[7-9] However, for IgA nephropathy patients with significant risk for rapid disease progression,[12, 13] it is still unclear whether the addition of anti-oxidant therapy increases the therapeutic efficacy. In the present study, to examine of the clinical benefits and safety of

probucol (an anti-oxidant and anti-hyperlipidemic agent) in combination with valsartan (an ARB) in patients with IgA nephropathy, we conducted a multi-centre, open labelled, randomized controlled study. This multi-centre, check details randomized, open-label, controlled and parallel clinical trial enrolled patients with biopsy-proven IgA nephropathy from January 2007 to January 2010. The inclusion criteria were: age of 18–75 years; 24-h urinary protein of 1.0–3.0 g; serum creatinine no more than 265.2 μmol/L; no treatment with an angiotensin converting enzyme inhibitor (ACEI), ARB, anti-oxidant, lipid-lowering drug in Z-VAD-FMK solubility dmso the previous 6 weeks, and no treatment with steroid or cytotoxic drug within the previous 6 months. Patients with any of the following were excluded: secondary IgA nephropathy (Henoch-schonlein purpura nephritis, hepatitis

B virus associated glomerulonephritis, cirrhosis, lupus nephritis, connective tissue diseases), malignant hypertension, acute kidney injury, crescentic glomerulonephritis, diabetes, renal artery stenosis, obstructive nephropathy, pregnancy, tumour, active gastrointestinal ulcer, coronary heart disease, cardiomyopathy, serious arrhythmia, cerebrovascular disease, and active infection (including tuberculosis). Patients who did not comply with the CYTH4 treatment were also excluded. A computer-generated list that was maintained by a third party not involved in the conduct of the study was used for randomization. Investigators were unaware of the randomization schedule when recruiting patients, and both investigators and patients were not blinded during the follow-up period. Two pathologists who were blinded to this study independently made all of the pathological examinations. At the end of study, the pathologists used the Oxford classification system

of IgA nephropathy to evaluate renal tissue sections. The study protocol was approved by the institutional review boards at each site, and all patients gave written, informed consent. All study procedures were performed in accordance with the principles of the Declaration of Helsinki. The flow chart of the study was shown in Figure 1. All 75 eligible patients were screened before formal enrolment. For screening, patients were treated with 80 mg/day valsartan for 4 consecutive weeks, during which blood pressure, serum potassium, serum creatinine, and cough were monitored. After 4 weeks, patients who had serum potassium less than 5.5 mmol/L, an increase in serum creatinine less than 30%, and without intolerable side-effects related to valsartan therapy were given 160 mg/day valsartan for 4 weeks.

86, p < 0.0001) as well as in a control group (r = 0.86, p < 0.0001).

However, the Bland-Altman procedure revealed a bias for the spot urine P/C ratio from MN patients as the ratio minus 24-h urine P/C ratio was positively correlated to the mean (r = 0.48, P < 0.001), which was not the case for the spot urine P/C ratio from control patients. In patients with MN, as much as 40% of the results from spot urine P/C ratio were overestimated more than 1.5 times compared to those from 24-h urine P/C ratio. Conclusion: In patients with MN, spot urine P/C ratio, at least obtained at daytime, may overestimate 24-h proteinuria, and thus should be followed by a 24-h urine collection to monitor disease activity. MIYAKE TAITO, MASAOKA TAKAHIRO, SHINOZAKI YASUYUKI, TOYAMA TADASHI, IWATA YASUNORI, SAKAI NORIHIKO, FURUICHI KENGO, WADA TAKASHI Division of Nephrology, Kanazawa University Hospital, selleckchem Kanazawa, Japan Introduction: Multicentric Castleman’s disease (MCD) is a polyclonal lymphoproliferative disorder. Recent studies revealed the atypical variant of MCD complicated with kidney dysfunction and thrombocytopenea. Here we report clinical and pathological characteristics of four patients of MCD with kidney dysfunction, including two patients showing the atypical variant. Methods: Four MCD patients with kidney dysfunction were diagnosed in Kanazawa University Hospital. Clinical and

pathological characteristics of these patients were evaluated. this website Results: Mean age at onset was 44 years old. Proteinuria (4/4) and acute kidney injury (3/4) were the main clinical manifestations. Mean serum creatinine and serum interleukin-6 (IL-6) on diagnosis were elevated (1.47 ± 0.25 mg/dl and 26.7 ± 3.83 pg/ml, respectively). All patients were diagnosed as MCD by clinicopathlogical findings including lymph node biopsy. Each case had characteristic clinical findings. Case 1 (47-years-old woman) showed nephrotic syndrome with high levels of serum amyloid A. Case 2 (40-years-old man) showed rapidly progressive glomerulonephritis with myeloperoxidase anti-neutrophil cytoplasmic antibody (MPO-ANCA). Kidney biopsy specimens revealed AA amyloidosis

and pauci-immune crescentic glomerulonephritis. Case 3 and 4 (47-years-old woman and medroxyprogesterone 40-years-old man) showed acute kidney injury with thrombocytopenia and massive ascites. Therefore, kidney biopsy was not performed. IL-6 and other cytokines including neopterin, soluble tumor necrosis factor receptor 1 and 2 were also elevated in these two patients. Although, only steroid was administered in case 2, other three cases were treated with steroid and tocilizumab (anti IL-6 receptor antibody). Kidney function of each patient recovered well after these therapies. Especially, complete remission of nephrotic syndrome was achieved in case 1. Although, no case progressed end-stage kidney disease, only one case died of cerebral hemorrhage (case 3).

The tissue expression profile of TSGA10 mRNA throughout various organs was studied by quantitative PCR performed on cDNA from human tissue. Primers were designed with Beacon Designer® version 5.11 software (Premier Biosoft, Palo Alto, CA, USA) with one primer flanking an intron–exon junction to avoid amplification of genomic DNA. Quantitative PCR was carried out on human normalized multiple-tissue cDNA panels (BD Bio Sciences, Palo Alto, CA, USA) as well as pituitary, aorta (Stratagene

Cloning Systems) and adrenal cortex cDNA prepared from normal adrenal tissue removed during adrenal adenoma surgery. Reactions were performed on a MyiQ iCycler (Bio-Rad, Hercules, CA, USA) in a volume of 25 μl, with 200 nm of each primer using iQ™ SYBR®Green DMXAA supermix (Bio-Rad) as per the manufacturer’s instructions. All samples were run in triplicate. Thermal cycles consisted of an initial denaturation step of 95 °C for 3 min, followed by 40 cycles of 95 °C for 15 s, 60 °C for 30 s and 72 °C for 30 s. Standard curves were then established from the serial dilution of TSGA10 and control glyceraldehyde-3-phosphate

dehydrogenase (GAPDH) PCR templates. TSGA10 mRNA levels were deduced from the standard curve and normalized to the endogenous GAPDH tissue content. A total of 27 cDNA clones were isolated and identified from immunoscreening of a human pituitary cDNA expression library with the sera from two APS1 patients, one with clinical GH deficiency and one with no reported pituitary manifestations. These clones represented 11 different proteins of selleckchem which one was TPH isoform 1, a well-known APS1 autoantigen [19]. Recombinant proteins check details from the remaining 10 cDNA clones were produced by ITT and immunoprecipitation was performed against a test panel of sera from six APS1 patients and five healthy blood donors to determine the possible antigenicity. Most of these recombinant products were recognized solely by the screening serum, by both APS1 sera and control sera or by none of the sera. A single clone TDRD6, isolated from the patient with pituitary manifestation was further analysed

and found in 49% of APS1 patients as reported previously [15]. An additional cDNA clone isolated from the patient without any pituitary deficits encoded testis specific, 10 (TSGA10), a gene located on chromosome 2q11.2. ITT of two of the TSGA10 clones resulted in good quantities of recombinant proteins that were used for immunoprecipitation with the test panel of sera. Both TSGA10 recombinant proteins were efficiently immunoprecipitated by the screening serum but not by any of the healthy controls; one of the corresponding TSGA10 clones was therefore selected for further studies. The TSGA10 gene consists of 19 exons spanning over 80 kb of genomic DNA. Two transcript variants have been reported, differing in the 5′ UTR. Both variants are transcribed from exon 6 to exon 21 and encode a 698 amino acid protein.

Triferic is well-tolerated with a safety profile similar to that of placebo patients. ISHIZAKA MASANORI1, GOHDA TOMOHITO1, GOTOH HIROMICHI1, YAMAGUCHI SAORI1, MARUYAMA SYUNTARO1, SONODA YUJI1, OMOTE KEISUKE1, TOMINO YASUHIKO1 1Division of Nephrology, Juntendo University Faculty of Medicine Introduction: Unlike brachial-ankle pulse wave velocity (baPWV), cardio-ankle vascular index (CAVI) is independent of blood pressure, and has adequate reproducibility for evaluating

arteriosclerosis. However, it is also considered to Buparlisib clinical trial be inaccurate if the ankle-brachial index (ABI) value is less than 0.95, as is the case for baPWV. The objectives of this study are 1) to compare the CAVI, ABI and carotid artery intima-media thickness (CA-IMT) between HD patients with and without type 2 diabetes (T2D) or prevalence of cardiovascular (CV) disease, and 2) also to evaluate the relationship of these indices with CA-IMT as a surrogate maker of carotid

arteriosclerosis in HD patients according to ABI levels since considerable number of HD patients have low ABI. Methods: This study consisted of 132 HD patients with T2D and the same number of patients without T2D. CA-IMT was measured by Branched chain aminotransferase high-resolution real-time B mode ultrasonography.

CAVI was measured before start of dialysis therapy Sirolimus in vivo using the VaSera VS-1000 vascular screening system with the patients resting in a supine position. Blood pressure was measured and then the ABI was calculated. Results: Diabetic patients had significantly higher CA-IMT and CAVI values and a lower ABI compared with those without diabetes. The patients with diabetes or prevalence of CV disease had significantly higher CA-IMT and lower ABI values than those without diabetes or prevalence of CV disease, respectively. Although diabetic patients had higher CAVI than those without diabetes, CAVI did not differ between patients with or without prevalence of CV disease. In univariate analysis, CA-IMT was more strongly correlated with ABI than CAVI. However, the opposite was true in patients with an ABI value of more than 0.95. In multivariate regression analysis, both indices were significantly correlated with CA-IMT although ABI was a powerful determinant than CAVI. Conclusion: It appears that both indices are associated with CA-IMT in HD patients, especially with an ABI value of more than 0.95.

Tumour necrosis factor-related apoptosis-inducing ligand has an intricate receptor system comprising

four distinct membrane receptors, designated TRAIL-R1, TRAIL-R2, TRAIL-R3 and TRAIL-R4. Of these receptors, only TRAIL-R1 and TRAIL-2 transmit the apoptotic signal. These two receptors belong to a subgroup of the TNF receptor family, the so-called death receptors, and contain the hallmark intracellular death domain (DD). This DD is critical for apoptotic signalling by death receptors. Tumour necrosis factor-related apoptosis-inducing ligand activates the extrinsic pathway of apoptosis by binding to TRAIL-R1 and/or NVP-BEZ235 manufacturer TRAIL-R2 (Figure 1), whereupon the adaptor protein Fas-associated

death domain and initiator caspase-8 are recruited to the DD of these receptors. Assembly of this so-called death-inducing signalling complex leads to the sequential activation of initiator and effector caspases, and ultimately results in apoptotic cell death. In certain cells, the execution of apoptosis by TRAIL further relies on an amplification loop via the intrinsic mitochondrial pathway of apoptosis. The mitochondrial pathway of apoptosis is a stress-activated pathway, e.g. upon radiation, and hinges on the depolarization of the mitochondria, leading to release of find more a variety of pro-apoptotic factors into the cytosol (Figure 2). Ultimately, this also triggers effector caspase activation and apoptotic cell death. This mitochondrial release of pro-apoptotic factors is tightly controlled by the Bcl-2 family of pro- and anti-apoptotic proteins [14]. In the case of TRAIL receptor signalling the Bcl-2 homology (BH3) only protein Bid is cleaved into a truncated form (tBid) by active caspase-8. Truncated Bid subsequently activates the mitochondrial pathway. TRAIL-R3 is a glycosylphosphatidylinositol-linked

receptor that lacks an intracellular domain, whereas TRAIL-R4 only Resminostat has a truncated and non-functional DD. The latter two receptors are thought to function as decoy receptors that modulate TRAIL sensitivity; however, the mechanism underlying this decoy function is not yet elucidated. Evidence suggests that TRAIL-R3 binds and sequesters TRAIL in lipid membrane microdomains. TRAIL-R4 appears to form heterotrimers with TRAIL-R2, whereby TRAIL-R2-mediated apoptotic signalling is disrupted. TRAIL-R4 might activate nuclear factor kappa B, although conflicting evidence concerning activation of nuclear factor kappa B exists [15,16]. Of note, TRAIL also interacts with the soluble protein osteoprotegerin, although the exact consequence of this interaction remains to be clarified.

The meta-analysis may identify clinical subgroups that benefit the most from IVIg treatment. The inclusion criteria for this study were as follows: ≥ 4 confirmed early miscarriages, at least three consecutive after a birth and ≥ 3 miscarriages with present

partner. Following a positive pregnancy test, serum human chorionic gonadotrophin (s-HCG) was measured twice in 2 days. Treatment with either IVIg or placebo was initiated if s-HCG increased by at least 30%. IVIg treatment doses were simplified to either a high or low dose according to pre-pregnancy weight. Similar doses https://www.selleckchem.com/products/KU-60019.html of 5% human albumin were used in the placebo group. Studies have shown that pregnant and non-pregnant RM patients may have elevated levels of NK cells [17, 18]. Furthermore, Decitabine order there have been a number of studies showing that NK cells, such as CD56+, decline in RM patients treated with IVIg [17-22]. Heilmann et al. conducted a study that showed a correlation between the decline in NK cells and pregnancy

outcomes. The results of this study found that the number of NK cells (CD3−, CD56+ and CD16+) declined in women who gave birth after IVIg treatment [23]. In the future, identifying immune biomarkers that characterize RM patients who may benefit from IVIg therapy is worth investigating. There is evidence from placebo-controlled trials to suggest that IVIg improves pregnancy outcomes in secondary RM. However, large heterogeneity in patient populations and dosing regimens has been observed in previously conducted trials in RM. Therefore, our study will hopefully provide decisive data on the efficacy

of IVIg treatment in secondary RM. O. B. Cytidine deaminase C. thanks Dr Henriette S. Nielsen, Dr Elisabeth C. Larsen and Dr Pia Egerup for help in the conduction of the trial of IVIg and performing the meta-analysis. Further thanks go to Mrs Louise Lunoee, Mrs Lisbeth Egestad and Mrs Karen Kirchheiner for assisting in performing the trial. The Danish Council for Independent Research funded the trial. O. B. C. would also like to thank Meridian HealthComms Ltd for providing medical writing services. O. B. C. has no conflicts of interest to disclose. “
“Center for Infectious Disease Dynamics and Biology Department, The Pennsylvania State University, University Park, PA, USA We studied diverse antigen binding in hosts and the outcome of parasitism. We used captive-bred F1 descendants of feral rock pigeons (Columba livia) challenged with blood-feeding flies (Hippoboscidae) and a protozoan parasite (Haemoproteus). Enzyme-linked immunosorbent assays (ELISAs) and immunoblots were used to test (i) whether pre-infection IgY antigen binding predicts parasite fitness and (ii) whether antigen binding changes after infection.

These changes increase the ability of DC to stimulate T cells and activate the immune Sorafenib response [2]. One problem concerning immune responses towards tumours is that cancer cells have the ability to evade the immune system surveillance and thereby avoid being eliminated by effector cells [3, 4]. Owing to their outstanding ability to initiate immune responses, DC have, for a long time, been in the focus of immunotherapy. The development of protocols for the ex vivo generation of DC [5–7] led to the design and clinical application of tumour vaccination therapies using DC. Such DC vaccines aim to activate tumour-specific effector T cells [8]. Several trials have been performed

the last decade [9–12]. However, the different steps of the protocol still need to be optimized. One element that needs improvement is the maturation of the DC. Cells used in trials today are often stimulated with the Jonuleit cytokine cocktail consisting of interleukin (IL)-1β, IL-6, tumour necrosis factor (TNF)-α and prostaglandin E2 (PGE2) [13]. Because these cells are lacking IL-12p70 production in addition to having low migratory capacity [14, 15], they are not optimal for inducing

strong cell-mediated immune responses. Studies indicate that PGE2 is necessary for CCR7 surface expression on DC and for their potential to migrate [16]. Nevertheless, it has also been shown that PGE2 can be the cause for low IL-12p70 secretion learn more [17, 18]. It is therefore an ongoing quest to find the optimal DC population for cancer immunotherapy. Bromelain is an extract from the stem of the pineapple plant (Ananas comosus). Immunological and enzymological data indicate that the crude extract contains different cysteine proteases and other compounds with distinct characteristics [19, 20]. Bromelain has been used in tropical

health regimens for centuries, and the last decades, it has been used clinically as an additive to cancer treatment [19]. It has been shown to reduce side effects of chemotherapy, reduce skin tumour formation as well as to reduce oedema and improve wound healing after radiotherapy and surgery [19, 21, 22]. In human glioblastoma cells treated with bromelain, reduced adhesion, Cyclic nucleotide phosphodiesterase migration and invasive capacity were noted [23]. In addition to modulating cancer cells, bromelain has been shown to trigger and regulate cytokine production from different immune cells and affect the function of adhesion molecules on endothelial and blood cells [19]. As bromelain has the potential to activate and stimulate several different cell types, we have examined how it affects DC maturation. The aim was to analyse the DC maturation effect of bromelain, with respect to phenotype, cytokine production and T cell stimulatory capacity. Moreover, we investigated the possibility to replace PGE2 in the cytokine cocktail with bromelain.

While a number of functions are mediated by Abs without additional mediators or cells, others require interactions between Abs and other components of the immune system, e.g. complement, phagocytic cells, or effector cells (e.g. NK cells). The best-documented direct effect of Abs is neutralization. Ab-mediated neutralization

of bacterial toxins was already reported in the 19th century (pioneered by Adolf Emil Behring and Kitasato Shibasaburo) and is essential for the Selleck LY2835219 vaccine-mediated resistance against diphtheria, tetanus, and pertussis toxins. Furthermore, neutralization by Abs plays an important role in immune responses against viruses, as the Abs are able to inhibit virus attachment to specific host cell receptors, to block uncoating of the virus and therefore interfere with productive infection, and to inhibit viral assembly and release 1. Very recently, an additional mechanism of Ab-mediated interference of viral replication was described, showing that Abs bound to the capsid of nonenveloped viruses can bind to the cytoplasmic Fc-binding protein TRIM21 and target these cytosolic viruses for proteasomal degradation 2. The ability of Abs to block receptors required for pathogen uptake and thereby to inhibit

infection is not limited to viruses, but has also been reported for intracellular bacteria and for the malaria-causing protozoan parasite Plasmodium falciparum3, 4. Furthermore, Abs specific for effector proteins secreted by bacteria, such as listeriolysin O, the pore-forming toxin of Listeria monocytogenes, can neutralize Poziotinib solubility dmso these effectors and thereby protect

the host from productive infection 5. Similarly, Abs directed against pathogen components involved in locomotion, e.g. the flagella of Pseudomonas aeruginosa, mediate their protective effect by interfering with pathogen motility 6. Abs also prevent pathogen Farnesyltransferase entry at mucosal sites and play an important role in promoting compartmentalization of bacteria in these tissues 7; however, Abs can not only block infection but, under certain circumstances, also enhance infection as has been documented for Dengue virus and HIV 8. In addition to mediating direct protective effects, Abs can fulfill protective functions via activation of the classical complement pathway, which results in pathogen opsonization, chemoattraction of leukocytes, and the formation of the membrane attack complex 9. Abs also mediate a number of effector functions through the interaction with Fc receptors (FcRs) on innate immune cells, thereby linking the specificity of the humoral immune response to the powerful effector functions of innate immunity. One such effector mechanism is ADCC, an important effector mechanism for the elimination of virus-infected cells, multicellular parasites, and tumor cells. ADCC directs nonspecific cytotoxic cells, such as NK cells, neutrophils, and eosinophils, in an FcR-dependent manner to specific target cells which are marked by Ab bound to surface Ag.

© 2013 Wiley Periodicals, Inc. Microsurgery 34:287–291, 2014. “
“The purpose of this study was to identify if a modified end-to-side repair can achieve equal results of nerve regeneration compared to an end-to-end repair using donor phrenic nerves in repair of the musculocutaneous nerve and

also pulmonary protection. Eighteen GSK458 cell line rats were divided into three groups of six each comparing two nerve graft techniques: helicoid end-to-side plus distal oblique repair vs. traditional end-to-end repair, using a donor phrenic nerve. The saphenous nerve was used as a graft between the phrenic nerve and the musculocutaneous nerve. The third group was used as control; the musculocutaneous nerve was transected without any repair. Three months postoperatively, electrophysiology, tetanic force, moist muscle weight, histology, nerve fiber counting, and chest X-ray were evaluated. All results have shown that this modified

end-to-side repair was superior to the end-to-end repair. The former did not compromise the diaphragm function, but the latter showed an elevation of the diaphragm. Little recovery was seen in the third group. The conclusion is that this modified end-to-side repair can replace the traditional end-to-end repair using donor phrenic nerves with better results of nerve regeneration without diaphragm compromise. © 2011 Wiley-Liss, Inc. Microsurgery, 2011. “
“Esophageal Akt inhibitor strictures may be

caused by many etiologies. Patients suffer from dysphagia and many are tube-feed dependent. Cervical esophageal reconstruction is challenging for the plastic surgeon, and although there are reports utilizing selleck products chest wall flaps or even free flaps, the use of a sternocleidomastoid (SCM) myocutaneous flap provides an ideal reconstruction in select patients who require noncircumferential “patch” cervical esophagoplasty. We present two cases of esophageal reconstruction in which we demonstrate our technique for harvesting and insetting the SCM flap, with particular emphasis on design of the skin paddle and elucidation of the vascular anatomy. We believe that the SCM flap is simple, reliable, convenient, and technically easy to perform. There is minimal donor site morbidity with no functional loss. The SCM myocutaneous flap is a viable option for reconstructing partial esophageal defects and obviates the need to perform staged procedures or more extensive operations such as free tissue transfer. © 2011 Wiley-Liss, Inc. Microsurgery, 2011. “
“Standard vein graft (SVG) and inside out vein graft (IOVG) techniques to promote peripheral nerve regeneration have been widely studied since last two decades. In this experimental study, we attempted to compare these two techniques and analyze the differences in the expression of the neurotrophins during peripheral nerve regeneration.

04 1.00–1.10 and 1.22 1.12–1.33) but less likely to undergo lipid or HDL cholesterol (0.81 0.48–0.53 and 0.85 0.79–0.90). Thus while disadvantaged people had poor access, once in the

health system the level of monitoring received was similar. They note, however, that the majority of medical practitioners are located in capital cities yet the majority of people in NSW at most social disadvantage Lapatinib in vitro live outside the Sydney metropolitan area. In addition the gap between Medicare reimbursement and the amount charged by medical practitioners is often greater in rural areas. People at most social disadvantage may be selectively disadvantaged in regard to access to health care services in the current system. The reluctance to test the most socially disadvantaged group for lipid abnormalities may reflect the cost of lipid lowering treatment (at the time of the survey). The relationship between social disadvantage and access to GPs is further demonstrated in the study by Turrell et al.48 who conducted an analysis of 1996–1997 Medicare data to evaluate associations between utilization of GPs, socioeconomic disadvantage, geographic remoteness and Indigenous status. The review was undertaken at the level of Statistical Local Areas (SLA) after assigning an buy Gefitinib Index of Relative Socio-economic Disadvantage (IRSD) and Accessibility/Remoteness Index of Australia (ARIA). The proportion

of Indigenous Australians was calculated from the number of self-identified persons of Aboriginal and Torres Strait Islanders background. In relation to socioeconomic disadvantage the following

points were noted: the number of full time equivalent GPs decreased with decreasing Urease socioeconomic status and increasing remoteness of SLAs, The authors concluded that in areas of adequate GP supply, ready geographic and financial access, equity of access appears to prevail. However, in socioeconomically disadvantaged areas where GPs are least accessible and affordable, the principle of equity of access to services is compromised. Furthermore, these latter areas are also those with highest medical needs. The best available evidence supports screening and intensive management of the three risk factors for CVD, namely diabetes, high blood pressure and protein in urine. KDOQI: Clinical Practice Guidelines and Clinical Practice Recommendations for Diabetes and Chronic Kidney Disease, AJKD, Suppl 2. 49(2):S46, February 2007. No recommendation. UK Renal Association: No recommendation. Canadian Society of Nephrology: No recommendation. European Best Practice Guidelines: No recommendation. NICE Guidelines: National Collaborating Centre for Chronic Conditions. Type 2 diabetes: national clinical guideline for management in primary and secondary care (update). London: Royal College of Physicians, 2008. No recommendation. No recommendation. No recommendation. None identified.