, 1996). Even where both sexes appear to be supported by their same-sex peers, male and female rats exhibit anxiety responses and adrenal reactions under different combinations of conditions (Westenbroek et al., 2005). Some of these differences may

relate to neurochemical variation in the brains of males and females. Both oxytocin and vasopressin are important for social behavior, and there are sex differences in the production and release of these neuropeptides, the location and density of their receptors, and their roles in social behavior (Bales and Carter, 2003 and Carter, 2007). There are many sex differences in human psychiatric disorders, most notably anxiety and depression, which some argue are based on sex differences in responses to stress (Bangasser and Valentino, 2014). One selleck chemicals llc consequence of these findings is that we must study the interactions of stress and social behavior in both sexes in order to make meaningful conclusions about each sex. This idea is gaining greater appreciation within the scientific and funding communities (Mogil and Chanda, 2005, Cahill, 2006, Zucker and Beery, 2010, Couzin-Frankel, 2014, Clayton and Collins, 2014 and Woodruff et al., 2014). The social environment can cause

stress or ameliorate the impacts of stress, and social behavior responds to stress. These effects may happen all together or at different times, and vary with individual genetic background, experience, sex, species, and other XAV-939 molecular weight factors. While it is not feasible to study all such factors in a single study, almost a century of research has helped to show which stressors are most impactful in males and females, and how such stress is reflected in neurochemistry. Interaction time is a longstanding measure of social behavior, but recent studies have begun to employ more most nuanced approaches – for instance measuring helping behavior and distinguishing preferences for familiar Libraries versus unfamiliar individuals. While adverse

social conditions (from subordination to isolation) are potent stressors, the interactions between stress and social behavior also offer multiple entry points into the study of stress resilience. Stress resilience varies with early life social environment—in particular with experience of maternal behavior and life history of exposure to mildly stressful experiences. Resilience can also arise from the mitigating or buffering effects of positive (or negative) social interactions. There is a vast body of literature linking stress and social behavior and their roles in resilience. We may learn the most from these studies when we consider the social life of the organism, and look beyond group averages to individual variability. We are grateful to Dr. Julio Ozores for engaging discussions on this topic, and to Drs.

Each pair of electrodes was aligned parallel to the line of underlying muscle fibres. Electromyographic data were sampled at 1000 Hz. The signals were amplified and digitisedc. A bandpass filter (20–450 Hz) was used. The root mean square was

calculated from the raw data using a moving window of 50 msec and was converted CHIR-99021 mw to ASCII files for analysis. For normalisation, 5 sec of reference contraction data were recorded while the participant performed three trials of maximal voluntary isometric contraction in the manual muscle testing position for each muscle (Kendall et al 1993). To ensure maximal effort, verbal encouragement was given. To minimise compensation during data collection, subjects were encouraged to maintain the testing position (Boettcher et al 2008). The middle 3 sec of the 5-sec contraction were used for data analysis. The initial 1 sec was excluded to ensure maximal amplitude had been reached, and the final 1 sec was discarded to avoid possible fatigue from sustained maximal muscle contraction (Soderberg and Knutson, 2000, Dankaerts et al 2004, Tucker et al 2010). A 3-min rest period was provided between trials. The mean root mean square of the three trials was calculated for each muscle. The electromyographic signals collected during each angle of shoulder flexion were expressed as a percentage

of the calculated root mean Mephenoxalone square of maximal voluntary isometric contraction. The inhibitors secondary measure in the study was displacement of the acromion in the Inhibitor Library frontal and sagittal planes. A reflective marker 14 mm in diameter was placed on the skin at the midpoint of the acromion to measure its displacement in the frontal and sagittal planes during shoulder flexion (Figure 4). The reflective markerd was not used for visual feedback, but was used

for measuring the displacement of acromion. Two video cameras were placed 1.5 m from the shoulder joint; one was located behind the subject to capture the superior and inferior displacement of the marker in the frontal plane, and the other was placed to the side of the subject to capture the anterior and posterior displacement of the marker in the sagittal plane. Two 30-cm-long wooden rods attached to the side and back of a wooden chair were used as reference points to calibrate the motion analysis systeme in the frontal and sagittal planes (Figure 5). Video files captured during the shoulder flexion test were used to calculate the displacement of the marker. The distance of the acromion movement was measured from the starting position to the end of the predetermined shoulder flexion position in cm by the video motion analysis system software (Figure 5). For each combination of flexion angle and feedback condition, the average of the three trials was calculated for the data analysis.

Pre-publication history The pre-publication history for this paper can be accessed here: http://www.biomedcentral.com/1471-227X/13/15/prepub Acknowledgements Authors are thankful to the HIAE’s ER staff for its support and to HIAE and HMMD for the support to the study development and publication.
Pediatric shock is a recognized medical emergency [1]. Aggressive fluid resuscitation is recognized as a critical component of early non-cardiogenic shock management [1-4]. The American College of Critical Care Medicine (ACCM) guidelines

for early goal-directed pediatric septic shock Inhibitors,research,lifescience,medical management recommend to, “Push boluses of 20 cc/kg isotonic saline or colloid up to & over 60 cc/kg until perfusion improves or unless rales or hepatomegaly develop” [4]. Clear pragmatic recommendations for health care providers (HCPs) as to how to achieve rapid fluid resuscitation are lacking in current guidelines. An important aspect limiting fluid flow is that the intravenous (IV) cannulas most commonly used in pediatric patients have a small radius Inhibitors,research,lifescience,medical relative to those used in adults [5]. In adult patients, buy Enzalutamide options for rapid fluid resuscitation include rapid infuser devices and pressure bag support [6-8]. While these modalities are available for use in pediatric

resuscitation, in our experience, syringes are most commonly used for this purpose, likely due to their relative availability Inhibitors,research,lifescience,medical and health care providers’ comfort using them. A randomized controlled trial by Stoner et al. determined that manual syringe and pressure bag methods were an equivalent means of delivering fluid rapidly in an emergency department setting [9].

However, in this study only 58% of children resuscitated in the pressure bag and 68% in the syringe group met the ACCM benchmarks. In the clinical setting, we have observed Inhibitors,research,lifescience,medical and health care providers have endorsed two different manual syringe techniques used for the purpose of rapid isotonic fluid resuscitation for children in shock: 1) the ‘disconnect-reconnect’ technique and 2) the ‘push-pull’ technique [10]. When initiating manual Inhibitors,research,lifescience,medical fluid resuscitation using syringes, a health care provider must make a decision regarding what syringe size to use. A larger syringe has a larger radius relative to a given IV catheter. To create the GBA3 same pressure gradient (which is proportional to flow rate) across an IV catheter, a health care provider must apply a comparatively greater force to the plunger when a larger syringe size is used, as dictated by the formula. F = ΔP(πr2). Where the force applied is constant, a slower fluid flow rate results when a larger radius syringe is used. When using the ‘disconnect-reconnect’ technique (Figure 1) to perform manual fluid resuscitation, one must also consider that total fluid administration time is actually the sum of the “fluid push time” plus the “syringe swap time”, as time is required to disconnect and replace empty syringes with new fluid filled ones.

The Delphi Technique Delphi studies are frequently used in healthcare, with the goal of establishing consensus on a particular topic [13]. Iterative rounds of structured Epigenetics inhibitor surveys are administered

to a group of experts on the topic, who rank each item. On subsequent rounds, each panel member views the ranking they assigned to each item, as well as the group mean ranking. Participants have the opportunity to revise their Inhibitors,research,lifescience,medical ranking, taking into consideration the group mean. The rounds continue until consensus is achieved, or a predetermined end point is met. The technique is beneficial because consensus can occur in an anonymous format, without physically bringing experts together. Four key features make Delphi studies well suited for determining group consensus: Inhibitors,research,lifescience,medical anonymity of responses; iteration with controlled feedback; statistical group response; and, the use of experts [14]. The results of a Delphi study can help direct future research, continuing education and allocation of resources. The obvious limitation of such a consensus

study is the results are not linked to actual patient outcomes, and therefore the results are only as good as the panel members’ opinions. Nevertheless, the opinion and experiences of EMS experts is useful to inform the most important instances of CDM that occur during a high acuity ambulance calls. The CDM instances that are found to be the Inhibitors,research,lifescience,medical most important will be organized in a process analysis map. This Inhibitors,research,lifescience,medical strategy has been developed for emergency medicine using a modified Delphi approach [15-17]. The model will enable gaps in research, knowledge and practice to be identified. Objective Using expert consensus, the instances of clinical decision making that are required by paramedics on typical high acuity ambulance calls will be determined, in terms of their importance to clinical outcome and patient safety. Methods and design Study Design This cross-sectional study will use the Delphi technique to achieve consensus amongst EMS experts

on the most important instances of Inhibitors,research,lifescience,medical clinical decision making by paramedics during high acuity emergency calls, in the ground ambulance setting. These all instances will be scored on importance, based on their anticipated impact on patient clinical outcome and patient safety. The final consensus will be used to develop a process analysis map of paramedic clinical decision making. Setting and Population Subjects for this study will be recruited using purposive and criterion sampling. The goal is to have a sample of EMS experts from across Canada, which will include EMS medical directors and paramedic leaders. Two key organizations will be targeted for recruitment: the Canadian Association of Emergency Physicians EMS Committee and the EMS Chiefs of Canada. An expression of interest posting will be distributed throughout these two organizations.

The categories are nonaggressive physical behavior and nonaggressive verbal behavior. The symptoms are pacing and aimless wandering, constant request for attention, repetitive questions, trying to get to different places, complaining, and general restlessness. Finally, anxiety is one of the ten items evaluated for frequency and severity Inhibitors,research,lifescience,medical in the Neuropsychiatrie Inventory (NPI). It is, however, surprising that, despite leading investigators’ acknowledgment of the presence of anxiety symptoms in dementia, no widely accepted qualitative definition is available for generalized anxiety disorder (GAD), the most common anxiety disorder in dementia.

In the absence of other options, it is of interest to observe that Chemerinski and associates, using DSM-III-R GAD criteria managed to identify a distinct group of demented anxious patients.32 To date, there is no universally accepted definition of agitation in BPSD. In the absence of such a definition, we propose using the clinical approach advocated byCohen-Mansfield Inhibitors,research,lifescience,medical and collaborators. They view agitation as a group of inappropriate

verbal and motor behaviors that are unrelated to the presence of unmet needs or confusion per se.8 Pharmacological treatment As in previous sections the treatment of BPSD will be reviewed syndrome by syndrome. Because to our knowledge no specific Inhibitors,research,lifescience,medical syndromal approach is available for behavioral treatments, those will be jointly reviewed. Psychosis and Inhibitors,research,lifescience,medical aggression In 1998, little information was available on the treatment of psychosis and aggression in AD. An attempt

to bridge this gap in knowledge was made using an expert consensus approach (A Special Report April 1998).33 The resulting report, which Inhibitors,research,lifescience,medical included survey see more results from approximately 80 experts, concluded that risperidone was the first-line treatment for psychosis in AD, followed by conventional antipsychotics. Extrapyramidal symptom (EPS) reactions and the long-term risk of tardive dyskinesia (TD) are potential concerns with conventional antipsychotics, especially at. higher doses. Indeed, the rate of extrapyramidal side effects is reported to be as high as 20% in this population.34 Further, the annual incidence of TD with conventional antipsychotic therapy is reported to be 25% in this population.35 If patients are aminophylline unresponsive to first-line therapy, the report recommended switching to another atypical antipsychotic, high-potency neuroleptic, or adding divalproex or trazodone. With regard to aggression, there was no majority agreement on first-line treatment; however, valproex was cited as the most popular of the treatment options. Divalproex was also suggested to be useful as an adjunct to antipsychotics in psychotic patients who continue to be severely aggressive (Expert Consensus Guideline Series, 1998).

Hyperhomocysteinemia is a known risk factor for venous thrombosis. It results from low socioeconomic conditions secondary to deficient nutritional status, low plasma folate and vitamin B12 levels, which are associated with an increased risk of CVST in some developing countries.12,13 A small percentage (5.64%) of our patients had BD. The prevalence of BD is 16 in 100,000 people in Iran.14 The frequency of neurological manifestations in Inhibitors,research,lifescience,medical Behcet’s disease ranges from 5% to 30%.15 Borhani−Haghighi et al,16 reported that 22% of patients with Neuro-Behcet’s disease developed

CVST. This might justify the high frequency of the disease as an underlying cause of CVST in Iran. Some patients of this study had primary antiphospholipid antibody syndrome (APLS) and systemic lupus erythematosus (SLE). The role of antiphospholipid antibodies and other lupus anticoagulants in the evolution of CVST has been previously reported.17,18 Thrombophilia conditions including deficiency of proteins Inhibitors,research,lifescience,medical C and S appeared in 6.5% of the patients. One of our patients, who was also reported by Borhani−Haghighi et al,19 had a rare sporadic combined hyperhomocysteinemia and protein C deficiency. The mortality and morbidity rates in our patients were higher than some

previous studies. The mortality rate was 14.51% in the present study, whereas that of patients with Inhibitors,research,lifescience,medical CVST in an international study on cerebral vein and dural sinus ABT-199 in vivo thrombosis (ISCVT) was 8.3%.9 Higher mortality in the present study might be due to the referral nature of our center, which excluded patients with milder course as well as the lack of neuro-intensive care units. Presence of coma or stupor (P=0.001), parenchymal hemorrhage (P=0.005) Inhibitors,research,lifescience,medical at the time of admission, and cancer were common predictors of high mortality rate in this study and other previous studies.3,6,8,20 Increased morbidity in the present study (35.48%) compared to that of ISCVT (26.92%) may be attributed to retrospective nature of our study in a clinic-based Inhibitors,research,lifescience,medical follow-up. Headache, optic atrophy and focal neurological deficits were major sequels, which were similar to those

reported in Azin et al.3 and Hameed et al.21 Extracranial venous thrombosis in our study was approximately two times more than what was reported in a study by Ferro et al.6 (8.06% vs 4.3%). Predisposing Unoprostone factors for recurrent thrombosis were malignancy, postpartum state, OCP, BD, SLE, and APLS. This study sheds new light on the subject, and suggests using important methods including organ mobilization and prophylactic anti-coagulative drugs in patients with cerebral venous-sinus thrombosis. It also emphasizes prompt diagnosis and treatment of thrombophilic conditions to prevent thrombosis formation more than before. Conclusion The findings of the study indicate that the use of OCPs was a main factor associated with CVST.

22 Additionally, 5 µl of the final products were run on 1.5% (V/V) agarose gel marked with ethidium bromide and visualized by ultraviolet trans-illumination. The size of each

band was estimated by comparison with the size of the reference strains. Leishmania Reference Strains Reference strains of Leishmania infantum (MCAN/IR/96/Lon 46), L. major (MHOM/IR/54/LV 39), and L. tropica (MHOM/IR/89/ARD 2) were used as standards. All of these strains were obtained from the Medical Parasitology Laboratory, School of Public Health, Inhibitors,research,lifescience,medical and Institute of Health Research, Tehran University of Medical Sciences. Also, DDW was included in each run as a negative control. Sequencing The PCR products of all the positive samples were purified using the Gel Purification Kit Inhibitors,research,lifescience,medical (AccuPrep®, Cat. No. k-3035-1, Bioneer, USA). Both forward and reverse sequencing of the strands of amplified DNA were sequenced with the PCR primers on an automated sequencer (Applied Biosystems 377XL). After utilization of the TritrypDB blast program, the nucleotide homologies of the sequenced products were evaluated with Leishmania spp., available in GenBank. The determination of sequences was learn more performed using the FASTA formatted sequences, associated with the Chromas program.15 Results Inhibitors,research,lifescience,medical A total of 2543 sand flies, comprised

of 730 females and 1813 males, were collected. Of these, 10 phlebotomine species were identified; they belonged to Phlebotomus (5 species) and Sergentomyia (5 species).The most prevalent species was P. papatasi, representing 53.9% of the total sand flies. This species was the most common species both outdoors and indoors, representing 37.55% and 16.35% Inhibitors,research,lifescience,medical of the specimens, respectively. Two species of Sergentomyia (S. baghdadis and S. squamipleuris) were just captured outdoors Inhibitors,research,lifescience,medical (table 1). Table 1 The species and numbers of male (♂) and female (♀) sand

flies caught indoors and outdoors, Beiza District, 2010 Randomly, 70 female specimens, consisting of 48 P. papatasi, 17 P. sergenti, and 5 P. tobbi, were assessed for Leishmania infection. Leishmania DNA was detected only in 5 (10.41%) specimens of P. papatasi, all of which had been collected outdoors from near the rodents’ burrows. The band size of the provided impression smears from the P. papatasi specimens was about 560 bp, PAK6 equal to the band size of the L. major standard strain. No amplicon was detected in the band size of L. tropica (750 bp) and negative samples (table 2, figure 2). Table 2 Number and percentage of the infected dominant phlebotomine sand flies, Beiza District, Fars Province, 2010 Figure 2 This is an illustration of the results of the polymerase chain reaction-based amplification of kinetoplast DNA. The samples investigated came from 7 wild-caught Phlebotomus papatasi (lanes 7-13) or reference strains of Leishmania tropica (lane 2), L. … Using TritrypDB sequence analysis against the Trypanosomatidae species, the target sequence of the PCR products showed 75-88% similarity with L. major.

48 In another study, heavy cannabis use was found to cause an amotivational syndrome in adolescents.49 The treatment of cannabis use disorders has recently been reviewed.12

However, the occurrence of amotivational syndrome as a result of cannabis Talazoparib ic50 exposure remains controversial.50 The data from other studies do not support the hypothesis that marijuana impairs motivation.51,52 Although most of the cannabis-related negative effects relate to Inhibitors,research,lifescience,medical its neuropsychologic and behavioral effects, other negative reactions to cannabis are sometimes found. For example, cannabis can cause acute pancreatitis, although the exact mechanism remains unknown.53 Therapeutic uses of cannabinoids Obesity, anorexia, emesis Cannabis has been known for centuries to increase appetite and food consumption.54 More recently this propensity of the drug was substantiated when the CB1 receptor was shown to have a role in central appetite control, peripheral metabolism, and

body weight regulation.55 Genetic variants at CB1 coding gene CNR1 are associated Inhibitors,research,lifescience,medical with obesity-related phenotypes in men.56 In animals, CB1 receptor antagonism decreases motivation for palatable foods. Rimonabant administration caused suppression of the intake of Inhibitors,research,lifescience,medical a chocolate-flavored beverage over a 21-day treatment period, without any apparent development of tolerance.57 CB1 receptors were found to be preferentially involved in the reinforcing effects of sweet, as compared to a pure fat, reinforcer.58 Rimonabant selectively reduces sweet rather than regular food intake in primates,59 which suggests that rimonabant is more active on the hedonic rather than nutritive properties of diets. Rimonabant leads to significant weight loss in obese human subjects. Treatment with rimonabant Inhibitors,research,lifescience,medical was also associated with beneficial effects on different metabolic parameters and cardiovascular risk factors linked with overweight.60,61 In clinical trials rimonabant Inhibitors,research,lifescience,medical was found to cause a significant mean weight loss, reduction in waist circumference,

increase in HDL cholesterol, reduction in triglycerides, and increase in plasma adiponectin levels.62 Patients who were switched from the rimonabant treatment to placebo after a 1-year treatment regained weight, while those who continued to receive rimonabant maintained their weight loss and favorable changes Carnitine palmitoyltransferase II in cardiometabolic risk factors.63,64 Rimonabant was shown to be safe and effective in treating the combined cardiovascular risk factors of smoking and obesity.65 It also diminishes insulin resistance, and reduces the prevalence of metabolic syndrome. Many of the metabolic effects, including adiponectin increase, occur beyond weight loss, suggesting a direct peripheral effect of rimonabant.66 Therapy with rimonabant is also associated with favorable changes in serum lipids and an improvement in glycemie control in type 2 diabetes.67 The activity of rimonabant in the management of obesity has been described in recent reviews.

Both hippocampal atrophy and hippocampal-based memory deficits reversed with treatment with the selective serotonin reuptake inhibitor (SSRI) paroxetine, which has been shown to promote neurogenesis (the growth of neurons) in the hippocampus in preclinical studies.163

In addition, treatment with the anticonvulsant phenytoin led to an improvement in PTSD symptoms164 and an increase in right hippocampal and right cerebral volume.165 We hypothesize that stress-induced hippocampal dysfunction may mediate many of the symptoms of PTSD which are related to memory dysregulation, including both explicit memory Inhibitors,research,lifescience,medical deficits as well as fragmentation of memory in abuse survivors. It is unclear at the current time whether these changes are specific to PTSD, whether certain common environmental events (eg, stress) in different Inhibitors,research,lifescience,medical disorders lead to similar brain changes, or whether common genetic traits lead to similar outcomes. The meaning of findings related to deficits in memory and the hippocampus in PTSD, and questions

related to the relative contribution of genetic and environmental factors, has become an important topic in the field of PTSD and stress research. There are three possible models, taking into Inhibitors,research,lifescience,medical account genetic or environmental factors, which have been proposed to explain smaller hippocampal volume in PTSD: Model A (Environment), Model B (Environment and Genetic), and Model C (Genetic).166-169 In Model C (Genetic), Inhibitors,research,lifescience,medical smaller hippocampal volume represents a premorbid risk factor for PTSD. In support of this model Pitman and colleagues170 have demonstrated that lower premilitary IQ is associated with combat-related PTSD, as well as finding a correlation between PTSD symptoms and Inhibitors,research,lifescience,medical hippocampal volume in twin brothers.151 Model A (Environment) states that stress leads to damage or Epigenetics inhibitor inhibition of neurogenesis via hypercortisolemia, decreased BDNF, or increased glutamate. Model B (Environment/Genetic) states that a combination of environmental and genetic

factors leads to deficits in hippocampal function and structure. Showing that an intervention like medication Phosphatidylinositol diacylglycerol-lyase changes hippocampal volume and cognition would provide support for at least a partial contribution of the environment to the outcomes of interest. In addition to the hippocampus, other brain structures have been implicated in a neural circuitry of stress, including the amygdala and prefrontal cortex. The amygdala is involved in memory for the emotional valence of events, and plays a critical role in the acquisition of fear responses. The medial prefrontal cortex includes the anterior cingulate gyrus (Brodmann’s area [BA] 32) and subcallosal gyrus (area 25) as well as orbitofrontal cortex.

Dose increase by 50%

(6 mg q 2 weeks) of Trastuzumab led to … Discussion We present a case of HER2-positive metastatic gastric cancer that required a higher than standard dose of trastuzumab to achieve a response to therapy. Standard breast cancer dosing of trastuzumab on a 3-week schedule is 8 mg/kg load followed by 6 mg/kg q 3 weeks, or on a weekly schedule (4 mg/kg load, 2 mg/kg q week) (1). Our patient was treated with FOLFOX chemotherapy every two weeks, and thus Inhibitors,research,lifescience,medical received an appropriate proportional trastuzumab dose (6 mg/kg load, 4 mg/kg q 2 weeks). The patient progressed very quickly following initiation of therapy (after 3 treatments), and subsequently responded immediately following an increase in trastuzumab dose to 6 mg/kg q 2 weeks (i.e., 50% dose increase in maintenance). This response was

noted without a change in the FOLFOX cytotoxic therapy, suggesting that the initial administered Inhibitors,research,lifescience,medical dose of trastuzumab was insufficient for treatment response; more specifically, the patient required a higher dose of trastuzumab to achieve a response to therapy. The observation that our patient responded to a higher dose of trastuzumab than routinely administered suggests that some Torin 1 clinical trial patients with HER2-positive gastric cancer may be underdosed. It is suggested that gastric cancer patients may have a higher renal clearance of trastuzumab than patients with HER2-positive Inhibitors,research,lifescience,medical Inhibitors,research,lifescience,medical breast cancer. Bruno and colleagues (4) determined the steady state pharmacokinetics of trastuzumab in patients with metastatic breast cancer. On the weekly trastuzumab schedule, trastuzumab clearance is 0.231 L/day (for a median body weight of 68 kg) with a corresponding elimination half-life of approximately 3 weeks. On the every 3-week schedule in metastatic breast cancer, the trastuzumab pharmacokinetics is very similar (1). In contrast, the pharmacokinetic

Inhibitors,research,lifescience,medical profile of trastuzumab reported from the ToGA study in patients with metastatic gastric cancer demonstrate a higher clearance is 0.378 L/day (~70% higher), with a corresponding elimination half-life of approximately only 2 weeks (Roche, Inc 2011) (Table 1) (5). This suggests that the current “standard” dosing of trastuzumab in 4-Aminobutyrate aminotransferase metastatic gastric cancer may be grossly underdosed by nearly 50%, and that higher trastuzumab doses may be necessary in some patients for maximum efficacy. Table 1 Pharmacokinetics of trastuzumab (Herceptin) in breast cancer vs. metastatic gastric cancer In breast cancer, it has been shown that patients with four or more metastatic sites of disease have faster clearance, independent of HER-2 extracellular domain levels (4). Trastuzumab elimination appears to depend on serum levels of circulating HER-2 extracellular domains, which can be cleaved from the surfaces of cancer cells by matrix metalloproteinase.