Two retrospective studies in the early 1980s demonstrated that sm

Two retrospective studies in the early 1980s demonstrated that small increases in urinary AER predicted the development of overt nephropathy in people with type 1 diabetes.53,54 This increase in AER was termed microalbuminuria and by consensus, referred to levels of AER of 20–200 µg/min in at lease two of three samples.

By comparison, in healthy subjects, AER ranges from 3 to 11 µg/min54 and routine dipstick tests do not become positive until AER exceeds 200 µg/min (equivalent to total proteinuria of 0.5 g/24h). this website Subsequent studies showed that microalbuminuria also predicts the development of clinical overt diabetic nephropathy in type 2 diabetes55,56 although it is not as strong a predictor as it is in type 1 diabetes. Persistent microalbuminuria confers an approximately 5-fold increase in the risk of overt nephropathy GSI-IX order over 10 years in Caucasian persons with type 2 diabetes (approximately 20% cumulative

incidence), compared with a 20 fold increase in risk of nephropathy in type 1 diabetes (approximately 80% cumulative incidence). However, in certain ethnic populations with a high prevalence of type 2 diabetes and diabetic nephropathy, including Pima Indians, Mexican Americans, African Americans, Maoris and Australian Aborigines, microalbuminuria is as strong a predictor of nephropathy as in type 1 diabetes.56–58 The prospective cohort type study of 599 normoalbuminuric people with type 2 diabetes,59 found the baseline AER as a significant predictor of a subsequent decline in renal function as well as the risk of mortality and CVD (median follow-up of 8 years). The usefulness of microalbuminuria as a predictor of overt nephropathy in people with type 2 diabetes

eltoprazine is shown in the accompanying Table A2 adapted from Parving et al.60 The selected studies are RCTs of varying size and duration that measured the progression of albuminuria as a primary outcome. Parving et al.60 concluded that the studies collectively show the value of microalbuminuria as a predictor of overt nephropathy based on the rate of development of overt nephropathy among the placebo groups. Other prospective studies where the rate of decline in GFR was found to be enhanced in people with microalbuminuria are: Murussi et al.61 (n = 65) – normoalbuminuric people with type 2 diabetes showed a similar rate of decline in GFR over a 10 year period (<2 mL/min per 1.73 m2 per year) as people without type 2 diabetes. In contrast in people with type 2 diabetes and microalbuminuria a GFR decline of 4.7 mL/min per 1.73 m2 per year was recorded. While microalbuminuria in people with type 2 diabetes is an important risk factor for CKD and CVD, it is important to recognize that kidney disease in type 2 diabetes is more heterogeneous than in type 1 diabetes and that a significant number of people will develop CKD (i.e. declining GFR) without development of persistent microalbuminuria as shown in the following studies.

It is unlikely that any single treatment option will significantl

It is unlikely that any single treatment option will significantly alter patient outcomes, but rather incremental

gains will be achieved with an integrated, multidisciplinary approach. BVM devices have had a moderate effect on the reduction of the incidence of IDH; however, its effects are limited to an at-risk population. The expansion and integration of these technologies to create an individual patient dialysis profile may prove more successful. The role of cool temperature dialysis shows greater promise in reducing IDH; however, there is still uncertainty about the necessary reduction in temperature to achieve optimal results. With the technologies available today, BTM technology is more mature and offers a relatively simple and effective means of combating IDH in susceptible patients. The widespread use of BVM and BTM monitoring in the general HD population, not prone to IDH, cannot be supported with the evidence MLN2238 currently available. Ultimately, these technologies will need to be trialled in combination, in a way that demonstrates a mortality and morbidity benefit, and to effectively allow the determination of an individualized HD profile that can account for the multitude of dialysis and patient factors that contribute to IDH. “
“The BLOCADE Feasibility Study aims to determine the feasibility of a large-scale randomised controlled trial with clinical endpoints comparing Fer-1 concentration the beta-blocking

agent carvedilol to placebo in patients receiving dialysis. The BLOCADE Feasibility Study is a randomised, double blind, placebo-controlled, parallel group feasibility study comparing the beta-blocking agent carvedilol to placebo. Patients receiving dialysis for ≥3 months and who are aged ≥50 years, or who are ≥18 years and have diabetes or cardiovascular disease, are eligible. The primary outcome is the proportion of participants who complete Meloxicam a 6-week Run-in phase in which all participants receive carvedilol titrated from 3.125mg twice daily to 6.25mg twice daily. Other measures include how many patients

are screened, the proportion recruited, the overall recruitment rate, the proportion of participants who remain on study drug for 12 months and the incidence of intra-dialytic hypotension while on randomised treatment. The BLOCADE Feasibility Study commenced recruiting in May 2011 and involves 11 sites in Australia and New Zealand. The BLOCADE Feasibility Study will inform the design of a larger clinical endpoint study to determine whether beta-blocking agents provide benefit to patients receiving dialysis, and define whether such a study is feasible. “
“1. Targets Patients with diabetes, hypertension Those with family history of chronic kidney disease (CKD) Individuals receiving potentially nephrotoxic drugs, herbs or substances or taking indigenous medicine Patients with past history of acute kidney injury Individuals older than 65 years 2.

In the presence of the TCR signal, CpG-ODN induces IL-2 productio

In the presence of the TCR signal, CpG-ODN induces IL-2 production, IL-2R expression and thus T cell proliferation. Furthermore, CpG-co-stimulated T cells differentiate into cytolytic T lymphocytes in vitro[54]. Naive human T cells express

high levels of cell-surface TLR-2 after activation by anti-TCR antibody and interferon (IFN)-α. Activated cells produce more cytokines in response to the TLR-2 ligand, bacterial lipopeptide [44]. Furthermore, memory human CD4+CD45RO+ T cells express TLR-2 constitutively and produce IFN-γ in response to bacterial lipopeptide [44]. Co-stimulation of antigen-activated murine CD8+ T cells with the lipopeptide Pam3CysSK4 (Pam), a TLR-1/2 ligand, enhances the proliferation, survival and effector functions Ensartinib of these cells [54]. TLR-2 engagement on CD8+ T cells reduces significantly their need for co-stimulatory signals delivered usually by mature APCs [39].

Importantly, human T cells were also reported to respond similarly to the endogenous ligand HSP60 through TLR-2, although these results could reflect potential contamination of commercially available HSP60 with bacterial TLR-2 ligands [55]. T cells responding to endogenous TLR ligands is intriguing, because it opens the possibility that DAMPs may potentially support T cell responses at sites of damaging tissue. It should be noted that TLR ligands do not induce functional responses in T cells in the absence of concurrent TCR stimulation [11], indicating that TLR-induced signals in T cells are strictly co-stimulatory, which may be important this website for preventing TLR signal-mediated non-specific T cell activation. On the other hand, LPS treatment results in increased adhesion of mouse and human T cells to fibronectin and inhibited chemotaxis [56]. Thus, in addition to functioning as potential co-stimulatory second molecules, TLRs may also play

a role in controlling T cell trafficking. Naturally occurring and antigen-induced CD4+CD25+ Treg cells have been studied extensively in mice and humans. Depletion of the naturally occurring subset of CD4+CD25+ Treg cells results in various types of autoimmune diseases [57,58]. TLR ligands modulate CD4+CD25+ Treg cell responses indirectly by promoting inflammatory cytokine production in APCs, which can inhibit the suppressive capacity of CD4+CD25+ Treg cells [59]. However, some TLRs are expressed on CD4+CD25+ Treg cells. It has been reported that naive CD4+CD25+ Treg cells express TLR-4, -5, -7 and -8 selectively, whereas TLR-1, -2, -3 and -6 appear to be expressed more broadly on CD4+ T cells, but not confined to CD4+CD25+ Treg cells [10]. The distinct expression pattern of TLRs on CD4+CD25+ Treg cells supports the potential involvement of these TLRs in the direct regulation of CD4+CD25+ Treg cells [9,60]. It has been shown that ligands for TLR-2, -5 and -8 modulate the proliferation and suppressive functions of CD4+CD25+ Treg cells.

How IL-21 promotes pathogenesis of T1D is not yet clear IL-21 is

How IL-21 promotes pathogenesis of T1D is not yet clear. IL-21 is produced mainly by natural killer

(NK) T cells and CD4+ T cells [12, 13]. All CD4+ T helper subsets can produce varying amounts of IL-21, depending on the context of stimulation and the cytokine milieu [14, 15]. Crizotinib IL-21 acts as an autocrine growth factor that shifts the balance away from Tregs towards the T helper type 17 (Th17) lineage, promoting inflammation and immune response [16, 17]. In psoriasis and multiple sclerosis Th17 cells, driven partly by IL-21, play a significant role in promoting tissue damage [18-20]. Early studies in NOD mice lacking IL-21Rα have also implicated IL-21 in T1D pathogenesis via Th17 cells [8, 15]. However, the role of Th17 cells in the pathogenesis of T1D remains controversial. In fact, Th17 cells produced in the

gut have been shown to exert a protective effect in T1D [21-25]. CD8+ T lymphocytes play a key role in the pathogenesis of autoimmune diseases by causing damage to target organs [26]. Two recent studies have implicated IL-21 in T1D pathogenesis via promoting expansion and survival of CD8+ T cells [9, 11]. Studies on the role of IL-21 in viral infections showed BMN 673 clinical trial that IL-21 signalling is indispensable for robust primary and secondary CD8+ T cell responses to chronic viral infections [27-31]. These studies suggested that IL-21 may also be needed for the efficient activation of autoreactive CD8+ T cells. This possibility is supported by our recent finding that IL-21, in synergy with IL-15, enables naive autoreactive CD8+ T cells to respond

to weak TCR agonists and induce disease in an engineered model of T1D [32]. In the present study, we have examined click here the role of IL-21 in activating autoreactive CD8+ T cells in the NOD mouse expressing the transgenic 8.3 T cell receptor (TCR) [33]. Our findings indicate that IL-21 is required for the initial activation of autoreactive CD8+ T cells, but is dispensable for sustaining their effector functions and their ability to induce disease. NOD mice (NOD/ShiLtJ) and 8.3 TCR transgenic NOD mice [NOD.Cg-Tg(TcraTcrbNY8.3)1Pesa/DvsJ; for brevity, 8.3-NOD] were purchased from the Jackson Laboratory (Bar Harbor, ME, USA). Il21−/− mice generated in a 129/SvEvBrd × C57Bl/6/J background (Lexicon Genetics Inc., The Woodlands, TX, USA) were obtained from MMRRC (Mutant Mouse Regional Resource Centre, Jackson Laboratory), back-crossed to NOD mice for 10 generations and back-crossed further to 8.3-NOD mice for two generations. At the fifth back-cross, mice were genotyped for known Idd loci and were selected for further breeding. The progeny of the 11th back-cross were intercrossed to generate NOD.Il21−/−, NOD.Il21+/− and NOD.Il21+/+ littermates. Mice were housed in micro-isolated sterile cages under specific pathogen-free (SPF) conditions. All experimental protocols were approved by the institutional ethical committee. Antibodies against mouse CD3ε, CD4, CD8α, TCRVβ8.

Herein, we compare the overall outcomes between hemodialysis (HD)

Herein, we compare the overall outcomes between hemodialysis (HD) and peritoneal dialysis (PD) to address this issue. Methods: Data on 7925 patients aged ≥70 years were obtained from the Korean Health Insurance database, all of whom started HD (n = 6715) or PD (n = 1210) between 2005 and 2008. To compare the risks of cardiovascular morbidity and all-cause mortality between HD and PD, Cox proportional hazard ratio (HR) analysis was used after adjusting multiple variables. Results: The risks of cardiovascular events such as

acute myocardial infarction, percutaneous coronary intervention, or hemorrhagic stroke were similar between both dialysis modalities. Composite risks considering cardiac and cerebral events together were also similar between Selleckchem CP 673451 dialysis modalities. However, the risk of ischemic stroke was lower in the PD group: HR, 0.67 (0.43–0.99). For all-cause mortality, patients undergoing PD were at greater risk: HR, 1.30 (1.21–1.39) [Figure]. When limiting analyses into the patients without diabetes or cardiovascular comorbidities (n = 2330), patients undergoing PD had a slightly

greater risk of mortality than HD patients: HR, 1.16 (0.99–1.33). Conclusion: Overall cardiovascular risks are similar between dialysis modalities in the elderly patients with end-stage renal disease. However, the mortality risk is greater in the elderly patients undergoing PD. MORINAGA HIROSHI1, SUGIYAMA HITOSHI1, ITO YASUHIKO2, TSURUYA KAZUHIKO3, YOSHIDA HISAKO3, MARUYAMA HIROKI4, GOTO SHIN4, NISHINO TOMOYA5, TERAWAKI HIROYUKI6, buy Dinaciclib NAKAYAMA MASAAKI6, NAKAMOTO HIDETOMO7, MATSUO SEIICHI2, MAKINO HIROFUMI1 1Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences; 2Nagoya University Graduate School of Medicine; 3Graduate School of Medical Sciences, Kyushu University; 4Niigata University Graduate School of Medical and Dental Sciences; 5Nagasaki University School of Medicine; 6Fukushima Medical University; 7Saitama

Medical School Introduction: Beta-2 microglobulin Miconazole (B2M) is an 11,800-molecular-weight polypeptide that is generated at a constant rate and eliminated by the kidneys. An elevated serum level of B2M is a potential risk factor predicting mortality in predialysis patients. However, it remains unknown whether B2M has an impact on the outcomes of patients on peritoneal dialysis (PD). Methods: A prospective multicenter observational study of Japanese PD patients, called the PDR-CS, began enrolling patients in December 2009. The data including demography, comorbidities, laboratory data at the baseline, cardiovascular complications, onset of EPS, and prognosis are collected using a web-based case report form. Five university hospitals participated in the PDR-CS and 227 PD patients were enrolled in the study, as of December 2012 (mean age, 59.1 years; male, 67.4%; diabetic nephropathy, 26.0%). Results: The serum B2M level increased with PD duration.

It has not been proved formally that changes in T cell function o

It has not been proved formally that changes in T cell function observed with advancing age are completely disconnected from the consequences of modification in the peripheral T cell pool, as events such as proliferation induced by the homeostatic milieu of the ageing organism may contribute to the reduced functional capacity of T cells [11]. A potential driver of age-related learn more changes in the peripheral T cell pool is atrophy of the thymus. A reduction in thymic activity is a feature of ageing in mammals. In humans, fat accumulates in the thymus throughout

life [12] reducing the active areas of thymopoiesis, and this contributes to a decline in the output of T cells. Measurement of this decline in previous studies has produced different views on the kinetics of this process. Some studies indicate an exponential decline [13] with T cell output beginning early in life and estimated to terminate at approximately

75 years of age [14]. Others suggest that the thymus atrophies in a biphasic manner [15] with the initial phase beginning early in life, at least as early as the first year and proceeding at a rate of 3% per year until middle age. Thereafter the rate changes to a constant rate of 1% per year, leading to the estimated total loss of thymic tissue by 105 years of age [16,17]. Recent work shows that the reversal of thymic atrophy is a viable option, but the timing of when selleck Leukocyte receptor tyrosine kinase such a procedure should begin would be critically dependent upon determining the period when thymic output ceases. In order to provide more information about the decrease in thymic output later in life we analysed samples collected from 215 healthy elderly individuals, with ages ranging from 60 to 100 years, and to reduce any bias related to environmental factors and/or lifestyle we obtained samples from participating centres across five European countries

(France, Germany, Greece, Italy and Poland)) [18]. We quantified changes in thymic output using signal-joint T cell receptor excision circles (sjTRECs) per T cells measured by real-time polymerase chain reaction (PCR), as described previously [19]. Peripheral blood (PB) samples were collected from healthy elderly individuals from participating centres across five European countries (France, Germany, Greece, Italy and Poland) [18]. Informed consent was obtained from healthy adult volunteers, with ages ranging from 58–104 years. Peripheral blood mononuclear cells (PBMC) were isolated and the samples were stored at −140°C until required for analysis. Frozen PBMC were thawed and an aliquot containing 1 × 105 cells stained with phycoerythrin (PE)-conjugated anti-CD3 (BD Bioscience, Oxford, UK) according to the manufacturer’s instructions.

008 and P = 0 011, respectively) and the control group (P = 0 001

008 and P = 0.011, respectively) and the control group (P = 0.001). No difference, however, was observed in IFN-γ production among all four groups (data not shown). MS-275 in vivo Cutaneous lymphocyte antigen is highly expressed on skin-infiltrating T cells in inflammatory skin diseases, including allergic contact dermatitis and atopic dermatitis [27]. The expressions of peripheral blood CD3+ CLA+ T cells were significantly increased in children with AD compared with those

in control subjects [28]. We found that the infiltration of Df-induced CLA+ and CD3+ T cells (coloured green with cell surface) in NC/Nga mice was inhibited by combination therapy of glucosamine plus tacrolimus (FK-506) (Fig. 5A,B). In addition, there was no significant difference between the combination group and normal (no dermatitis) group. Atopic dermatitis has AZD2014 been treated by the regular use of corticosteroids, which is not a perfect treatment because sufficient results cannot be provided in a number of cases as a result

of adverse events such as steroid-induced skin atrophy. Therefore, identified combinations of immunosuppressive agents are expected to be among the important future strategies for improved treatment of AD. It has been reported that the use of combinations of immunosuppressive agents may be more effective than single-modality treatment with either agent. In this study, we found that combination therapy with immunosuppressive agent glucosamine plus tacrolimus (FK-506) has a synergistic effect on Df-induced atopic dermatitis-like skin lesions in NC/Nga mice. For instance, combination treatment with glucosamine plus tacrolimus (FK-506) improved the severity of the dermatitis with reduction

in inflammatory cellular infiltrate, such as mast cells and eosinophils. For each parameter, we have repeated the experiment once using the same number of animals per group and found a similar type of profile, indicating that the results are reproducible (data not shown). These results indicated that combination therapy suppressed the development of Df-induced dermatitis, probably by controlling various inflammatory cells including mast cells and eosinophils. Because Th2 cytokines induce proliferation and activation Decitabine of mast cells as well as eosinophils in the skin, massive infiltration of mast cells and eosinophils would be expected in Df-induced NC/Nga mice, as previously reported [24]. Th2 cytokines are considered to play a major role in the pathogenesis of AD [5]. In fact, Th2 immune responses mediated by IL-4, IL-5 and IL-13 are critical in the pathogenesis of AD [9], because the upregulation of IgE production, one of the major causes of atopic inflammation, has been extensively studied with Th2 cytokines, IL-5 and IL-13. Moreover, Th2 cell numbers are increased in lesional tissue of patients who suffer from patients with AD frequently show elevated IgE levels in response to many kinds of allergens, including mite antigen [29].

This work was supported by NIH/NIAID R01 award


This work was supported by NIH/NIAID R01 award

AI50113-10 to J. H., NIH/NIAID R21 award AI085331-02 to J. H. and S. C. L., and Astellas IIT funding (MYCA-12J06) to J. H. and S. C. L. The authors have no conflict of interest to report. “
“The European Committee on Antimicrobial Susceptibility Testing Subcommittee on Antifungal Susceptibility Testing has determined breakpoints for micafungin and revised breakpoints for anidulafungin and fluconazole for Candida spp. This Technical Note is based on the corresponding rationale documents ( The micafungin breakpoints are based on PK data, animal PK/PD data, microbiological data and clinical experience. The anidulafungin breakpoints for C. parapsilosis and fluconazole breakpoints for C. glabrata have been modified to GW-572016 nmr species-specific values that categorise the wild-type

as intermediate to accommodate use of these compounds in some clinical situations. “
“Clinic of Infectious Diseases, Department of Internal Medicine, Geriatrics and Nephrologic Diseases, S’Orsola Malpighi Hospital, University of Bologna, Bologna, Italy Pulmonary mucormycosis (PM) is a life-threatening opportunistic mycosis with a variable clinical evolution and few prognostic markers for outcome assessment. Several clinical risk factors for poor outcome present at the check details diagnosis of PM were analyzed in 75 consecutive hematology patients from 2000–2012. Significant variables (P < 0.1) were entered into a multivariate Cox-proportional hazard regression model adjusting for baseline APACHE II to identify independent risk factors for Megestrol Acetate mortality within 28 days. Twenty-eight of 75 patients died within 4-week follow up. A lymphocyte count < 100/mm3 at the time of diagnosis (adjusted hazard ratio 4.0, 1.7–9.4, P = 0.01) and high level of lactate dehydrogenase (AHR 3.7, 1.3–10.2, P = 0.015) were independent predictors

along with APACHE II score for 28-day mortality. A weighted risk score based on these 3 baseline variables accurately identified non-surviving patients at 28 days (area under the receiver-operator curve of 0.87, 0.77–0.93, P < 0.001). A risk score > 22 was associated with 8-fold high rates of mortality (P < 0.0001) within 28 days of diagnosis and median survival of 7 days versus 28 days in patients with risk scores 22. We found that APACHE II score, severe lymphocytopenia and high LDH levels at the time of PM diagnosis were independent markers for rapid disease progression and death. Pulmonary infections caused by Mucorales have increased in incidence over the last two decades due to an expanding population of severely immunocompromised patients and improved treatment of more common invasive mould infections such as aspergillosis.[1-3] Mucormycosis is a unifying term used to describe infections caused by fungi belonging to the order Mucorales.

[44] Although, Blantz et al observed an increase in reactivity o

[44] Although, Blantz et al. observed an increase in reactivity of TGF at both 2 and 12 hours after nephrectomy, they LY294002 manufacturer did not observe a decrease in sensitivity of TGF at either time-point.[44] Together, these data suggest that there are temporal adaptations in TGF following a reduction in renal mass and alterations in TGF per se may be both an adaptation and a cause for the increase in SNGFR following nephron loss. The age at which nephron mass is reduced appears to affect the characteristics of the subsequent compensatory renal growth and hyperfiltration. GFR appears to increase to a maximal level of ∼70–80% of the value observed before nephrectomy, regardless of the age at which

renal mass is reduced. However, the rate of increase is faster in the young compared with the adult.[47,

48] The degree and duration of compensatory renal growth appears to be greater in the young compared with the adult. Nyengaard et al. showed a greater increase in number of glomerular capillaries and volume of glomeruli when uninephrectomy was performed in the rat neonate compared with the adult rat.[49] Additionally, following uninephrectomy in the rat at 10 days of age, weight of the remaining kidney increased until week 12 following uninephrectomy whereas in the adult rat, maximal growth was achieved by day 7.[50] The mechanisms underlying the greater degree of hypertrophy and the Selleckchem Cobimetinib more rapid increase in GFR in the young are unclear but perhaps very a reduction in renal mass in the young ‘forces’ the kidney

to assume a more adult phenotype. Of importance, in human preterm neonates, in whom nephrogenesis has not reached completion owing to their premature birth, accelerated maturation of the kidney has also been observed as indicated by an increase in number of glomerular generations and a decrease in width of the nephrogenic zone.[51] Furthermore, Chevalier et al. demonstrated a greater increase in effective filtration pressure (the drive for glomerular ultrafiltration) between postnatal days 10 and 21 in neonatal guinea pigs that underwent uninephrectomy compared with guinea pigs with intact kidneys,[52] indicating accelerated functional maturation of the kidney with reduced renal mass. This shift towards a more adult phenotype may be compensatory to minimize disturbances in fluid and electrolyte homeostasis. Individuals born with a solitary functioning kidney are presumed to have a congenital nephron deficiency but the time course over which functional and structural adaptations occur is less well understood. In human fetuses, between gestational ages of 20–36 weeks, 11% increase in the volume of the solitary kidney has been observed in almost 90% of fetuses.[53] This increase in size of the solitary kidney is likely due to both hyperplasia and hypertrophy.

There are numerous interested and experienced parties that could

There are numerous interested and experienced parties that could be assembled into a network of clinical centres to conduct small, short-duration, early-stage, proof-of-concept studies focused predominantly upon mechanistic outcomes, in order to permit a more rapid assessment of the clinical viability of find more a novel combination. Combinations that show

clear evidence of modulation of the immune system would be prioritized for more comprehensive clinical evaluation with C-peptide preservation as the preferred outcome. JDRF, through its Autoimmunity Centers Consortium [28], is currently assessing the feasibility of establishing such a network. Clearly, combinations that will be supported by industry and can navigate the regulatory process successfully will be those for which there is a compelling argument in terms of both efficacy and safety. In addressing the safety of the combinations, several key strategies can be applied to minimize the risk of harmful interactions between agents. Limit to two agents.  First, combinations should be limited to two agents. Both

agents may be immunotherapeutics, or one immunotherapeutic and one drug with an alternate mechanism – one that stimulates β cell regeneration, for instance. For reasons stated above, approved agents (or those nearing approval) would have initial priority for development in combination therapies. Independent/complementary mechanisms.  In the case of two immunotherapeutics, combinations should be selected such CP-690550 in vivo that individual agents work via mechanisms that are significantly different, so that safety 4-Aminobutyrate aminotransferase profiles could be considered as, essentially, independent. For instance, combining an antigen-specific therapy and a non-specific therapy would have a reduced theoretical likelihood of resulting in hitherto unrecognized side effects. Antigen-specific therapies in general are regarded as a safer treatment modality, with fewer systemic risks associated

with them, and so should be priority considerations for initial combination trials. Safety in protocol design.  Designing safety into clinical protocols is critical and there are a number of steps that can be taken to reduce the risks of harmful drug interactions. For instance, design of a protocol that uses sequential, rather than simultaneous, treatment would be preferred. Similarly, the dose of one or both of the drugs may be reduced in the combination protocol to increase the safety profile. In designing the protocol, implementation of these strategies can be guided by available pharmacodynamic data on each of the agents. With these considerations in mind, the Assessment Group listed and prioritized combination therapies (Table 1) with the understanding that developments in preclinical (combination safety and efficacy) testing and/or ongoing clinical trials could subsequently affect the relative ranking.