Unavoidably, at times, this approach may ignore

some aspects of mental disorders. A discourse with clinicians allows neuroscientists to realign their models to ensure that they represent processes thought to cause or maintain these disorders. Benefits to clinicians involve being informed of new research findings that have the potential to be applied in new pharmacological and nonpharmacological treatments. We provide two examples of how findings on memory, ie, this research reconsolidation and forgetting, may provide the impetus for new treatment interventions for Inhibitors,research,lifescience,medical several mental disorders. More generally, we believe that an elucidation of the selleck chem Cabozantinib memory processes not only provides clinicians with a list of potential clinical phenomena that could be the target of interventions, but it can also permit an understanding of why some kinds of treatments are more efficacious than others. In addition, our understanding of the memory processes can provide significant contribution to the refinement of extant Inhibitors,research,lifescience,medical psychotherapies, including cognitive behavioral therapy (CBT). The aim of this review is to advocate how an understanding of the brain mechanisms involved in memory provides a basis for: (i) re-conceptualizing some of the mental disorders; (ii) refining existing therapeutic Inhibitors,research,lifescience,medical tools; and (iii) designing new ones for targeting processes that maintain

these disorders. We start by defining some of the stages which a memory undergoes and discuss why an understanding of memory Inhibitors,research,lifescience,medical processing by the brain has clinical relevance. We then briefly review some of the clinical studies that have targeted memory processes. We end by discussing some new insights from the field of neuroscience that have implications for conceptualizing mental disorders. Defining memory phases Forgetting

As Ebbinghaus1 demonstrated in his classic work, new memories can do one of two things; persist Inhibitors,research,lifescience,medical or be forgotten (Figure 1). It is generally assumed that forgetting is more a vice (ie, dysfunction) than a virtue (ie, constitutive process). However, the idea that forgetting might be beneficial for memory has been frequently expressed.2-6 GSK-3 In the literary world, Jorge Luis Borges illustrated the essential role of forgetting for the human experience in his short story about Funes.7 As Funes could not forget anything, he could not live a normal life because a sea of unimportant details swamped every moment of awareness. We agree that, without constitutive forgetting, efficient memory would not be possible in the first place. Forgetting of established long-term memory (LTM) may indicate that memory is either physically unavailable (ie, lost), or that it is (temporarily) inaccessible. With some exceptions, theories proposed within the domains of experimental and cognitive psychology often emphasize one type of forgetting over the other.

111 In ascertaining why patients discontinued their lithium treatment, Pope and Scott found that the most commonly endorsed items were “bothered by the idea of a chronic illness,” “bothered by the idea that moods were controlled by medication,” and “felt depressed.” In contrast, clinicians believed that patients stopped taking lithium either because of “feeling down” or because of “feeling Inhibitors,research,lifescience,medical better,” assuming that if they felt

well they no longer needed medication.116 Rather than greater knowledge about lithium, what is needed is to modify patients’ attitudes to improve adherence.117 Being female, older, living with a partner, having a higher educational level, and perceiving the benefits and obstacles of lithium treatment were all factors in better compliance.118,119 Studies show that www.selleckchem.com/products/z-vad-fmk.html bipolar patients with substance use disorder have better compliance when taking valproate than lithium, and that poor adherence to lithium is the result Inhibitors,research,lifescience,medical of side effects.120 One of the main side effects of mood stabilizers is weight gain, which can be a major obstacle to maintaining prophylactic treatment. Topiramate is an alternative to lithium and valproate that causes a drop

in weight and body mass index.121 Weight monitoring and education on this issue must not be overlooked in order to promote better adherence. Conclusion Today’s maintenance treatments of various mental illnesses Inhibitors,research,lifescience,medical are very challenging to the clinician because his or her responsibility in a patient’s adherence to treatment goes beyond simply a correct diagnosis and choice of medication. A good doctor-patient relationship with an emphasis on communication is the best way to ensure compliance Inhibitors,research,lifescience,medical with therapy. Given the high noncompliance rates, this is an issue that must be dealt with in each clinical appointment. Family participation, patient psychoeducation, and reinforcement programs with telephone Inhibitors,research,lifescience,medical calls and information mailings all help improve adherence. The concept of therapeutic dosage should

be selleck chemicals paramount from the onset, ie, the smallest effective dosage, taken the fewest times per day, with the fewest side effects, and for the length of time needed to obtain remission Dacomitinib of symptoms and the best quality of life. Despite physicians’ best efforts, patient’s decision is the main reason for abandoning treatment.122 Attitudes and behaviors toward the illness and treatment are better adherence predictors than are drugs’ side effects. Clinical guidelines are a major help in improving treatments, but clinicians do not always follow these guidelines.123,124
Nonresponse is a frequent phenomenon in both somatic and psychiatric pharmacotherapy. A considerable number of drugs have become available for the treatment, of various psychiatric diseases since the discovery of chlorpromazine 50 years ago.1 Despite all the progress in this field, there are still many patients who do not, respond to treatment, so-called nonresponders.

SIGN-R1 also binds to zymosan, to the capsular polysaccharide of S. pneumoniae, and with low affinity to dextran and is Abiraterone manufacturer highly expressed by macrophages [101, 103–105]. Bovine serum antigen (BSA) consisting, 51 mannoside residues (Man(51)-BSA) binds to SIGN-R1 on lamina propria DCs in the gastrointestinal tract and induces IL-10 cytokine secretion by DCs, but not IL-6 and IL-12p70 [106]. In vitro and in vivo, Man(51)-BSA stimulates CD4+ type 1 regulatory T-like cells (Tr-1) but not CD4+CD25+Foxp3+ Inhibitors,research,lifescience,medical regulatory T cells, suggesting that SIGN-R1 induces tolerance to antigens [106]. LSECtin. LSECtin (liver and lymph node sinusoidal endothelial cell C-type lectin, Clec4G) is

a type-II transmembrane C-type Inhibitors,research,lifescience,medical lectin protein, similar to the related proteins DC-SIGN and L-SIGN and is expressed in liver, lymph node cells, and sinusoidal endothelial cells but

not monocyte derived DCs (Table 1). LSECtin binds to N-acetyl-glucosamine and fucose but does not bind to galactose and may function in vivo as a lectin receptor [107]. LSECtin is coexpressed Inhibitors,research,lifescience,medical with DC-SIGNR and CD23 and binds to ebola virus, filovirus glycoproteins, lymphocytic choriomeningitis virus, and, to the S-protein of SARS coronavirus but does not interact with HIV-1 and hepatitis C [108]; although a study suggested that LSECtin binds to hepatitis C virus, the interaction was in association DC-SIGNR with [109]. Ligands binding to LSECtin are not inhibited Inhibitors,research,lifescience,medical by mannan but by EDTA suggesting that the LSECtin does not bind to mannose [108]. Recently, LSECtin was shown to bind with CD44 [110]. Another study, regarding the expression of LSECtin demonstrated LSECtin, to be expressed on human peripheral

blood, thymic DCs, monocyte-derived macrophages and DCs [111], and to human Kupffer cells [112]. Antibody or ligand-mediated engagement of LSECtin activates rapid internalization Inhibitors,research,lifescience,medical of LSECtin [111] indicating that LSECtin may be a suitable receptor for targeting antigens in the development of vaccination regimes. Further Anacetrapib work is required to determine the viability of LSECtin to be an appropriate target for immunotherapy studies. CIRE. CIRE (C-type lectin immune receptor, CD209) is a selleck chemicals Volasertib murine type 2 membrane protein which belongs to the C-type lectin receptors and is preferentially expressed by immature CD8− splenic DCs (CD8−CD4+ and CD8−CD4−), on some CD4+ DCs, and on plasmacytoid pre-DCs, with no expression on CD8+ DCs, macrophages, or monocytes (Table 1 and Figure 1) [113]. CIRE that has 57% identity with DC-SIGN is the murine homolog to human DC-SIGN and both bind mannose residues [114]. However, CIRE is downregulated after activation, and incubation with cytokines IL-4 and iL-13 does not enhance expression of CIRE, even though DC-SIGN is enhanced, suggesting differences in gene regulation between the two receptors [113].

Flight and other active coping behaviors are unconditional responses to proximate threat, whereas passive coping strategies such as selleck chem Ponatinib freezing are conditioned responses to distal stimuli predictive of danger. These strategies are modulated by the (cognitive) apprehension of the environment and probability of success, eg, whether or not there is a route of escape. Thus, when an animal faces a predator, Inhibitors,research,lifescience,medical freezing is preferentially activated when the source of known danger is still far away. When danger gets closer, and the stimulus passes through some critical “psychometric” distance, it becomes a true unconditional stimulus and a flight pattern is activated.34 Coping strategies provide a new, interesting theoretical

framework for models investigating the role of individual differences Inhibitors,research,lifescience,medical in vulnerability to anxiety disorders, and their genetic and epigenetic determinants. Fear sellckchem conditioning Learning the relationships between aversive events and environmental stimuli which predict these events is essential

for survival. The neurobiological bases of fear conditioning have been extensively investigated during the last decades.35 , 36 The major aspects of the relationship between conditioned fear and anxiety are the fact that a fearful response can be associated with specific cues (conditional Inhibitors,research,lifescience,medical stimuli, CS), and that this learned association can be “unlearned,” ie, not forgotten, but actively repressed.37 This fear conditioning (or learned fear) Inhibitors,research,lifescience,medical paradigm is highly relevant for some anxiety disorders, eg, phobias and post-traumatic stress disorder (PTSD) in particular, and is used in several animal models. The critical stage appears to be not the training (conditioning) phase, when the conditional

(CS) and unconditional (US) stimuli are presented in a meaningful temporal relationship, but the extinction phase, when the CS is presented alone (without the reinforcement stimulus), during the time Inhibitors,research,lifescience,medical necessary for extinction to occur; some individuals fail to repress the memory of fear and show all the behavioral and physiological signs normally triggered in the presence Cilengitide of an actual threat. Thus, fear conditioning provides another relevant theoretical framework for translational studies on anxiety disorders. Conflict Motivational conflict This can be a major source of anxiety. Indeed, making a wrong decision in the face of danger can be fatal, and having to decide on the right way of doing constitutes a form of “psychological threat.” More frequently, the consequences of a wrong choice are not life-threatening, but can change an inidividual’s life (losing one’s partner, territory, or social status), or be only unpleasant (being momentarily deprived of food). In any case, making a decision when the consequences are unpredictable is a source of stress. Frustration Frustration can also be a source of anxiety, could be considered as a particular form of conflict.

17 Figure 3 Estech COBRA Fusion™ System. SURGICAL

APPROACHES In the past decade, several surgical ablation approaches to treat atrial fibrillation as a stand-alone or concomitantly with other cardiac surgical procedures were developed.1–6,24–31 The use of the heart–lung machine is required to perform the Cox maze procedure in its current form and with the available ablation devices.1–3 It can be performed as a full selleck Sorafenib sternotomy or minimally invasive procedure.1-6,24–31 If other procedures such as valve repair/replacement or coronary bypass are to be performed concurrently with the Cox maze Inhibitors,research,lifescience,medical procedure, then the standard open chest Ruxolitinib JAK inhibitor approach is likely to be used; however, when atrial septal defect closure, Inhibitors,research,lifescience,medical mitral valve repair or replacement, and tricuspid valve surgery are required, a minimally invasive right mini-thoracotomy can be applied.1–6,24–31 The overall operative risk is low in morbidity and mortality and might be impacted by the individual’s specific health conditions.8–10 Cox Maze Procedure by Mini-Thoracotomy Despite the proven efficacy of surgical ablation, Inhibitors,research,lifescience,medical a fraction of patients and referring physicians are still unwilling to tolerate sternotomy for an arrhythmia-corrective procedure.18 This has led to the development and evaluation of minimally invasive surgical ablation

procedures. The term “minimally invasive” as Inhibitors,research,lifescience,medical it applies to cardiac surgery incorporates a combination of small, sternum-sparing incisions, alternative cannulation techniques, modified instruments, thoracoscopic visualization, and robotic assistance. Given that the Cox maze III has a proven track record for sinus restoration and improved quality of life, surgeons must be careful in performing a minimally invasive procedure with inferior results, particularly in those with non-paroxysmal

atrial fibrillation. Inhibitors,research,lifescience,medical The two current major strategies are a complete Cox maze III using minimally invasive approach and totally endoscopic left-sided surgical ablation approach. PROCEDURE Briefly, our approach is described here. We use double-lumen endotracheal intubation Anacetrapib for selective right-lung deflation. The patient is placed in the supine position with a single towel roll underneath the posterior right rib cage. The right shoulder is abducted and arm is flexed and secured to an arm bar. A 5–6 cm incision is placed beneath the right breast, and the right chest is entered through the fourth or fifth intercostal space. CO2 insufflation is used. The pericardium is opened approximately 2 cm anterior to the phrenic nerve. The pericardium is secured to the chest wall for retraction, and umbilical tapes are placed around the superior vena cava (SVC) and inferior vena cava (IVC). The right femoral artery and femoral vein are exposed through a 3 cm oblique groin incision, heparin is administered, and vessels are cannulated.

Ectopic glands may be intra-thyroidal or located in the thymus, carotid sheath, retroesophageal, anterior mediastinum, or pericardium. Some patients may have supernumerary glands. Superior and inferior glands are usually located third within 1 cm from the crossing point of the inferior thyroid artery and the recurrent

laryngeal nerve.24–26 Parathyroid autotransplantation should be performed if the gland’s viability is questionable or the gland has been dissected off the vascular pedicle, especially during a challenging dissection for intracapsular or intra-thyroidal glands. In general, superior glands Inhibitors,research,lifescience,medical are easier to preserve in situ during thyroid cancer surgery, whereas the inferior glands are more often caught up with the tumor or central lymph nodes, making these glands more difficult to find and Inhibitors,research,lifescience,medical preserve. Of note, frozen section analysis should be done to confirm the parathyroid tissue while ruling out cancer, lymph node, or residual thyroid tissue prior to autotransplantation. Transplantation can be performed into a strap muscle or the sternocleidomastoid muscle by creating a pocket(s) in the muscle and implanting the cold-saline-preserved gland after mincing it into multiple tiny fragments. The pocket can be closed with a permanent Inhibitors,research,lifescience,medical suture or a clip. Implanted gland tissues will induce neovascularization and typically regain function in several weeks.27,28

FOLLOW-UP Postoperative patients can be Inhibitors,research,lifescience,medical followed with annual history and physical exams, serum thyroglobulin (Tg), and US imaging. 131I imaging can be used in the follow-up of high-risk patients or in patients who demonstrate concern for recurrence or potential new disease. The use of radioactive iodine (RAI) ablation treatment in the postoperative management of thyroid cancer patients is somewhat controversial. It is used with the aim of eradicating all remnants of normal thyroid tissue as well as any disease, including potentially involved nodal Inhibitors,research,lifescience,medical beds. In addition, RAI treatment facilitates postoperative screening with serum Tg. The 2009 ATA Guidelines currently recommend the use of RAI postoperatively in patients

with T3, T4, or M1 disease.3 Recent literature suggests that the use of RAI in patients with high-risk variants of selleck kinase inhibitor papillary thyroid cancer (PTC) can prolong survival.29 AREAS OF CONTROVERSY IN SURGICAL MANAGEMENT Lobectomy versus Drug_discovery Total Thyroidectomy for Papillary Thyroid Microcarcinoma Papillary thyroid carcinoma is the most common subtype of thyroid cancer, generally associated with an excellent overall prognosis.30 A microcarcinoma of the thyroid is defined as a tumor of less than 1 cm, which falls under the classification of T1a by the current American Joint Committee on Cancer. Microcarcinomas account for roughly 40% of all papillary thyroid cancers.31 A recent SEER review found a disease-specific survival for PTC microcarcinoma to be 99.3%.

12,22–24 The first CPVT transgenic mouse model was produced by Priori’s group in 2005. These authors introduced the RyR2 inhibitor price R4496C mutation into the mouse genome by homologous recombination and successfully reproduced the human phenotype.24 This in-vivo model proved the concept that RyR2 mutations may cause polymorphic and bidirectional Inhibitors,research,lifescience,medical ventricular tachycardia in a knock-in mouse model and mimic the clinical phenotype of CPVT patients.24 Subsequently, Priori’s group demonstrated that myocytes isolated from the heart of the RyR2 R4496C knock-in mouse generated DADs and triggered activity upon exposure to β-adrenergic stimulation, while the control myocytes isolated from wild-type

mouse did not.25 Similar results were reported by Kannankeril et al. who generated a knock-in mouse model of RyR2 R176Q mutation and demonstrated the disease phenotype in vivo and in vitro.26 Priori’s group was also the first to generate in-vitro modeling of the

CASQ2 D307H mutation Inhibitors,research,lifescience,medical using infected rat myocytes with adenoviruses engineered to express the sellectchem mutated CASQ2. In this study the authors demonstrated that the mutated myocytes developed DADs upon adrenergic stimulation while the control myocytes did not, as shown in Figure 2. This model provided the first evidence that mutant CASQ2 can generate DADs.12 Inhibitors,research,lifescience,medical Using the same model of rat myocytes infected with adenoviruses, Terentyev et al. and di Barletta el al. generated in-vitro models of the CASQ2 R33Q and L167H mutations, respectively, and reported on the generation of DADs in the mutated myocytes.22,23 Nonetheless, these models suffer from several limitations because the Inhibitors,research,lifescience,medical myocytes express both the mutant and the endogenous wild-type CASQ2. Inhibitors,research,lifescience,medical In 2006, Knollmann et al. generated CASQ2-null (CASQ2−/−) mice which were viable and exhibited the human-like arrhythmias. Despite the absence of CASQ2, these animals maintained relatively normal Ca2+ release and contractile function. However, myocytes isolated from these mice had

exceptional increases in SR volume, increased gain of Ca2+-induced SR Ca2+ release, and increased diastolic SR Ca2+ leak.27 Other transgenic models with deficient RyR2 or CASQ2 genes were generated and have confirmed the correlation between the arrhythmogenic phenotype to the mutant genes, although the Drug_discovery observed phenotype did not always resemble the human disease.28 Figure 2 Disturbances in rhythmic [Ca2+]i transients and membrane potential induced by ISO in myocytes expressing CASQ2D307H. HUMAN MODELS OF CPVT The recent discovery of genomic reprogramming of human somatic cells into induced pluripotent stem cells (iPSC) offers an innovative and practical approach to study inherited diseases including heart pathologies. Induced pluripotent stem cells are the product of somatic cell reprogramming to an embryonic-like state.

Tumor-associated Wortmannin antigens include viral proteins (e.g. HPV), chromosomal translocation products (e.g. bcr/abl), overexpressed proteins likeHER2/neu, telomerase, MUC1 and others [Kozako et al. 2012]. In Table 3 some recent examples of experimental liposome-based cancer vaccines are listed. Table 3. Examples of liposomal therapeutic cancer vaccines. Archaeosomes Archaebacteria (Archaea) were discovered and classified by Woese and Fox as a new group of prokaryotes, besides the Eubacteria (Bacteria)

[Woese and Fox, 1977]. Archaea contain DNA-dependent RNA polymerases and proteinaceous cell walls that lack peptidoglycan. Their cell membranes are composed of L-glycerol ether lipids with isoprenoid chains instead of D-glycerol ester lipids with fatty acid chains [Spang et al. 2013]. Archaeal lipids are uniquely constituted of ether-linked isoprenoid phytanyl archaeol (diether) or caldarchaeol (tetraether) cores conferring high

membrane stability. Archaeosomes are liposomes prepared with archaeal glycerolipids. The head groups displayed on the glycerol lipid cores of archaeosomes interact with APCs and induce TH1, TH2 and CD8+ T-cell responses to the entrapped antigen. The immune responses are persistent and subject to strong memory responses [Krishnan and Sprott, 2008; Benvegnu et al. 2009]. The polar lipid from the archaeon, Methanobrevibacter smithii, has been well characterized for its adjuvant potential. It contains archaetidyl serine, promoting interaction with a PS receptor on APCs. These archaeosomes mediate MHC-I cross priming and promote costimulation by APCs without inflammatory cytokine production [Krishnan et al. 2000]. Patel and colleagues showed that archaesomes prepared from M. smithii lipids were suitable

adjuvants for multivalent mucosal vaccines. Archaeosomes containing the encapsulated antigens OVA, bovine serum albumin and hen egg lysozyme conferred strong and sustained specific antibody responses to all three antigens [Patel et al. 2004]. Intranasal immunization of mice with the archaeal lipid mucosal vaccine adjuvant and delivery (AMVAD) system, obtained by interaction of archaeosomes/antigens with multivalent cations, induced robust mucosal antigen-specific IgA responses. AMVAD formulations are stable, safe and show protective efficacy in murine models of infection/challenge [Patel and Chen, 2010]. Archaeosomes prepared from lipids of Entinostat the nonpathogenic bacteria Leptospira biflexa (leptosomes) and Mycobacterium smegmatis (smegmosomes) were used as adjuvants. Both vesicles caused strong APC activation, cytokine release and expression of costimulatory signals, which was significantly higher for smegmosomes compared with leptosomes. APC activation by both formulations induced immune responses in mice to entrapped OVA [Faisal et al. 2009, 2011].

Current arrays are in the hundreds of electrodes, and keeping total volume of the multielectrode below 1% of the brain volume is challenging. Alternatively, wireless data transmission or implanted recording are options. Wireless data transmission at optical and infrared (IR)

frequencies are needed to obtain adequate single-channel data rates. Radio-frequency (RF) transmission of whole-brain data would draw Inhibitors,research,lifescience,medical excessive power due to bandwidth constraints. Multiplexing RF wavelengths is likely inadequate, but optical/IR or ultrasound allow frequency and spatial multiplexing. Implanted electrical recording would require a 1000-fold increase in the power efficiency of electronics relative to current devices to scale to whole-brain simultaneous recordings. Optical imaging Light scattering Inhibitors,research,lifescience,medical imposes significant limits on optical techniques, but strategies exist which could negate the effects of scattering, such as implantable optics, infrared fluorescence or bioluminescence, and online inversion of the Inhibitors,research,lifescience,medical scattering matrix. In larval zebrafish, a calcium indicator (GCaMP5G) in vivo captured, at 0.8 Hz, 80% of all

of the 100 000 neurons of the whole brain at single-cell resolution3 but scaling this to thicker, less transparent brains is quite challenging. Whole-brain multi-photon excitation could overheat the brain, except in very short experiments, unless ultrabright Inhibitors,research,lifescience,medical newsletter subscribe inorganic indicators or similar strategies can be developed.4 For beam

scanning microscopies, optical phase modulators, in principle, could reposition beams at 1-GHz switching rates with fluorescence lifetimes in the 0.1-1.0 ns range constrain and enable design of ultrafast scanning. Ultrasound Ultrasound is attenuated by brain tissue at the 100-MHz frequencies needed for single-cell resolution ultrasound imaging such that it is hard to detect even Inhibitors,research,lifescience,medical in theory. Nevertheless, ultrasound may be a viable medium for spatially multiplexed data transmission from embedded selleck products devices5. Molecular recording devices These fall within reasonable physical limits, but their development represents major challenges in synthetic biology. Innovative therapeutic Anacetrapib and preventative neurotechnologies A subset of the above imaging methods have variations capable of patterned neuronal stimulation, notably electrical and optical methods. This may enable repair or accommodation of disorders acquired during a lifetime of trauma and environmental and immune factors. Some psychiatric and neurodegenerative diseases can be prevented at even earlier stages, via their inherited, (auto)immune and microbial/viral origins. Genomics is finally overcoming decades of false-positives in such diseases including autism, schizophrenia, obsessive-compulsive disorder, bipolar disorder, etc.

On the other hand, the application of the dilation operator to an image produces an output image, which shows where the SE hits the objects in the image. All other MM operations can be expressed in terms of erosion and dilation [8]. For instance, the notion behind the opening operator is to dilate an eroded image in order to recover as much as possible of the eroded image. In contrast, the closing operator erodes a dilated image so as to recover the initial shape of image structures that have been dilated. The filtering properties of the opening and closing are based on the fact that, depending on the size and shape of the considered SE, not all structures from the original image will be recovered when these operators are applied. MM operations have found success in different application domains, including remote sensing [15].Although MM operators were originally defined for binary images, they have been extended to gray-tone (mono-channel) images by viewing these data as an imaginary topographic relief; in this regard, the brighter the gray tone, the higher the corresponding elevation [8]. It follows that, in grayscale morphology, each 2-D gray tone image is viewed as if it were a digital elevation model (DEM). In practice, set operators directly generalize to gray-tone images. For instance, the intersection �� (respectively,
The concept of pH was first introduced by S?rensen in 1909 [1]. Over the past century, Gemcitabine manufacturer measurements of pH have become arguably the most numerous analytical measurements made [2-5]. Examples of areas where pH measurements are frequently made involve chemical and drug manufacture, blood gas determinations, effluent discharge control, food and drink processing and water purity. It is therefore essential to ensure the validity and traceability of these measurements [6, 7].Primary pH standard values are determined from an electrochemical cell arrangement known as the ��Harned cell�� which does not contain a liquid junction and relies on well characterised Ag/AgCl reference electrodes for operation [8]. The Harned cell has the potential to be a primary method for the absolute measurement of pH, providing that it can conform to the accepted definition of a primary method [9] that requires a methodology and operation that can be completely described and understood, for which a complete uncertainty statement can be written down in terms of SI units.The long and short term stability of Ag/AgCl reference electrodes is of paramount importance for accurate pH measurement as a small change in the potential of a Ag/AgCl reference electrode makes a significant contribution to the measurement uncertainty. Therefore in an attempt to select a set of similar reference electrodes and reduce the risk of changes in potential between electrodes, it is common practice to reject individual reference electrodes which differ from the average of the group by more than 100 micro volts [4].