A walk in the PARC: developing and implementing 21st century chemical risk assessment in Europe.

Current approaches for the assessment of environmental and human health risks due to exposure to chemical substances have served their purpose reasonably well. Nevertheless, the systems in place for different uses of chemicals are faced with various challenges, ranging from a growing number of chemicals to changes in the types of chemicals and materials produced. This has triggered global awareness of the need for a paradigm shift, which in turn has led to the publication of new concepts for chemical risk assessment and explorations of how to translate these concepts into pragmatic approaches. As a result, next-generation risk assessment (NGRA) is generally seen as the way forward. However, incorporating new scientific insights and innovative approaches into hazard and exposure assessments in such a way that regulatory needs are adequately met has appeared to be challenging. The European Partnership for the Assessment of Risks from Chemicals (PARC) has been designed to address various challenges associated with innovating chemical risk assessment. Its overall goal is to consolidate and strengthen the European research and innovation capacity for chemical risk assessment to protect human health and the environment. With around 200 participating organisations from all over Europe, including three European agencies, and a total budget of over 400 million euro, PARC is one of the largest projects of its kind. It has a duration of seven years and is coordinated by ANSES, the French Agency for Food, Environmental and Occupational Health & Safety.

Patient perspective on remission in rheumatoid arthritis: Validation of patient reported outcome instruments to measure absence of disease activity.

OBJECTIVE: Patients have identified pain, fatigue and independence as the most important domains that need to be improved to define remission in rheumatoid arthritis (RA). This study identified and validated instruments for these domains and evaluated their added value to the ACR/EULAR Boolean remission definition. METHODS: Patients with a 28-joint Disease Activity Score (DAS28) ≤3.2 or in self-perceived remission (declaring their disease activity 'as good as gone') from the Netherlands, Portugal, Australia, and Canada, were assessed at 0, 3 and 6 months for patient-reported outcomes and the WHO-ILAR RA core set. Instrument validity was evaluated cross-sectionally, longitudinally and for the ability to predict future good outcome in terms of physical functioning. Logistic regression quantified the added value to Boolean remission. RESULTS: Of 246 patients, 152 were also assessed at 3, and 142 at 6 months. Most instruments demonstrated construct validity and discriminative capacity. Pain and fatigue were best captured by a simple numerical rating scale (NRS). Measurement of independence proved more complex, but a newly developed independence NRS was preferred. NRS for pain, fatigue and independence, in addition to or instead of patient global assessment did not add enough information to justify modification of the current Boolean definition of remission in RA. CONCLUSION: Key elements of the patient perspective on remission in RA can be captured by NRS pain, fatigue, and independence. Although this study did not find conclusive evidence to improve the current definition of remission in RA, the information from these instruments adds value to the physician's assessment of remission and further bridges the gap between physician and patient.

Targeting myelin lipid metabolism as a potential therapeutic strategy in a model of CMT1A neuropathy.

In patients with Charcot-Marie-Tooth disease 1A (CMT1A), peripheral nerves display aberrant myelination during postnatal development, followed by slowly progressive demyelination and axonal loss during adult life. Here, we show that myelinating Schwann cells in a rat model of CMT1A exhibit a developmental defect that includes reduced transcription of genes required for myelin lipid biosynthesis. Consequently, lipid incorporation into myelin is reduced, leading to an overall distorted stoichiometry of myelin proteins and lipids with ultrastructural changes of the myelin sheath. Substitution of phosphatidylcholine and phosphatidylethanolamine in the diet is sufficient to overcome the myelination deficit of affected Schwann cells in vivo. This treatment rescues the number of myelinated axons in the peripheral nerves of the CMT rats and leads to a marked amelioration of neuropathic symptoms. We propose that lipid supplementation is an easily translatable potential therapeutic approach in CMT1A and possibly other dysmyelinating neuropathies.

Content Validity of a Short Calcium Intake List to Estimate Daily Dietary Calcium Intake of Patients with Osteoporosis.

PURPOSE: Calcium supplements are prescribed for prevention of osteoporotic fractures, but there is controversy whether excess of calcium intake is associated with cardiovascular events. While an accurate estimation of dietary calcium intake is a prerequisite to prescribe the adequate amount of supplementation, the most adequate tools for estimating intake are time-consuming. The aim of this study is to validate a short calcium intake list (SCaIL) that is feasible in daily clinical practice. METHODS: Based on the food groups contributing most to daily dietary calcium intake and portion sizes determined in an earlier study, a three-item, 1-min SCaIL was designed. As a reference method, an extensive dietary history (DH) with specific focus on calcium-rich foods and extra attention for portion sizes was performed. Beforehand, a difference of ≥250 mg calcium between both methods was considered clinically relevant. RESULTS: Sixty-six patients with either primary (n = 40) or secondary (n = 26) osteoporosis were included. On average, the SCaIL showed a small and clinically non-relevant difference in calcium intake with the DH: 24 ± 350 mg/day (1146 ± 440 vs. 1170 ± 485 mg, respectively; p = 0.568). Sensitivity and specificity of the SCaIL, compared to the DH, were 73 and 80%, respectively. However, in 50% of the individuals, a clinically relevant difference of ≥250 mg calcium was observed between both methods, while in 17% this was even ≥500 mg. CONCLUSIONS: The SCaIL is a quick and easy questionnaire to estimate dietary calcium intake at a group level, but is not sufficiently reliable for use in individual patients. Remarkably, the mean dietary calcium intake estimated by the DH of 1170 mg/day indicates that a large proportion of osteoporosis patients might not even need calcium supplementation, although more data are needed to confirm this finding.

EULAR/EFORT recommendations for management of patients older than 50†years with a fragility fracture and prevention of subsequent fractures.

The European League Against Rheumatism (EULAR) and the European Federation of National Associations of Orthopaedics and Traumatology (EFORT) have recognised the importance of optimal acute care for the patients aged 50 years and over with a recent fragility fracture and the prevention of subsequent fractures in high-risk patients, which can be facilitated by close collaboration between orthopaedic surgeons and rheumatologists or other metabolic bone experts. Therefore, the aim was to establish for the first time collaborative recommendations for these patients. According to the EULAR standard operating procedures for the elaboration and implementation of evidence-based recommendations, 7 rheumatologists, a geriatrician and 10 orthopaedic surgeons met twice under the leadership of 2 convenors, a senior advisor, a clinical epidemiologist and 3 research fellows. After defining the content and procedures of the task force, 10 research questions were formulated, a comprehensive and systematic literature search was performed and the results were presented to the entire committee. 10 recommendations were formulated based on evidence from the literature and after discussion and consensus building in the group. The recommendations included appropriate medical and surgical perioperative care, which requires, especially in the elderly, a multidisciplinary approach including orthogeriatric care. A coordinator should setup a process for the systematic investigations for future fracture risk in all elderly patients with a recent fracture. High-risk patients should have appropriate non-pharmacological and pharmacological treatment to decrease the risk of subsequent fracture.

Induction chemotherapy with capecitabine and oxaliplatin followed by chemoradiotherapy before total mesorectal excision in patients with locally advanced rectal cancer.

BACKGROUND: Preoperative chemoradiation in patients with locally advanced rectal cancer has no impact on overall survival (OS) and distant recurrences. The aim of the study was to evaluate local downstaging, toxicity and long-term outcome in patients with locally advanced rectal cancer after induction therapy with capecitabine and oxaliplatin (CAPEOX) followed by radiotherapy concomitant with capecitabine [chemoradiotherapy (CRT)] before total mesorectal excision (TME). PATIENTS AND METHODS: Patients with T4 tumors, all T3N+ tumors or T3 tumors involving or with a distance ≤1 mm to the mesorectal fascia were included. Patients were planned for two cycles of CAPEOX followed by radiotherapy concomitant with capecitabine. TME was carried out 6 weeks after the completion of CRT. RESULTS: Of 84 consecutively admitted patients starting induction CAPEOX, 77 patients underwent surgery. R0 resection was seen in 94% and T downstaging in 69%. In the intention-to-treat group, pathological complete response was seen in 23%. Five-year disease-free survival (DFS) and OS were 63% [95% confidence interval (CI), 52.2% to 73.7%] and 67% (95% CI, 56.1% to 77.3%), respectively. Grade 3/4 toxicity was seen in 18%, and four deaths occurred within 2 months of therapy. CONCLUSION: Induction chemotherapy before CRT and surgery showed a high local control rate and promising long-term outcome as OS and DFS.

The effects of a pesticide mixture on aquatic ecosystems differing in trophic status: responses of the macrophyte Myriophyllum spicatum and the periphytic algal community.

The effects of a pesticide mixture (asulam, fluazinam, lambda-cyhalothrin, and metamitron) on aquatic ecosystems were investigated in 20 outdoor aquatic microcosms. Ten of the microcosms simulated mesotrophic aquatic ecosystems dominated by submerged macrophytes (Elodea). The others simulated eutrophic ecosystems with a high Lemna surface coverage (Lemna). This paper describes the fate of the chemicals as well as their effects on the growth of Myriophyllum spicatum and the periphytic algal community. In the Elodea-dominated microcosms significant increase in the biomass and alterations of species composition of the periphytic algae were observed, but no effect on M. spicatum growth could be recorded in response to the treatment. The opposite was found in the Lemna-dominated microcosms, in which decreased growth of M. spicatum was observed but no alterations could be found in the periphytic community. In the Elodea-dominated microcosms the species composition of the periphytic algae diverged from that of the control following treatment with 0.5% spray drift emission of the label-recommended rate (5% for lambda-cyhalothrin), while reduced growth of M. spicatum in the Lemna-dominated microcosms was recorded at 2% drift (20% for lambda-cyhalothrin). This study shows that the structure of the ecosystem influences the final effect of pesticide exposure.

Effects of metsulfuron methyl and cypermethrin exposure on freshwater model ecosystems.

The aim of this study was to investigate the short-term (2 weeks) effects of the herbicide metsulfuron methyl alone and in combination with the insecticide cypermethrin in freshwater enclosures (80 l). We used a factorial design with four levels of herbicide (0, 1, 5, 20 microg/l) and two levels of insecticide (0 and 0.05 microg/l). The root growth of the macrophyte species Elodea canadensis and Myriophyllum spicatum decreased following exposure to the lowest concentration of metsulfuron methyl tested. Metsulfuron methyl exposure resulted in a decreased pH in the aquatic enclosure at the lowest concentration tested, which is most likely a further indication of decreased macrophyte primary production. The biomass of periphytic algae growing on the leaves of M. spicatum increased in the enclosures exposed to metsulfuron methyl. The species composition of the periphytic algae differed significantly from the controls in the enclosures exposed to 20 microg/l of the herbicide. The increased biomass of periphytic algae on the leaves of the macrophytes is probably an indirect effect of the herbicide exposure. The exposure to metsulfuron methyl possibly induced a leakage of nutrients from the macrophyte leaves, which promoted an increased algal growth. The exposure to metsulfuron methyl did not alter the biomass or the species composition of the phytoplankton community. The zooplankton communities in the enclosures were dominated by rotifers, which were not affected by the exposure to cypermethrin. However, a cypermethrin exposure of 0.05 microg/l initially decreased the abundance of copepod nauplii. Ten days after exposure, the abundance of nauplii was significantly higher in the insecticide-exposed enclosures compared with the non-exposed enclosures. This might be an indication of a sub-lethal stress response, which either increased the number of offspring produced or induced an increased hatching of copepod resting stages. No combined effects of the herbicide and insecticide exposure, either direct or indirect, were observed in the enclosure study. Significant effects on the macrophytes were observed following exposure to 1 microg metsulfuron methyl per litre in the enclosure study. Furthermore, a single species laboratory assay indicated that the shoot elongation of E. canadensis decreased following exposure to >or=0.1 microg metsulfuron methyl per litre. These concentrations are well within the range of expected environmental concentrations, thus this study shows that aquatic ecosystems, in particular those which are macrophyte-dominated, may be affected by metsulfuron methyl at concentrations that may well occur in water bodies adjacent to agricultural land.

Thromboembolectomy in geriatric patients from long-stay wards.

The results of arterial embolectomy with the Fogarty balloon catheter in patients over 70 years of age with acute ischaemia of the lower limbs were evaluated. Twenty-three geriatric patients from long-stay wards, median age 81 years, range 70-92, were compared with 45 independent patients, median age 81 years, range 70-91, living in their own homes. The period of ischaemic symptoms before admission was on average shorter for patients coming from long-stay wards, but the outcome was less successful. Recurrent occlusion during the first postoperative month took place in 12 patients (52%) from long-stay wards as compared to eight (18%) among independent patients (p < 0.01). The mortality was 35% and 18% respectively (p > 0.2). After six months, only 35% of patients from geriatric institutions were alive with a functional extremity as compared to 62% in the independent group (p > 0.01).

Pulmonary hamartoma.

Eighty-nine cases of pulmonary hamartoma were studied. There were 51 men and 38 women, with a mean age of 57.5 years (range 14 to 76 years). A histologic diagnosis from examination of the resection specimens was obtained in all patients who had operations. Moreover, transthoracic needle aspiration biopsies were performed in 40 patients, with a diagnostic result in 34 (85%). The hamartomas were equally distributed in the pulmonary lobes; mean transverse diameter at the time of diagnosis was 21.7 +/- 16.2 mm. Tumor size was independent of the anatomic localization, but it correlated with the age of the patients (p less than 0.01). Tumor growth was recorded in 15 of 31 patients who had follow-up (45%); mean expansion in transverse diameter was 3.2 +/- 2.6 mm per year during an average observation time of 4.1 years (range 1 to 20 years). Pulmonary symptoms were present in 35 patients (39%). Seventy-five patients underwent operations as follows: enucleation (54), resection (11), lobectomy (5), pneumonectomy (4), and bronchoscopic removal (1). Since most pulmonary hamartomas are nonexpanding or slowly growing neoplasms, it is concluded that operation is necessary only when expansion is recorded in young or middle-aged patients and in patients with pulmonary symptoms.

The results of completion angiography after acute lower limb thromboembolectomy.

The results of completion angiography after acute thromboembolectomy with a Fogarty balloon catheter were evaluated. There were 62 patients (median age 72 years, range 44-92 years) and completion angiograms were made in 44 of them (71%). Incomplete runoff was demonstrated in 26 patients (59%) and rethromboembolectomy or vascular reconstruction was made in 18 cases (41%) under the same anaesthesia, while additional vascular surgery was technically impossible in 8 patients (18%). Supplementary surgery resulted in radiological improvement in 56% of operated cases. Reocclusion rate after 6 months was 50% in patients without patent tibials compared to 15% in patients with two or three patent tibial arteries (P less than 0.05). Eighteen patients had no completion angiograms after thromboembolectomy and 5 (28%) required early reoperation due to ischaemia. Completion angiograms are advocated in all cases of acute thromboembolectomy before the patient leaves the operating table.

[Retrograde colo-colic invagination]. / Retrograd kolo-kolisk invagination.

A case of retrograde colo-colic intussusception, diagnosed preoperatively by straight films of the abdomen and confirmed by barium enema X-ray, is presented. The mechanisms behind intussusception are discussed briefly.

Predictability of esophagus- and cardiatumor resectability by preoperative computed tomography.

Prior to operation, 32 patients with a tumor in the esophagus or in the cardia region were examined with computed tomography (CT), to evaluate the predictability of tumor resectability by CT. Twenty patients had the tumor operatively resected, in 2 patients the bulk of tumor could only be partly resected, and 10 patients were non-resectable due to invasion into the surrounding structures. The tumor resectability evaluated by preoperative CT resulted in positive/negative predictive values of 91 and 90%, respectively. This indicates that CT is a valuable method in planning the therapeutic strategy in cases of carcinoma of the oesophagus and the cardia region. The predictability of lymph-node involvement in the mediastinum and abdomen was less convincing.

Correlation of abdominal ultrasound and computed tomography scans with second- or third-look laparotomy in patients with ovarian carcinoma.

To determine the best noninvasive means of evaluating response in patients with advanced ovarian carcinoma, 50 abdominal ultrasound (US) and computed tomography (CT) scans were performed in clinically disease-free ovarian cancer patients. The scans were correlated with the results obtained at a subsequent second- or third-look laparotomy. CT and US were not complementary, and only metastases larger than 2 cm were detected. The overall positive predictive value of nonconcordant scans was 57% compared with 100% for concordant CT and US (95% confidence limits: 18.4-90.1 and 29.2-100%, respectively). The corresponding negative predictive values were 45 and 47% (30.2-59.9 and 30.4-61.2%, respectively), if undetected microscopic disease was classified as a false-negative result. The negative predictive value of US and CT increased only to 60% in both cases, if undetected microscopic disease was registered as a true-negative result. Compared with the pelvic examination CT and US added positive information for 4 of 22 (18%) patients with macroscopic residual disease. In this study neither CT nor US was sensitive enough to preclude second-look laparotomy.

[Candidiasis of the stomach as a complication of hiatal hernia surgery]. / Candidiasis i ventriklen som komplikation til hiatushernieoperation.

Candidiasis in the stomach after hiatus hernia sac operation has not previously been reported in the literature. We present a case in which a 46 year old woman developed candidiasis of the stomach, two months after hiatus hernia sac operation. The disease was primarily diagnosed radiologically and was later confirmed by gastroscopy and culture of gastric fluid. The pentagastrin test was performed six months after the operation and showed significantly reduced acid production. The most probable explanation for the condition is peroperative accidental lesion of branches of the vagus nerve resulting in reduced acid production thus facilitating growth of gastric candidiasis.

Sultamicillin versus amoxicillin in the treatment of tonsillitis and pharyngitis: a European multicenter study.

In this multicenter open, comparative study, 135 patients were treated with sultamicillin (67 subjects; 500 mg every 12 h) or amoxicillin (68 subjects; 500 mg every 8 h) for 10 d. Of the pathogens isolated pre-treatment, 24 of 29 (including 4 of 6 resistant strains) in the sultamicillin group were eradicated at the end of treatment, as were 17 of 22 in the amoxicillin group. At follow-up, the figures were 17 of 25 and 16 of 19, respectively. Clinical success was achieved in 55 of 55 sultamicillin and 40 of 43 amoxicillin patients at the end of treatment, and in 40 of 42 and 29 of 31, respectively, at follow-up. Overall success was recorded in 20 of 25 and 15 of 23 sultamicillin, and 14 of 19 and 13 of 17 amoxicillin patients at the two assessments. Side effects were reported for 21 sultamicillin patients, 1 of whom withdrew because of diarrhea, and 15 amoxicillin patients, 4 of whom withdrew because of rash. One sultamicillin and 4 amoxicillin patients developed minor abnormalities in laboratory safety parameters.

Epidemiological studies of diabetes mellitus in Denmark. II. A prevalence study based on insulin prescriptions.

The study aimed at tracing the population of insulin-treated diabetics living in the Funen County, Denmark (approximately 450000 inhabitants) on 1 July 1973. It was based on a recording of insulin prescriptions among all prescriptions handled by the pharmacies in Funen County during a five-month period. Through information from medical records and public registries the verification of the diagnosis and the identity of the insulin prescription holders were checked, and it is estimated that the completeness of the study material was above 98%. Age- and sex-specific prevalence rates of insulin-treated diabetes mellitus were calculated. The overall prevalence rate for males was 3.6 per 1,000 and that for females 3.3 per 1,000.

Epidemiological studies of diabetes mellitus in Denmark. I. A case finding method based on the National Service Conscript Registry.

To provide unbiased material for epidemiological studies of diabetes mellitus a case finding method based on the Danish National Service Conscript Registry and death certificates is presented and discussed. Eight Danish total male birth cohorts, totalling 320 162 persons, have been observed as to the occurrence of diabetes mellitus during the first twenty years of life, and it is concluded that the conscript registry represents an ideal basis for case identification, if the individual cases are further elucidated. The material is estimated to be about 95% complete. The main source of error originates from omissions when the registries are scrutinized. The cumulative incidence rates for the birth cohorts range from 1.3 to 3.2 per thousand; in the total material 2.4 per thousand.