stability, a plain radiograph was obtained after 7-9 days and on the day of retrieval. After cavography, filter retrieval with an endovascular snare and retrieval catheter was performed in three animals after 12 days and in three others after 14 days. In one animal, retrieval of one filter was performed after 18 days, and one filter was intended to be permanent. Twenty-eight days after filter retrieval, cavography was performed before inferior vena cava removal for gross and histologic examination., Results: All filters (N = 20) were implanted without complications. There was no migration during the implantation period. Preretrieval cavography demonstrated all filters to be patent and centered. Filters intended for retrieval (n = 19) were all successfully extracted at 12 (nine filters), 14 (nine filters), and 18 days (one filter). For the animal with the filter extracted at 18 days, one filter remained in situ intentionally. Postretrieval cavography showed no visible signs of vessel wall anomalies. There were no complications during the 28 days of follow-up after retrieval. Presacrifice cavography showed no evidence of caval wall abnormalities. In all animals, gross examination of the inner wall of the explanted vena cava showed only minimal macroscopic changes. The struts of the filter in situ for 46 days (18 days with 28 days of follow-up) were overgrown with neointima. Histological study of the 19 filter retrieval sites revealed no to moderate intima proliferation, minimal residual signs of hemorrhages, and no or only occasional slight inflammatory reaction., Conclusions: In this animal model, the new vena cava filter demonstrated event-free retrieval, without postretrieval complications, up to 18 days postimplantation. After implantation of 46 days, the filter showed neointima overgrowth of the struts.

Epidemiologic investigations have suggested a relationship between dietary fat intake and various types of cancer incidences. Furthermore, epidemiologic studies as well as studies with animal models have demonstrated that not only the amount but also the type of fat consumed is important. At present, the mechanism by which dietary fat modulates carcinogenesis has not been elucidated. The effects of dietary fat on the development of tumours have been summarized in the present review with emphasis on colorectal, pancreas, breast and prostate cancer. It is concluded that influence on synthesis of prostaglandins and leukotrienes may be the universal mechanism by which dietary fats modulate carcinogenesis., (Copyright 1999 Elsevier Science B.V.)

Phytosterol esters (PE) are intended for use as a novel food ingredient with plasma cholesterol lowering activity which works by inhibiting the absorption of cholesterol from the gut. Although PE are naturally present in the normal diet, the levels are insufficiently large to ensure lowering of plasma cholesterol levels. Therefore PE may be added to spreads to achieve the desired cholesterol lowering activity. As part of an extensive programme of safety evaluation studies a two-generation reproduction study has been conducted in Wistar rats, in which the possible effect of PE on male and female reproductive performance and on the growth and development of the offspring was studied. Rats were fed diets containing PE at levels of 0, 1.6, 3.2 and 8.1% (w/w) PE over two successive generations, and a wide range of reproductive and developmental parameters, including sexual maturation parameters and oestrous cycle length, were determined. Macroscopic and microscopic examinations were conducted including a histological examination of selected organs from F1- and F2-weanlings and from F0- and F1-parental animals. Daily clinical observations did not reveal any unusual findings. In both generations, no effects of PE were observed on pup mortality (calculated on litter basis), precoital time, mating index, male and female fertility index, female fecundity index, gestation index, duration of gestation, number of females with stillborn pups, post-implantation loss and pup development. Furthermore, PE had no effect on sexual maturation parameters (preputial separation and vaginal opening) and oestrous cycle length. In addition, there were no dose-related effects on selected organs following histological examination. In conclusion, dietary administration of up to 8.1% PE (equivalent to a dose of 2.5 to 9.1 g PE/kg body weight/day, dependent on the period of the study) during two generations had no effect on reproduction of parental F0- and F1-generation Wistar rats, nor on the development of the F1- and F2-pups, nor on the sexual maturation of the F1-weanlings. Therefore, a nominal dietary PE concentration of 8.1% (equivalent to a dose of 2.5-9.1 g PE/kg body weight/day or 1.54-5.62 g phytosterol/kg body weight/day dependent on the period of the study) was considered to be the no-observed-adverse-effect level following daily oral administration of PE for two successive generations.

The ability of saponins and glycoalkaloids to permeabilise the mammalian intestinal barrier has been previously demonstrated in vitro, leading to the hypothesis that membranolytic saponins may facilitate transfer to the tissues of otherwise excluded macromolecules. An enhanced uptake of, for instance, potentially allergenic species from the lumen is one of the factors that may affect the induction of food allergy, and its presentation in already sensitised individuals. In the experiments described here, an increase in the transmucosal uptake of the milk allergen beta-lactoglobulin (beta LG) was assessed in non-sensitised and sensitised Brown Norway rats in the presence of Gypsophila saponin. Isolated jejunal loops were exposed in vivo to either beta LG followed by saponin, saponin followed by beta LG or the two compounds simultaneously. Portal vein blood samples were collected and assayed for beta LG and rat mucosal mast cell protease (RCMP II) activity. Mucosal tissue was also examined histologically and assayed for histamine content. Sham-operated animals, exposed to physiological buffer alone, were included as controls and beta LG measurements corrected for this component which was negligible. No transfer of beta LG occurred in the absence of saponin in non-sensitised rats, whereas a significant enhancement was observed in the presence of saponin. beta LG was detected in the portal circulation of sensitised rats exposed to beta LG alone; however addition of saponin to the intestinal lumen further enhanced this uptake, possibly by an independent mechanism. Histological examination of the mucosal epithelium exposed to saponin revealed damage, especially at the villus tips. Mucosal histamine and serum RCMP II concentrations were consistent with the differences observed between sensitised and non-sensitised animals. It is concluded that exposure to food constituents capable of permeabilising the mucosal epithelium may increase the risk of sensitisation to dietary antigens.

In the present study the effects of dietary galactooligosaccharide (GOS) on dietary fat-promoted pancreatic carcinogenesis in azaserine-treated rats were investigated. The aims of this study were to determine 1) whether GOS acts as an inhibitor of pancreatic carcinogenesis and 2) whether GOS interacts with dietary fat-promoted pancreatic tumor development. Four groups of 39 azaserine-treated rats were maintained on different experimental diets that were formulated as follows: 4.3 wt% fat-8.3 wt% GOS (low fat-low GOS), 3.5 wt% fat-27.4 wt% GOS (low fat-high GOS), 15.5 wt% fat-9.5 wt% GOS (high fat-low GOS), and 14.3 wt% fat-28.6 wt% GOS (high fat-high GOS). Autopsies were performed after 6 months (9 animals/group) and 12 months (30 animals/group). Five rats per group were treated with bromodeoxyuridine before autopsy. Parallel sections of the pancreas were stained with hematoxylin and eosin or with hematoxylin and a monoclonal antibody against bromodeoxyuridine and examined by light microscopy. A high-fat diet caused a significant decrease, whereas a diet high in GOS caused a significant increase, in absolute and relative weight of the cecum content. A high level of dietary fat caused a highly significant increase in multiplicity and incidence of pancreatic (pre)neoplastic lesions after 6 and 12 months of feeding. A high level of GOS in the diet did not influence the number of atypical acinar cell nodules or the tumor incidence in comparison with controls. Dietary fat and dietary GOS caused a significant increase in cell proliferation in atypical acinar cell nodules after six months. It was concluded that dietary GOS has no modulating effect on pancreatic carcinogenesis in azaserine-treated rats or on the tumor-promoting effect of a high-fat diet.

Erythritol was fed at dietary concentrations of 0, 2.5, 5, or 10% to Crl:(WI) WU BR rats of both sexes through two successive generations (F0 and F1). Twenty-four rats of each sex were mated in each group. For each generation one litter was reared until the pups were 21 days old. In the 10% erythritol group, food consumption among F0-males and -females was initially significantly reduced until the animals adapted to the erythritol diet during the first week of the study. Thereafter, food intake was higher than in controls. A consistently increased food intake also was seen in F1-males and-females of this dose group. This effect was considered to result from the caloric dilution of the food by erythritol, which has a low physiological energy value. The lower body weight and weight gain of the F0-animals of the 10% erythritol group were attributed to the initially reduced food consumption and occurrence of transient diarrhea until the animals had adapted to the erythritol intake. In the F1-animals of the 10% erythritol group, which were adapted to the treatment from weaning, the rate of body weight gain did not differ from controls. The F1-males and -females of this dose group did, however, have a reduced body weight from weaning, which was attributed to a reduced energy intake among the corresponding F0-dams during Weeks 2 and 3 of lactation. This effect was not seen in the F2-generation. It is concluded that under the conditions of this experiment, the intake of erythritol had no adverse effect on fertility and reproductive performance of parent rats or on the development of their progeny. Gross necropsy and microscopic examination of the parenteral reproductive organs also did not reveal treatment-related changes.

Therapy with disease modifying antirheumatic agents (DMARDs) is often complicated by the occurrence of adverse effects. Although risk factors for several DMARDs have been reported, the prediction of adverse drug reactions is not yet possible. Therefore regular monitoring remains mandatory. Monitoring for adverse effects to DMARDs usually includes one or more of the following: blood count, liver, kidney, urine or ophthalmologic tests. Since most adverse reactions occur during the first few months of treatment, monitoring should be more intense and frequent in this initial phase. Some adverse effects are dose-dependent, and therefore dosage reduction may help alleviate these. Others are idiosyncratic, and often necessitate drug withdrawal. Except for (hydroxy)chloroquine-induced retinopathy and methotrexate-induced liver cirrhosis, most adverse reactions to DMARDs are fortunately reversible.

Objective: To describe causality, morphology, course, and risk factors of mucocutaneous reactions to gold., Methods: A prospective study of 74 patients with rheumatoid arthritis starting with gold thioglucose., Results: Thirty-nine patients experienced an episode of gold dermatitis. Sixteen patients continued gold treatment. The estimated treatment withdrawal at 1 year was 26%. The clinical picture was variable and nonspecific. Gold dermatitis was associated with HLA-B35 and disease duration., Conclusion: Mucocutaneous reactions to gold are nonspecific, therefore a causality assessment is necessary. Incidence is high, but treatment can often be continued with dose reduction and local steroids. The predictive value of risk factors is low.

Clinical and laboratory factors influencing the discontinuation of second-line antirheumatic drugs were prospectively studied using survival analysis in a consecutive series of 245 patients with recently diagnosed rheumatoid arthritis. A statistically significant influence of age, sex, serum IgA and HLA-DR3 on the discontinuation rate of chrysotherapy because of toxicity was observed. The discontinuation of sulfasalazine was increased by advanced age and high rank order of prescription. With respect to efficacy, high initial disease activity appeared to predispose to treatment termination of hydroxychloroquine, sulfasalazine and penicillamine. Furthermore, an influence of the rank order of prescription on discontinuation of sulfasalazine therapy because of lack of efficacy was found. Of interest is that discontinuation of hydroxychloroquine therapy because of lack of efficacy occurred less frequently in HLA-DR3-positive than in HLA-DR3-negative patients. Although these prognostic factors are of secondary importance in clinical practice, they may be of significance in the interpretation and comparison of clinical trials.

The longterm use of nonsteroidal antiinflammatory drugs (NSAID) was studied in a consecutive sample of 148 patients with recently diagnosed rheumatoid arthritis. A survival analysis was done in which treatment terminations due to side effects and to insufficient therapeutic effect were used as index causes. Cumulative drug 'survival' of indomethacin with treatment terminations due to untoward reactions as endpoints was significantly less compared to naproxen and diclofenac (p less than 0.001). No significant difference with termination due to lack of efficacy as index cause was observed (p greater than 0.90). No influence of sex or age on the drug survival with the different endpoints mentioned above could be established.

A stone, which had been accidentally swallowed by a ratsnake (Elaphe obsoleta rossaleni) and which had been present in the stomach for as long as four days, was surgically removed by coeliotomy and gastrotomy. Anaesthesia was produced by Metomidate (Hypnodil) in a doses of 10 mg/kg of body weight. The wall of the stomach was sutured by continuous Lembert sutures. The skin and muscles were closed with single sutures. Recovery was successful and complete.