The importance of environmental exposures to physical, mental and social well-being

"Health is a state of complete physical, mental and social well-being and not merely the absence of disease or infirmity" states the WHO. However, the current focus in this important area seems to be on reducing diseases, while less attention is paid on aspects how to increase the well-being of populations. This paper reviews three examples where well-being has drawn attention of the public and policy makers, and compares the policies of two wealthy countries. The first example is noise. Noise can reduce sleep quality and cause physiological, mental, and social effects. In Switzerland, noise receives a lot of attention by the public. Swiss laws are extensive, e.g., they prohibit trucks and planes from traveling at night. In the USA, there is little public attention and no national strategy against environmental noise. The second example is aesthetics and recreation. Many humans seek contact with the beauty of nature. The USA and Switzerland have similar strategies for achieving clear waters, while the protection of scenic views is approached very differently. Lifestyle is the last example. In the USA, the desire for individual freedom is a leading cause for suburban sprawl, a car-dependent sedentary lifestyle resulting in obesity, asthma and loss of community spirit. In Switzerland, a strict land use planning seeks to balance individual and public interests and stresses public transportation, which seems to be a more promising approach. Paying attention to aspects of well-being while developing political strategies might be a promising model to tackle environmental problems. Successful strategies employed so far seem to include the public, local authorities, politicians and scientists in this process, which might have been a key for their success. [Authors]

Appropriateness of colonoscopy in Europe (EPAGE II). Functional bowel disorders: pain, constipation and bloating.

BACKGROUND AND STUDY AIMS: To summarize the published literature on assessment of appropriateness of colonoscopy for the investigation of functional bowel symptoms, and report appropriateness criteria developed by an expert panel, the 2008 European Panel on the Appropriateness of Gastrointestinal Endoscopy, EPAGE II. METHODS: A systematic search of guidelines, systematic reviews and primary studies regarding the evaluation and management of functional bowel symptoms was performed. The RAND/UCLA Appropriateness Method was applied to develop appropriateness criteria for colonoscopy for these conditions. RESULTS: Much of the evidence for use of colonoscopy in evaluation of chronic abdominal pain, and/or constipation and/or abdominal bloating is modest. Major limitations include small numbers of patients and lack of adequate characterization of these patients. Large community-based follow-up studies are needed to enable better definition of the natural history of patients with functional bowel disorders. Guidelines stress that alarm features ("red flags"), such as rectal bleeding, anemia, weight loss, nocturnal symptoms, family history of colon cancer, age of onset > 50 years, and recent onset of symptoms should all lead to careful evaluation before a diagnosis of functional bowel disorder is made. EPAGE II assessed these symptoms by means of 12 clinical scenarios, rating colonoscopy as appropriate, uncertain and inappropriate in 42 % (5/12), 25 % (3/12), and 33 % (4/12) of these, respectively. CONCLUSIONS: Evidence to support the use of colonoscopy in the evaluation of patients with functional bowel disorders and no alarm features is lacking. These patients have no increased risk of colon cancer and thus advice on screening for this is not different from that for the general population. EPAGE II criteria, available online (http://www.epage.ch), consider colonoscopy appropriate in patients of > 50 years with chronic or new-onset bowel disturbances, but not in patients with isolated chronic abdominal pain.

Assessment of skinfold thickness equations in estimating body composition in children with inflammatory bowel

Introduction: Growth is a central process in paediatrics. Weight and height evaluation are therefore routine exams for every child but in some situation, particularly inflammatory bowel disease (IBD), a wider evaluation of nutritional status needs to be performed. The assessment of body composition is essential in order to maintain acceptable growth using the following techniques: Dual-energy X-ray absorptiometry (DEXA), bio-impedance-analysis (BIA) and anthropometric measurements (skinfold thickness skin), the latter being most easily available and most cost effective. Objectives: To assess the accuracy of skinfold equations in estimating percentage body fat (%BF) in children with inflammatory bowel disease (IBD), compared with assessment of body fat dual energy X-ray absorptiometry (DEXA). Methods: Twenty-one patients (11 females, 10 males; mean age: 14.3 years, range 12 - 16 years) with IBD (Crohn's disease n = 15, ulcerative colitis n = 6)). Estimated%BF was computed using 6 established equations based on the triceps, biceps, subscapular and suprailiac skinfolds (Deurenberg, Weststrate, Slaughter, Durnin & Rahaman, Johnston, Brook) and compared to DEXA. Concordance analysis was performed using Lin's concordance correlation and the Bland-Altman limits of agreement method. Results: Durnin & Rahaman's equation shows a higher Lin's concordance coefficient with a small difference amongst raw values for skinfolds and DEXA compared to the other equations. Correlation coefficient between mean and difference is close to zero with a non-significant Bradley-Blackwood test. Conclusion: Body composition in paediatric IBD patients using the Durnin & Rahaman skinfold-equation adequately reflects values obtained by DEXA.

Creatine deficiency syndromes and the importance of creatine synthesis in the brain.

Creatine deficiency syndromes, due to deficiencies in AGAT, GAMT (creatine synthesis pathway) or SLC6A8 (creatine transporter), lead to complete absence or very strong decrease of creatine in CNS as measured by magnetic resonance spectroscopy. Brain is the main organ affected in creatine-deficient patients, who show severe neurodevelopmental delay and present neurological symptoms in early infancy. AGAT- and GAMT-deficient patients can be treated by oral creatine supplementation which improves their neurological status, while this treatment is inefficient on SLC6A8-deficient patients. While it has long been thought that most, if not all, of brain creatine was of peripheral origin, the past years have brought evidence that creatine can cross blood-brain barrier, however, only with poor efficiency, and that CNS must ensure parts of its creatine needs by its own endogenous synthesis. Moreover, we showed very recently that in many brain structures, including cortex and basal ganglia, AGAT and GAMT, while found in every brain cell types, are not co-expressed but are rather expressed in a dissociated way. This suggests that to allow creatine synthesis in these structures, guanidinoacetate must be transported from AGAT- to GAMT-expressing cells, most probably through SLC6A8. This new understanding of creatine metabolism and transport in CNS will not only allow a better comprehension of brain consequences of creatine deficiency syndromes, but will also contribute to better decipher creatine roles in CNS, not only in energy as ATP regeneration and buffering, but also in its recently suggested functions as neurotransmitter or osmolyte.

Appropriateness of colonoscopy in Europe (EPAGE II). Iron-deficiency anemia and hematochezia.

BACKGROUND AND STUDY AIMS: To summarize the published literature on assessment of appropriateness of colonoscopy for the investigation of iron-deficiency anemia (IDA) and hematochezia, and report appropriateness criteria developed by an expert panel, the 2008 European Panel on the Appropriateness of Gastrointestinal Endoscopy, EPAGE II. METHODS: A systematic search of guidelines, systematic reviews and primary studies regarding the evaluation and management of IDA and hematochezia was performed. The RAND/UCLA Appropriateness Method was applied to develop appropriateness criteria for colonoscopy for these conditions. RESULTS: IDA occurs in 2 %-5 % of adult men and postmenopausal women. Examination of both the upper and lower gastrointestinal tract is recommended in patients with iron deficiency. Colonoscopy for IDA yields one colorectal cancer (CRC) in every 9-13 colonoscopies. Hematochezia is a well-recognized alarm symptom and such patients are likely to be referred for colonoscopy. Colonoscopy is unanimously recommended in patients aged > or = 50. Diverticulosis, vascular ectasias, and ischemic colitis are common causes of acute lower gastrointestinal bleeding (LGIB); CRC is found in 0.2 %-11 % of the colonoscopies performed for LGIB. Most patients with scant hematochezia have an anorectal or a distal source of bleeding. The expert panel considered most clinical indications for colonoscopy as appropriate in the presence of IDA (58 %) or hematochezia (83 %). CONCLUSION: Despite the limitations of the published studies, guidelines unanimously recommend colonoscopy for the investigation of IDA and hematochezia in patients aged > or = 50 years. These indications were also considered appropriate by EPAGE II, as were indications in patients at low risk for CRC with no obvious cause of bleeding found during adequate previous investigations.

Flow-targeted inversion-prepared b-TFE coronary MR angiography: initial results in patients.

PURPOSE: Visualization of coronary blood flow in the right and left coronary system in volunteers and patients by means of a modified inversion-prepared bright-blood coronary magnetic resonance angiography (cMRA) sequence. MATERIALS AND METHODS: cMRA was performed in 14 healthy volunteers and 19 patients on a 1.5 Tesla MR system using a free-breathing 3D balanced turbo field echo (b-TFE) sequence with radial k-space sampling. For magnetization preparation a slab selective and a 2D selective inversion pulse were used for the right and left coronary system, respectively. cMRA images were evaluated in terms of clinically relevant stenoses (< 50 %) and compared to conventional catheter angiography. Signal was measured in the coronary arteries (coro), the aorta (ao) and in the epicardial fat (fat) to determine SNR and CNR. In addition, maximal visible vessel length, and vessel border definition were analyzed. RESULTS: The use of a selective inversion pre-pulse allowed direct visualization of the coronary blood flow in the right and left coronary system. The measured SNR and CNR, vessel length, and vessel sharpness in volunteers (SNR coro: 28.3 +/- 5.0; SNR ao: 37.6 +/- 8.4; CNR coro-fat: 25.3 +/- 4.5; LAD: 128.0 cm +/- 8.8; RCA: 74.6 cm +/- 12.4; Sharpness: 66.6 % +/- 4.8) were slightly increased compared to those in patients (SNR coro: 24.1 +/- 3.8; SNR ao: 33.8 +/- 11.4; CNR coro-fat: 19.9 +/- 3.3; LAD: 112.5 cm +/- 13.8; RCA: 69.6 cm +/- 16.6; Sharpness: 58.9 % +/- 7.9; n.s.). In the patient study the assessment of 42 coronary segments lead to correct identification of 10 clinically relevant stenoses. CONCLUSION: The modification of a previously published inversion-prepared cMRA sequence allowed direct visualization of the coronary blood flow in the right as well as in the left coronary system. In addition, this sequence proved to be highly sensitive regarding the assessment of clinically relevant stenotic lesions.

Biodiversity of amoebae and amoeba-associated bacteria in water treatment plants.

In this study, we enlarged our previous investigation focusing on the biodiversity of chlamydiae and amoebae in a drinking water treatment plant, by the inclusion of two additional plants and by searching also for the presence of legionellae and mycobacteria. Autochthonous amoebae were recovered onto non-nutritive agar, identified by 18S rRNA gene sequencing, and screened for the presence of bacterial endosymbionts. Bacteria were also searched for by Acanthamoeba co-culture. From a total of 125 samples, we recovered 38 amoebae, among which six harboured endosymbionts (three chlamydiae and three legionellae). In addition, we recovered by amoebal co-culture 11 chlamydiae, 36 legionellae (no L. pneumophila), and 24 mycobacteria (all rapid-growers). Two plants presented a similar percentage of samples positive for chlamydiae (11%), mycobacteria (20%) and amoebae (27%), whereas in the third plant the number of recovered bacteria was almost twice higher. Each plant exhibited a relatively high specific microbiota. Amoebae were mainly represented by various Naegleria species, Acanthamoeba species and Hartmannella vermiformis. Parachlamydiaceae were the most abundant chlamydiae (8 strains in total), and in this study we recovered a new genus-level strain, along with new chlamydiae previously reported. Similarly, about 66% of the recovered legionellae and 47% of the isolated mycobacteria could represent new species. Our work highlighted a high species diversity among legionellae and mycobacteria, dominated by putative new species, and it confirmed the presence of chlamydiae in these artificial water systems.

Pharmacokinetic parameters of artesunate and dihydroartemisinin in rats infected with Fasciola hepatica

OBJECTIVES: The pharmacokinetic (PK) parameters of artesunate, recently discovered to possess promising trematocidal activity, and its main metabolite dihydroartemisinin (DHA) were determined in rats infected with hepatic and biliary stages of Fasciola hepatica and compared with uninfected rats after single intragastric and intravenous (iv) doses. METHODS: Rats infected with F. hepatica for 25 and 83 days and uninfected rats were cannulated in the right jugular vein and blood samples were withdrawn at selected timepoints following 10 mg/kg of iv and a single 100 mg/kg oral dose of artesunate. Plasma was analysed for artesunate and DHA by liquid chromatography coupled to tandem mass spectrometry. RESULTS: Rats harbouring juvenile and adult F. hepatica infections revealed considerable changes in PK parameters of artesunate and DHA. Following oral administration, maximum plasma concentrations (C(max)) of artesunate and DHA were 1.8-2.3-fold higher in infected rats [artesunate: 1334 +/- 1404 ng/mL (no infection) versus 2454 +/- 1494 ng/mL (acute infection) and 2768 +/- 538 ng/mL (chronic infection); DHA: 3802 +/- 2149 ng/mL (no infection) versus 6507 +/- 3283 ng/mL (acute infection) and 9093 +/- 884 ng/mL (chronic infection)]. The AUCs of artesunate and DHA were 2.1-4.4-fold greater in infected rats. An opposite trend was observed after iv injection. C(max) and AUC of artesunate and DHA following iv dosing were 5784 +/- 3718 and 140 938 +/- 128 783 ng.min/mL and 3849 +/- 3060 and 86 107 +/- 41 863 ng.min/mL, respectively, in uninfected rats versus 2623 +/- 1554 and 21 617 +/- 12 230 ng.min/mL and 2835 +/- 980 and 64 290 +/- 29 057 ng.min/mL, respectively, in rats harbouring a chronic infection. The elimination half-lives (t(1/2)) of artesunate and DHA were considerably altered in infected rats following oral and iv administration of artesunate. CONCLUSIONS: F. hepatica infections strongly influence the disposition kinetics of artesunate and its metabolite in rats. The clinical implications of this finding need to be carefully studied.

Colorectal polypectomy during insertion and withdrawal or only during withdrawal? A randomized controlled trial.

BACKGROUND AND STUDY AIMS: Removal of colorectal polyps is routinely performed during withdrawal of the endoscope. However, polyps detected during insertion of the colonoscope may be missed at withdrawal. We aimed to evaluate whether polypectomy during both insertion and withdrawal increases polyp detection and removal rates compared with polypectomy at withdrawal only, and to assess the duration of both approaches. PATIENTS AND METHODS: Patients were included into the study when the first polyp was detected, and randomized into two groups; in group A, polyps ≤ 10 mm in diameter were removed during insertion and withdrawal of the colonoscope, while in group B, these polyps were removed at withdrawal only. Main outcome measures were duration of colonoscopy, number of polyps detected during insertion but not recovered during withdrawal, technical ease, patient discomfort, and complications. RESULTS: 150 patients were randomized to group A and 151 to group B. Mean (± standard deviation [SD]) duration of colonoscopy did not differ between the groups (30.8 ± 15.6 min [A] vs. 28.5 ± 13.8 min [B], P = 0.176). In group A 387 polyps (mean 2.58 per colonoscopy) were detected and removed compared with 389 polyps detected (mean 2.58 per colonoscopy) in group B of which 376 were removed (13 polyps were missed, mean size [SD] 3.2 [1.3] mm; 7.3 % of patients). Patient tolerance was similar in the two groups. CONCLUSIONS: Removal of polyps ≤ 10 mm during withdrawal only is associated with a considerable polyp miss rate. We therefore recommend that these polyps are removed during both insertion and withdrawal.

Navigator-gated and real-time motion corrected free-breathing MR Imaging of myocardial late enhancement.

PURPOSE: A new magnetic resonance imaging approach for detection of myocardial late enhancement during free-breathing was developed. METHODS AND RESULTS: For suppression of respiratory motion artifacts, a prospective navigator technology including real-time motion correction and a local navigator restore was implemented. Subject specific inversion times were defined from images with incrementally increased inversion times acquired during a single dynamic scout navigator-gated and real-time motion corrected free-breathing scan. Subsequently, MR-imaging of myocardial late enhancement was performed with navigator-gated and real-time motion corrected adjacent short axis and long axis (two, three and four chamber) views. This alternative approach was investigated in 7 patients with history of myocardial infarction 12 min after i. v. administration of 0.2 mmol/kg body weight gadolinium-DTPA. CONCLUSION: With the presented navigator-gated and real-time motion corrected sequence for MR-imaging of myocardial late enhancement data can be completely acquired during free-breathing. Time constraints of a breath-hold technique are abolished and optimized patient specific inversion time is ensured.

Nuclear translocation and DNA recognition signals colocalized within the bZIP domain of cyclic adenosine 3',5'-monophosphate response element-binding protein CREB.

CREB is a cAMP-responsive nuclear DNA-binding protein that binds to cAMP response elements and stimulates gene transcription upon activation of the cAMP signalling pathway. The protein consists of an amino-terminal transcriptional transactivation domain and a carboxyl-terminal DNA-binding domain (bZIP domain) comprised of a basic region and a leucine zipper involved in DNA recognition and dimerization, respectively. Recently, we discovered a testis-specific transcript of CREB that contains an alternatively spliced exon encoding multiple stop codons. CREB encoded by this transcript is a truncated protein lacking the bZIP domain. We postulated that the antigen detected by CREB antiserum in the cytoplasm of germinal cells is the truncated CREB that must also lack its nuclear translocation signal (NTS). To test this hypothesis we prepared multiple expression plasmids encoding carboxyl-terminal deletions of CREB and transiently expressed them in COS-1 cells. By Western immunoblot analysis as well as immunocytochemistry of transfected cells, we show that CREB proteins truncated to amino acid 286 or shorter are sequestered in the cytoplasm, whereas a CREB of 295 amino acids is translocated into the nucleus. Chimeric CREBs containing a heterologous NTS fused to the first 248 or 261 amino acids of CREB are able to drive the translocation of the protein into the nucleus. Thus, the nine amino acids in the basic region involved in DNA recognition between positions 287 and 295 (RRKKKEYVK) of CREB contain the NTS. Further, mutation of the lysine at position 290 in CREB to an asparagine diminishes nuclear translocation of the protein.(ABSTRACT TRUNCATED AT 250 WORDS)

MR-venography using high resolution True-FISP.

A new fast MR-venography approach using a high resolution True-FISP imaging sequence was investigated in 20 patients suffering from 23 deep vein thromboses. Diagnosis was proven by x-ray venography, CT or ultrasound examination. The presented technique allowed for clear thrombus visualization with a high contrast to the surrounding blood pool even in calf veins. Acquisition time was less than 10 minutes for imaging the pelvis and the legs. No contrast media was needed. The presented high resolution True-FISP MR-venography is a promising non-invasive, fast MR-venography approach for detection of deep venous thrombosis.

Appropriateness of colonoscopy in Europe (EPAGE II). Screening for colorectal cancer.

BACKGROUND AND STUDY AIMS: To summarize the published literature on assessment of appropriateness of colonoscopy for screening for colorectal cancer (CRC) in asymptomatic individuals without personal history of CRC or polyps, and report appropriateness criteria developed by an expert panel, the 2008 European Panel on the Appropriateness of Gastrointestinal Endoscopy, EPAGE II. METHODS: A systematic search of guidelines, systematic reviews, and primary studies regarding colonoscopy for screening for colorectal cancer was performed. The RAND/UCLA Appropriateness Method was applied to develop appropriateness criteria for colonoscopy in these circumstances. RESULTS: Available evidence for CRC screening comes from small case-controlled studies, with heterogeneous results, and from indirect evidence from randomized controlled trials (RCTs) on fecal occult blood test (FOBT) screening and studies on flexible sigmoidoscopy screening. Most guidelines recommend screening colonoscopy every 10 years starting at age 50 in average-risk individuals. In individuals with a higher risk of CRC due to family history, there is a consensus that it is appropriate to offer screening colonoscopy at < 50 years. EPAGE II considered screening colonoscopy appropriate above 50 years in average-risk individuals. Panelists deemed screening colonoscopy appropriate for younger patients, with shorter surveillance intervals, where family or personal risk of colorectal cancer is higher. A positive FOBT or the discovery of adenomas at sigmoidoscopy are considered appropriate indications. CONCLUSIONS: Despite the lack of evidence based on randomized controlled trials (RCTs), colonoscopy is recommended by most published guidelines and EPAGE II criteria available online (http://www.epage.ch), as a screening option for CRC in individuals at average risk of CRC, and undisputedly as the main screening tool for CRC in individuals at moderate and high risk of CRC.

A frequency distribution approach to hotspot identification

We present a new global method for the identification of hotspots in conservation and ecology. The method is based on the identification of spatial structure properties through cumulative relative frequency distributions curves, and is tested with two case studies, the identification of fish density hotspots and terrestrial vertebrate species diversity hotspots. Results from the frequency distribution method are compared with those from standard techniques among local, partially local and global methods. Our approach offers the main advantage to be independent from the selection of any threshold, neighborhood, or other parameter that affect most of the currently available methods for hotspot analysis. The two case studies show how such elements of arbitrariness of the traditional methods influence both size and location of the identified hotspots, and how this new global method can be used for a more objective selection of hotspots.