Tariot et al65 assessed the efficacy, safety, and tolerability of carbamazepine in the treatment of agitation and aggression associated with severe dementia in a placebocontrolled trial. Clinical Global Impression (CGI) ratings showed global improvement, in 77% of the patients taking carbamazepine and 21 % of those taking placebo. The mean daily dose of carbamazapine at week 6 was 304 mg/day (SD=119) with a mean serum level of 5.3 ug/mL. The drug was generally well tolerated. Divalproex sodium with an average dose at week 6 of 826 mg/day (375–1.375 mg/day with an average level of 45 μg/mL) has been shown superior to placebo (reduced agitation on the Inhibitors,research,lifescience,medical CGI in 68% of patients on valproate vs 52% on placebo; P=0.06).

Side effects were generally rated as mild. These data suggest that anticonvulsants might, be a helpful strategy in the treatment of agitation and aggression in dementia. Inhibitors,research,lifescience,medical However, further placebo-controlled trials are required to explore the clinical efficacy and tolerability of these compounds, particularly of the new generation of anticonvulsants. Because aggressive patients do not always respond to medication (single drug or in combination), one-to-one nursing in a quiet room is sometimes indicated.

Sleep disturbances Sleep disturbances in AD patients are characterized by fragmented sleep or disruption in the day–night sleep Inhibitors,research,lifescience,medical cycle.8 They appear to become progressively worse as the disease progresses, although

the Vorinostat severity of this disturbance varies considerably among individual patients. Apart from the neurodegenerative disease process itself, various other factors Inhibitors,research,lifescience,medical may influence the quality of sleep including physical or environmental conditions and drug side effects. Pharmacological conditions and drug side effects. Pharmacologically, chloralhydrate Inhibitors,research,lifescience,medical (250–1000 mg/24 hours), new nonbenzodiazepine hypnotics, such as Zolpidem (5–10 mg at night), an imidazopyridine derivative, zopiclonc (3.75–7.5 mg at night), a cyclopyrrolone-dcrivative, and low-potency neuroleptics (eg,melperone 25–75 mg at night) have been found effective.20 Trazodone, a sedative antidepressant agent with anxiolytic properties and minor anticholinergic effects improves sleep disorders (25–75 mg). However, some patients may develop hypotension. Anxiety Anxiety occurs in 50% to 80% of patients with AD.7,9,13 However, in contrast to agitation, aggression, psychosis, and depression, anxiety has been less well studied in patients with Carfilzomib dementia. Anxiety and depression coexist and overlap with various symptoms, such as agitation and the awareness of the cognitive deficiencies with resulting helplessness. The etiology and pathophysiology of anxiety in AD is not well understood. There is evidence that, anxiety is associated with loss of serotonergic neurons in AD. Antidepressants enhancing serotonergic activity, particularly SSRIs, may improve depression and anxiety.

Logistic regression CI-1033 analyses in which sex and age were considered and population stratification analyses confirmed these findings. Additionally, specific haplotypes increased risk for CD in AAs and OD in EAs. In summary, as might be expected given that the brain’s opioidergic system plays a central role in reinforcement, which has important implications for addiction,36 variation Inhibitors,research,lifescience,medical in a number of functional candidate genes encoding opioidergic

proteins have been implicated in dependence on alcohol, cocaine, and opioids. Assuming independent replication of these findings, a key question to be addressed is the nature of gene-gene and gene by environment interactions to which risk of SD is attributable. Other studies have demonstrated associations with Inhibitors,research,lifescience,medical the cannabinoid receptor gene (CNR1),37-39 neurexin 1 (NRXN1),40 and a set of alcohol-metabolizing enzymes.41

A clear pattern emerges from the examination of this sampling of candidate gene associations with SD: insofar as genes with known function are concerned, there are no big surprises with respect to physiology. (This can not be said about genes without clearly delineated functional roles, such as ANKK1, Inhibitors,research,lifescience,medical which was identified, not incidentally, based on its position, rather than its function.) This highlights the limitations of the candidate gene approach, which is often inherently biased by prior knowledge about physiology. Unbiased studies have greater potential to reveal new mechanisms of addiction, and that is a key Inhibitors,research,lifescience,medical attraction of the genome -wide association study (GWAS) methodology discussed below. GWASs are an alternative to linkage

for locating genes anywhere in the genome without prior hypotheses. GWAS designs are of interest due to their potential to identify risk loci of relatively small effect, Inhibitors,research,lifescience,medical much smaller than through linkage strategies. (In fact, one controversy engendered by the widespread adoption of GWAS designs is that often risk alleles are identified that have such a small effect – typically with odds ratios less than 1.2 – that it is hard to know what to do with them once Calcitriol price they have been identified.) A second advantage of GWASs is that they may be based on case-control samples, which are easier to recruit than family sampling schemes, which must be deployed to prepare for linkage. Family samples are more difficult to recruit (markedly so for many kinds of SD because of the tendency of these disorders to fragment families) and can introduce certain kinds of bias. The first GWAS for a specific SD trait, excluding studies that used a pooling methodology exclusively (see ref 42), examined ND.43 This study employed a two-stage design; first pooled DNA was used to screen 2.4 million SNPs; second, >30 000 SNPs selected from the first stage were screened individually in ~1000 each cases and controls.

These patients were similar to the PARTNER high-risk group in age, sex, pre-op ejection fraction, and severity of aortic stenosis. The perioperative mortality was 2.7% (3 of 92), and the perioperative stroke rate was 4.3% (4 of 92). The 1-year survival rate was 85% (Kaplan-Meier).

There were no periprosthetic leaks. These outcomes indicate that in selected elderly patients treated in an experienced center, surgical results superior to those receiving AVR in the PARTNER trial high-risk cohort can be achieved with fewer late complications such as ongoing strokes and progressive aortic insufficiency. Current Intrinsic Limitations of TAVI A comparison of the capabilities of TAVI vs. AVR is shown in Table 2. In our unselected Inhibitors,research,lifescience,medical total series of 1,514 AVR

patients, only 44% had undergone an isolated AVR. The remainder have received concurrent CAB, ascending aortic aneurysm repair, or mitral or tricuspid valve surgery. While Inhibitors,research,lifescience,medical most patients had pure aortic stenosis, about one-third had some degree of aortic insufficiency, which is a contraindication to TAVI. AVR allows treatment of any size of aortic “annulus” because prosthetic valves are available up to a diameter of 33 mm. Table 2 Differences in indications Inhibitors,research,lifescience,medical for TAVI vs. AVR. Ascending aortic aneurysm surgery may be required in conjunction with AVR most commonly because of atherosclerotic degeneration, Marfan’s syndrome, or aneurysmal disease from bicuspid aortic valve Inhibitors,research,lifescience,medical disease. The latter may be present in a significant proportion of these patients. Bicuspid aortic valve disease is currently considered to be a contraindication for TAVI because the single-slit opening may not conform to the circular shape of the deployed prosthesis. The aortic root and ascending aorta also tend to be larger in these patients. Patient-Prosthesis Mismatch (PPM) The TAVI prostheses are designed to have maximal geometrical orifice area. This is achieved Inhibitors,research,lifescience,medical through selleck screening library direct attachment of the tissue leaflets to the stent and the absence of an external sewing ring. The Medtronic CoreValve has the leaflets attached above the “annular”

fixation zone to further enhance the post-implantation effective orifice area (EOA). Despite these technical advantages, the EOA achieved by TAVI is intrinsically limited by the presence of the retained calcified aortic leaflets (which are not removed) and by the extent to which the calcified ascending aortic root and annulus can be safely dilated. In addition, the range of sizes currently available is limited. Ewe et al.11 reported on data Drug_discovery from a multicenter study in which 165 patients were evaluated for PPM. Studies were performed at baseline, before hospital discharge, and 6 months after TAVI. They found that 30 patients (18.2%) had an indexed EOA of <0.85 cm2/m2. A substantially higher proportion of these patients with PPM did not show clinical improvement compared with those without PPM (36.7% vs. 1.5%, P <0.001). The major adverse cardiovascular- and valve-related events did not differ.

The method could be applied for a number of therapeutic applications. The brain-derived neurotrophic factor (BDNF) was delivered to the left hippocampus in mice through the noninvasively disrupted blood-brain barrier (BBB) using focused ultrasound. The BDNF bioactivity was found to be preserved following delivery as assessed quantitatively by immunohistochemical detection of the pTrkB receptor and activated pAkt, pMAPK, and pCREB in the hippocampal neurons.

It was shown that BDNF #BI2536 keyword# delivered this way induced signalling effects in a highly localized region in the brain [71]. However it is the area of targeting brain tumours that have attracted most interest in the FUS disrupted BBB [72]. Mei and colleagues investigated the effects of targeted and reversible disruption of the blood-brain Inhibitors,research,lifescience,medical barrier by MRI-guided focused ultrasound and delivery of methotrexate to the rabbit brain. The authors recorded that the methotrexate concentration in the sonicated group was notably higher Inhibitors,research,lifescience,medical than that in both the control group (intravenous administration) and the internal carotid artery administered group. They observed a greater than 10-fold increase in the drug level compared to internal carotid administration without FUS [73]. Liu et al. investigated the delivery of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) to glioblastomas

in rats with induced tumours with the help of FUS. The authors found that FUS significantly enhanced the penetration Inhibitors,research,lifescience,medical of BCNU through the BBB in normal and tumour-implanted brains without causing bleeding. Surprisingly, treatment of tumour-implanted rats with focused ultrasound alone had no beneficial effect on tumour progression. However, treatment with focused ultrasound before BCNU administration controlled tumour progression and improved Inhibitors,research,lifescience,medical animal survival relative to untreated controls [74]. Liu and colleagues recently assessed FUS-mediated delivery of an iron oxide magnetic nanoparticle (MNPs) conjugated to an antineoplastic agent,

epirubicin. They used MNPs because of the favourable MR imaging characteristics, which could facilitate imaging. They demonstrated a substantial accumulation of MNPs, as well as epirubicin, up to 15 times the therapeutic find more range in the brain when delivered with FUS. They further showed decreased tumour progression in animals with brain tumours that received MNP with epirubicin via FUS [75]. Receptors targeting liposomal nanocarriers have been combined with MRgFUS to treat brain tumours. In a recently presented study it was shown that pulsed HIFU and human atherosclerotic plaque-specific peptide-1- (AP-1-) conjugated liposomes containing doxorubicin (AP-1 Lipo-Dox) acted synergistically in an experimental brain tumour model.

Liposomal nanotechnology provides a versatile platform for exploring several approaches that can potentially enhance the delivery and targeting of therapies to tumors. As a biodegradable and essentially nontoxic platform, liposomes can be used to encapsulate both hydrophilic and hydrophobic materials and be utilized as drug carriers in drug delivery systems (DDSs). In addition, liposomes can be used to carry radioactive moieties, such as radiotracers, which can be bound at multiple locations within liposomes, making them Inhibitors,research,lifescience,medical attractive carriers for molecular imaging applications. In this study, gelatinase-binding peptides were attached to liposomes for synthesizing a targeted drug

delivery vehicle. For active targeting or drug delivery applications or both, intraliposomal encapsylation of multiple targeting agents or therapies can be (i) to the lipid bilayer, which can bind hydrophobic conjugates; (ii) to hydrated compartments for water-soluble components; (iii) by covalent binding directly or by utilizing spacer to the outer lipid HIF-1 pathway leaflet [1]. Delivery of Inhibitors,research,lifescience,medical these nanoformulations to the reticuloendothelial system (RES) is Inhibitors,research,lifescience,medical readily achieved since, given their larger size, the RES traps

most conventional liposomes that are not shielded by polyethylene glycol chains (PEGs) or other similar steric water carrying substance. RES uptake can be increased by altering particle surface chemistry and charge, for instance, by adding positively charged lipids or biologically activating proteins or sugars on the surface of the liposomes. For purposes of agent delivery to target organs other than the RES, long-circulating Inhibitors,research,lifescience,medical liposomes have been developed by modifying the liposomal surface [2]. Determination of the in vivo biodistribution and targeting kinetics of liposome-encapsulated drugs is required for the assessment of drug bioavailability. The most commonly used nanoformulated drug is Caelyx/Doxil, a liposomal doxorubicin product. It has nearly Inhibitors,research,lifescience,medical supplanted doxorubicin in the therapy of ovarian cancer, breast cancer,

and Kaposi’s sarcoma. It differs from the former generation liposomal delivery systems, as the outer surface of Caelyx/Doxil is coated Ulixertinib with PEG chains that protect the liposomes from being opsonized by components of the immune system in the circulation. These stealth-type liposomes have longer circulation half-times than those for uncoated liposomes. In addition, they are safer than the native drugs themselves (e.g., Caelyx/Doxil is not cardiotoxic, a major concern for native doxorubicin delivery). For cancer-based applications, peptides that can selectively detect and target metastatic disease and tumor invasive potential may offer critical prognostic information. Metastatic invasion is promoted by the attachment of tumor cells to the extracellular matrix, the degradation of matrix components by tumor-associated proteases, and the cellular movement into the area modified by protease activity.

DBS in the treatment of major depression To date, a few case reports suggest that DBS might be a useful treatment for refractory depression. Recently, Mayberg and colleagues158 found that DBS of the white matter tracts adjacent to the subgenual cingulate gyrus was associated with improvement in depressive symptoms in 6 patients with refractory depression. By 1 and 6 months, two and four Inhibitors,research,lifescience,medical patients met criteria for clinical response, respectively Remission was achieved by three patients after 6 months.158 Deep brain stimulation

of the ventral caudate CP-690550 nucleus improved anxiety, depressive, and compulsive symptoms in one patient who suffered from resistant obsessive-compulsive disorder and resistant major depression.159 Deep-brain stimulation of the inferior thalamic peduncle improved depressive symptoms in one patient suffering from recurrent

unipolar Inhibitors,research,lifescience,medical depression and borderline personality disorders.161 Adverse effects Major side effects of DBS are seizure (1% to 3%), hemorrhage (1% to 5%), infection (2% to 25%, usually superficial infections but rarely cerebritis or brain abscess) and hardware-related complications (about 25%) that include Inhibitors,research,lifescience,medical fracture of leads, disconnection, lead movement, and malfunction.162,163 Stimulation-induced adverse effects such as parasthesia, muscle contraction, dysarthria, or diplopia are usually reversible with changes in stimulation Inhibitors,research,lifescience,medical parameters.164 Mechanism of action Investigating the mechanism

of deep brain stimulation reveals a basic paradox: the clinical effect of deep brain stimulation, which is usually regarded as a method of activating neurons, is similar to the traditional ablation of specific brain areas.165 Studies aimed at resolving this paradox have led to the development of four major theories regarding the mechanism of action of DBS. The first theory suggests that irregular activity in neurons converging with Inhibitors,research,lifescience,medical other neurons can result in a loss of information transfer and thus cause clinical pathology. The therapeutic effect of DBS may be due to its driving neurons at regular frequencies, and thus modulating the pathological network activity and increasing neuronal activity in the output nuclei.166 Many studies using functional imaging demonstrate increased GSK-3 cortical activity during DBS treatment. For example, activation of the thalamus and basal ganglia was demonstrated by fMRI studies167 and activation of motor cortex and supplementary motor area was demonstrated by PET studies.168,169 The second theory suggests that excitation of axon terminals near the stimulation electrode releases inhibitory factors that cause synaptic inhibition of the neuron.170 The third theory suggests that high-frequency tetanus produces a blockade of the spontaneous activities of neurons as a result of a strong depression of intrinsic voltage-gated currents,171 and thus DBS causes a depolarization blockade.

Genes of the immune system The association between pain and inflammation has led physicians to suspect a connection between immunological mechanisms and headache syndromes for many years. Several immunological abnormalities, such as changes in serum levels of complement and immunoglobulins or increased TNF-α, have been described in body fluids of patients with migraine and may be related to susceptibility to increased infection.30 Inhibitors,research,lifescience,medical The cause for this increased susceptibility is unclear, but was discussed as a result of chronic stress, a well-known suppressor of the immune system. Stress relief enhances immune

activity and triggers a burst of circulating vasoactive neuropeptides (such as substance P or neurokinin A), which function as mediators of inflammation and potential precipitators of a migraine

attack in vulnerable subjects.30 It is well known that the production of cytokines is also regulated by genes,31 which might in Inhibitors,research,lifescience,medical turn have implications on the age of onset of several disorders as rheumatoid arthritis32 or Alzheimer’s disease.33 A recent observation indicated that migraine patients with aura who are carrying the T/T genotype of the interleukin-la C889T polymorphism Inhibitors,research,lifescience,medical have about 10 years earlier age of onset of their migraine attacks. This supports the hypothesis of a genetically driven sterile inflammation as one etiological factor.34 Moreover, an association was found for the cytokines produced by TNF genes Inhibitors,research,lifescience,medical with the TNFβ2 allele, but only in migraine sufferers without aura.35 These findings support the assumption that the abnormalities in immunological parameters are not only a consequence of the headache attacks, as has been repeatedly hypothesized, but

can also modify the clinical course and the phenotypic expression of the disease. Fibromyalgia FM is a syndrome characterized by chronic widespread, persistent pain associated with increased tenderness to palpation due to lowering of the mechanical pain threshold and additional symptoms such as stiffness, fatigue, and psychological distress.36 Several additional clinical features of FM, including depression, 2-Methoxyestradiol ic50 anxiety, and Inhibitors,research,lifescience,medical sleep disturbances, as well as the fact that it runs in families and shows an increased familial learn more loading with depressive disorders, have even lead to the suggestion that FM might be a “depressive spectrum disorder.”37 This assumption was further supported by positive therapeutic response to antidepressant drugs, as well as by the fact that pain perception threshold was found to be decreased during depression,38 which was considered as being attributable to dysfunction in several neurotransmitter systems.39 The etiology of FM is unknown, but a possible contribution of 5-HT has been suggested on the basis of multiple biological findings, as for example, low levels of serum 5mfjT40 and low 5-hydroxyindole acetic acid (5-HIAA) levels in cerebrospinal fluid (CSF) of idiopathic pain patients.

62,63 Since then, not much has changed in the recommended light treatment regimen, except that light intensity can be as great as 10 000 lux,64 and perhaps 1 h per day is sufficient, as long as it is scheduled immediately upon awakening. Once treatment is satisfactory, the duration of light exposure can almost always be reduced.65 Several other studies have supported these findings, but some have not66,67: these studies were usually parallel-designed, so that patients themselves did not have the opportunity to compare light exposure at different times (which would have minimized the placebo component). In 1998, three independent research groups Inhibitors,research,lifescience,medical published large-N studies in which morning light was shown to

be more antidepressant than evening light thereby moving the field towards consensus about the superiority of morning light.45,68,69 However, superior efficacy of morning light does not necessarily prove the PSH, because it could be more Inhibitors,research,lifescience,medical antidepressant at this time for some reason other than causing

a phase advance. However, it has been shown that the antidepressant response to morning light does, in some circumstances, correlate with the amount of phase advance in the DLMO. This was first reported with respect to treatment group means,61 followed by an analysis70 of individual DLMOs and depression scores collected independently.36,63 More recently, this latter finding was essentially replicated Inhibitors,research,lifescience,medical Inhibitors,research,lifescience,medical using another data set.71 Further support of the PSH along these lines will be discussed below. It should also be noted that a very small subgroup of SAD patients appear to be cueing to dusk and should be treated with evening bright light; clinically, these patients

can be identified by a history of early morning awakening year round, going to bed much earlier in the winter.65 In any event, the earliest and most common use of the DLMO has been to assess the phase-shifting effects of light. Bright light has also been used to treat a number of other circadian phase disorders, such as advanced sleep phase syndrome (ASPS), delayed sleep phase syndrome (DSPS), jet Inhibitors,research,lifescience,medical lag, and shift work maladaptation (see below). The melatonin PRC The phase-shifting effects of melatonin are also Dacomitinib described by a PRC. The melatonin PRC is about 12 h out of phase with the light. PRC.13,44 Both PRCs are phase-locked to each other, as well as to the melatonin profile (Figure 2). As mentioned above, waketime is usually designated ZT 0. Sleep time is therefore usually ZT 16. In the melatonin PRC studies of sighted people, the baseline plasma DLMO10 was designated CT 14. It is also designated CT 14 in free-running blind people. We call this phase marker the MO in blind people. inhibitor Lapatinib Saliva can also be used (at this time of the night, salivary melatonin levels are about one -third those of plasma).72 Measuring the MO in blind people provides a reference point to determine the phase of the endogenous circadian pacemaker and the melatonin PRC.

Their effects depend upon the concentration, whether they are given simultaneously or sequentially, the route of delivery, and on the age and health status of the women who receive hormone therapy. Turgeon et aP have provided a detailed review of our current understanding of estrogens, progestogens, their

related compounds, agonists, and Inhibitors,research,lifescience,medical antagonists. Estrogens and stroke Stroke is the third leading cause of death for middleaged and older women and a major health problem that affects 500 000 Americans each year.3 Every year approximately 40 000 more women than men are affected by stroke.4 Initially, this gender difference was thought to be explained by a combination of both the longer Inhibitors,research,lifescience,medical life expectancy of women and the protective roles of estrogen, since the incidence of stroke increases after menopause and the risk continues to rise with age.5 However, this interpretation has been questioned since recent clinical trials including the Women’s Health initiative (WHI) reported negative impact of estrogen therapy (ET)4,6-8 and some studies in animal models also suggest that estrogens are not universally protective and can be deleterious under some circumstances.9 In an attempt to reconcile these seemingly contradictory data, our lab has used animal Inhibitors,research,lifescience,medical models to explore the mechanisms of estrogen’s neuroprotective and neuroregenerative

actions. Estrogens and stroke: use of animal models to decipher mechanisms of action Even the best, well-designed Inhibitors,research,lifescience,medical clinical studies cannot benefit from the experimental advantages of many basic science studies, since studies performed with experimental animal models allow replication with adequate numbers of animals, controls with equivalent genetic backgrounds and

previous exposure to similar environments, Inhibitors,research,lifescience,medical wellcontrolled environments during the entire study, and lack of selection or recall bias. Thus, investigators have developed http://www.selleckchem.com/products/Temsirolimus.html several animal models to investigate the pathophysiology and potential treatments for stroke. Since most cerebrovascular strokes (>70%) in aging human populations are ischemic, and not hemorrhagic, we adopted an animal model that reproduces ischemic infarcts. We have utilized permanent middle cerebral artery Cilengitide occlusion (MCAO) as a model of permanent occlusion of the middle cerebral artery, which vascularizes the cerebral cortex, the striatum, and the hippocampus, to examine the effects of estrogen in neurodegeneration. Blockade of this artery at its base results in about a 50% decrease in blood flow and causes severe metabolic impairment in a core region, called the “ischemic core” and many neurons in these regions die by necrosis within hours following injury. In contrast, regions that surround the ischemic core, the ischemic penumbra, undergo more moderate metabolic impairment and are potentially salvageable by effective therapeutic agents.

The computerization of the study allowed the data to be presented to participants in a novel and more meaningful way. Data from rounds two and three were presented to participants as a color histogram (or heat map) where the depth of color indicated the frequency with which respondents in the previous round had chosen each rating. Figure 1 shows the frequency with which each of the five responses had been chosen in the previous round (dark being many, light being few). The grey circle shows the choice

that the current participant Inhibitors,research,lifescience,medical made on the previous round and the green circle shows the choice that they have made on the current round, (in round one each box was white as no previous selection had been made). In this way, participants could easily see how their responses compared to the consensus in the previous round and either confirm or update their www.selleckchem.com/products/Perifosine.html response accordingly. Figure 1 An example from the website of a

color histogram of previous Inhibitors,research,lifescience,medical responses. Inhibitors,research,lifescience,medical The second question required a numeric answer. As the user sample size in each round exceeded 30 (and therefore the number of independent responses was sufficient to assume that the central limit theorem held with responses tending towards being normally distributed), we proceeded Inhibitors,research,lifescience,medical to adopt a parametric approach in the iterative feedback to users between rounds. Feedback to the user was given as a color again, but in this case, the depth of color indicated the number of standard deviations between the user’s response and the mean response (in other words, the z-score). As the scale for each answer was different, the normalized z-score

provided a consistent measure of agreement for each question. Z-scores were calculated as, z=x-μσ Where x was the value for which the z-score is to be calculated, μ was the mean of the values of the previous round and σ was the standard Inhibitors,research,lifescience,medical deviation of the values from the previous round. The z-score was translated into a color depth Anacetrapib and shown around the input box for each item in the questionnaire. The mean value from the previous round, along with the participant’s own response from the previous round were also displayed on the questionnaire. An example of the quantity input box is given in Figure 2; the top box shows that the previous average quantity for this item was 73 and that this participant had said 53. The light color indicates the difference. The bottom box shows where the participant was in closer agreement in the last round. The numbers in the boxes show the participant’s updated response for this round. Figure 2 The quantity input box for two items as presented on the website.