It seems that pilocarpine acting centrally activates both salivar

It seems that pilocarpine acting centrally activates both salivary gland secretion

and vasodilation.7, 8 and 10 Because salivation depends on secretory mechanisms and on the increase in blood flow to the glands,23 reduction in salivation may occur if one or both mechanisms are affected. The activation of α2-adrenoceptor with moxonidine reduces the salivary secretion and the vasodilation induced by pilocarpine.15 and 10 Therefore, it is possible that moxonidine inhibits pilocarpine-induced salivation at least partially by reducing salivary gland blood flow. Besides XL184 mouse this, the vasoconstriction and the reduction of the blood flow to the salivary glands produced by the activation of the central α2-adrenoceptors is probably important for the sensation of dryness in the mouth by patients treated with moxonidine or the same type of drugs. In summary, the present results suggest that central cholinergic and α2-adrenergic mechanisms have opposite roles in the control of the salivary gland vascular resistance and blood flow. However, the increase in MAP, HR and mesenteric vascular resistance produced by the cholinergic activation in the forebrain is not affected by central α2-adrenoceptor activation, suggesting that different central mechanisms are activated by pilocarpine to produce the changes in the vascular resistance in different vascular beds. São Paulo State Foundation (FAPESP). None declared. Experimental protocols

were approved by the Animal Experimentation Ethics Committee of the Federal University of Sao Paulo (UNIFESP). We would like to thank also Solvay Pharma selleck compound and

Dr. P. Ernsberger for Succinyl-CoA the donation of moxonidine. This research was supported by public funding from Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) and Conselho Nacional de Pesquisa (CNPq/PRONEX). “
“Species of the genus Candida are considered commensal yeasts frequently isolated from the oral cavity of healthy patients. 1, 2 and 3 However, these microorganisms can act as opportunistic pathogens under certain circumstances, such as impairment of salivary glands, long-term use of immunosuppressive drugs and antibiotics, denture wear, and malignancies. 4 and 5Candida albicans is the most commonly isolated species, being present in around 20–50% of the cases of oral infections. 6 Recently, infections with species other than C. albicans, notably Candida glabrata and Candida dubliniensis have been increasingly described. 7, 8 and 9C. glabrata has become the second most frequently isolated commensal yeast from the oral cavity, 2, 7 and 8 and it is responsible for 15% of mucosal lesions. 2C. dubliniensis is a recently described species of the genus Candida 10 primarily associated with oral candidiasis 11 in acquired immunodeficiency syndrome (AIDS) patients. Denture stomatitis is a common superficial infection of the palate oral mucosa that affects more than 65% of denture wearers.

, 2004) Reduced secretion of IL-10 upon stimulation with Aβ1-40

, 2004). Reduced secretion of IL-10 upon stimulation with Aβ1-40 was previously observed in cultures of whole blood cells (Speciale et al., 2007). The missing increase in TNFα secretion and no obvious change in CD206 expression might indicate that the activation of macrophages by Aβ peptides was not clear-cut M1 polarization but was instead a mixed state with some preference for M1 characteristics. Although helpful as a basic model, dichotomous separation of M1 and M2 macrophages

seemed to be an oversimplification. There has been increasing evidence that macrophages and microglia primarily express markers of both extremes and that each stimulus results in a specific activation state (Xue et al., 2014). Microglia in a Tg2576 AD mouse

model were shown to express genes of classical activation (TNFα and NOS2), together with genes associated with an alternative activation (CD206, ariginase I, chitinase-3-like-3) (Colton et al., 2006). This heterogeneity was also found in brain samples from AD patients (Sudduth et al., 2013). Interestingly, receptors binding Aβ-peptides such as TLR4, TLR2, RAGE or Scavenger receptors can induce pro- as well as antiinflammatory reactions of phagocytes for example by NFκB or MAPK signaling (Salminen et al., 2009, Canton et al., 2013 and Zhang et al., 2014). In line IDH inhibition with our data, Michelucci and colleagues found that the phagocytosis of Aβ1–42 oligomeres induced markers that were associated with the M1 polarization of microglia (Michelucci et al., 2009). M1 polarization markers are especially induced by those Aβ-peptide variants that accumulate in Aβ-plaques during the course of AD (Guntert et al., 2006). Most likely as a consequence, microglia in the brains of AD patients shows signs of M1 polarization (Michelucci et al., 2009, Varnum and Ikezu, 2012 and Sudduth et al., 2013). Several studies have shown, in murine AD models, that inhibiting Glutamate dehydrogenase the proinflammatory M1 polarization of microglia with omega-3 fatty acids, IL10 or IL4 improved cognitive performance

and reduced AD neuropathology (Varnum and Ikezu, 2012 and Hjorth et al., 2013). The general proinflammatory M1 polarization of phagocytes is also found outside the CNS in AD patients (Varnum and Ikezu, 2012). Proinflammatory cytokines, which induce M1 polarization, seem to inhibit the clearance of Aβ by macrophages (Town et al., 2005 and Yamamoto, 2008). This activity might be explained by the observed lower phagocytosis rate of M1 compared to M2 macrophages. However, we found that the phagocytosis-inducing effect of Aβ-peptides was similar in M1 and M2 macrophages. This result indicates that opsonizing pathogens with Aβ-peptides improves phagocytosis, but a concurrent differentiation in the direction of M1 macrophages may ameliorate this effect.

The mean total bilirubin for the entire group did not change from

The mean total bilirubin for the entire group did not change from selleck chemicals baseline (0.68 mg/dl) to 1 month (0.68 mg/dl). However, at 3 and 6 months after TARE, the mean bilirubin of the group was higher at 0.95 mg/dl and 1.05 mg/dl, respectively. A clinically significant increase defined as a rise above 1.2 mg/dl was only seen in two patients at 3 and 6 months. In these patients, the rise in bilirubin was associated with

an increased burden of disease. Absolute neutrophil or lymphocyte count did not substantially change from baseline to 1 month or 3 months after treatment. No patient developed neutropenia defined as a neutrophil count of less than 1500 per microliter. Clinically, two patients developed worsening ascites following treatment requiring hospitalization and/or intervention. It is unclear if their ascites were directly related to treatment or tumor progression. No variceal bleeding or encephalopathy was seen following treatment. One patient developed a duodenal ulcer months after TARE which

was attributed to antiangiogenic therapy. For all patients, median survival from the time of gemcitabine plus TARE was 12.3 months, and the time to local failure, defined as progression in the region targeted by TARE, was 7.1 months. In the five patients with liver-confined HCC there were one complete response, three partial responses, one patient with stable disease, and one patient with no response/progressive disease after treatment (Figure 4). Median time to local failure was 9.9 months and overall survival was 12.5 months AZD2281 mw for the patients with HCC. The eight patients treated for liver metastases had a median Terminal deoxynucleotidyl transferase survival of 9.2 months and time to local failure of 6.4 months (Table 2). Overall, these findings suggest

that radiosensitizing doses of gemcitabine can be combined with 90Y microspheres in patients with HCC and liver metastases. Despite the proven benefit of adding chemotherapy to radiation in most GI malignancies, combining chemotherapy with 90Y microspheres for HCC has not been previously studied. In the current study, we found that gemcitabine and 5-FU were effective radiosensitizing agents at noncytotoxic and clinically achievable concentrations in HCC cell lines treated with LDR (0.07–0.26 Gy/h). Interestingly, the level of radiosensitization with LDR was greater than what was observed in cells treated with SDR (2 Gy/min) under otherwise similar conditions. Sorafenib produced radiosensitization when administered after LDR; however, the doses required to radiosensitize were above a concentration which is achievable in patients. Given these results, gemcitabine and 5-FU are promising agents to combine with 90Y microspheres, whereas sorafenib may not produce more than an additive effect at clinically relevant concentrations. Gemcitabine and 5-FU are antimetabolites with different mechanisms of action.

However, the exposure of the crystalline structures could be bloc

However, the exposure of the crystalline structures could be blocked by inducible aggregation or by the repolymerizing colonies, owing to the WEBI conditions (Fig. 3c). The changes in the total mass following all pretreatments were negligible to within a reasonable error AG-014699 mw range, regardless of the conditions. For reference, the two major changeable components of the WEBI-based RS, xylan

(approximately 12.5%) and lignin (approximately 8.3%), did not exhibit significant reductions of mass compared to those (12.1% and 7.7%, respectively) of the original EBI pretreatment. Furthermore, the extracellular portion of the reducing sugars (for the WEBI-based system or only for EBI) after the irradiation did not change with significant variance (below 0.8%), and thus it was actually similar to the percent yield of the theoretical glucose maximum. The formation of a water barrier may have prevented a direct attack to an external protective layer composed of hemicellulose and a lignin complex, thereby indirectly generating ROS or directly involving the oxidative degradation of the recalcitrant wall. Moreover, if Cetuximab manufacturer water soaking helps to loosen the cell wall, then electrons have more space for extensive participation. However, the regulation of the substrate-specific or non-specific cascades via ROS in the WEBI system needs to be further investigated. Loss of the external layer components can also

occur during the general conventional processes [19]. As for the pretreatment involving ammonia-soaking, the loss of lignin is significantly different during the removal of 50–85% of the initial content [14] and [13]. Lastly, regarding the Histone demethylase use of external inhibitory compounds against either the hydrolysis or fermentation, although the theoretical yields of the WEBI-straw were not higher than those of lignocellulose pretreated using conventional methods, the generation of inhibitors, such as hydrogen peroxide,

HMF, and furfural, was either negligible or not detected. In terms of the hydrolysis and fermentation yields, the intentional removal of the inhibitors was found to result in higher substrate conversion (% maximum) compared with substrate conversation on inhibitor accumulation [17]. Furthermore, in this system, I hypothesized that any accumulation of hydrogen peroxide would gradually be reduced to low levels (<0.01 mM) because of its utilization in the ligninolytic cascade. Therefore, although the accumulation of hydrogen peroxide has negative effects on the fermentable yeast [4] and carbon sources [6], SSF still functions under constant pH. Using the same assumption for untreated samples, WEBI pretreatment and enzymatic digestibility steps resulted in a total of 22.4 g (untreated RS, 9.4 g) of glucose from 100 g of RS (Fig. 1). Furthermore, when 100 g of initial RS was consecutively subjected to WEBI pretreatment and then SSF, 10.6 g (untreated RS, 3.7 g; and EBI-RS, 9.

Further advantages of TCS are its non-invasiveness, low costs, hi

Further advantages of TCS are its non-invasiveness, low costs, high acceptance by the patients, and relative independence from movement artefacts. This has promoted the development of a number of clinical TCS applications especially in patients with movement disorders, and in patients who need

bedside I-BET-762 chemical structure assessment. An important milestone was the establishment of consensus guidelines on TCS in movement disorders [1], which was triggered by an activity of the European Society of Neurosonology and Cerebral Hemodynamics (ESNCH) in 2004. The use of ultrasound contrast agents offers an improved assessment on TCS of patients with acute stroke [15], [16] and [17], with brain tumors [18], and inflammatory brain disorders [19], but is still on an experimental level and will be reviewed in another chapter of this serial. The present paper reviews TCS studies without contrast agent application published in the past decade that assessed novel TCS applications, which can be, as a result, recommended for clinical use. These applications include

the monitoring of space-occupying lesions in acute stroke patients, the early and differential diagnosis of PD, and the postoperative position control of deep brain stimulation (DBS) electrodes. For TCS, a contemporary high-end ultrasound system, as applied also for transcranial color-coded cerebrovascular ultrasound, equipped with a 2.0- to 3.5- (1.0- to 5.0-) MHz transducer can well be used. It has to be considered that certain Epacadostat measurements, e.g., of the size of a hyperechogenic area are dependent on the applied ultrasound system and the individual system settings. System parameters, such as the width of ultrasonic Immune system beam, the line density, and even the age of the probe influence the image resolution. Therefore, reference values need to be obtained (and ideally updated for the same probe every 2–3 years) separately for each ultrasound system. The following system settings are recommended: penetration depth 14–16 cm, dynamic range 45–55 dB, and if selectable a post-processing preset with moderate suppression of

low echogenic signals (Table 1). Image brightness and time gain compensation are adapted visually and/or with using automated image optimization (available with high-end ultrasound systems). For the examination, the patient is posed in a supine position, and the examiner usually sits at the head of the examination table. The investigation is usually performed through the transtemporal bone window consecutively from each side with preauricular position of the ultrasound probe (Fig. 2). Other transcranial approaches used for specific questions are the foramen magnum, the transfrontal, and the transoccipital bone window. The latter two, however are more frequently insufficient to insonate in adults. The structures assessed at different planes and windows are detailed below.

1) The minor spread of the injection into the MeAD does not seem

1) The minor spread of the injection into the MeAD does not seem to have affected significantly the distribution of anterograde labeling in case 565, as inferred by the virtual absence of labeling in major MeAD projection fields, such as the accessory olfactory bulb, nucleus of the horizontal limb of the diagonal band, olfactory tubercle and nucleus reuniens (Canteras et al., 1995 and de Olmos et al., 1978; present observations). 2) MeAV projections to other Me parts,

medial sublenticular extended amygdala and medial BST, continuum referred to as the medial extended amygdala Proteases inhibitor (Alheid and Heimer, 1988 and de Olmos and Heimer, 1999), are much less dense than those from the MeAD or MePV (Fig. 4 and Fig. 6). Varicose foci in BST subventricular districts (Figs. 3A, B, 6A, B) were observed only after injections involving the MeAV (cases 564 and 565 and case 6 from Dr. GDC-0199 in vitro Newton

S. Canteras collection). 3) The MeAV, MeAD and MePV have similar projections to the ventral part of the lateral amygdaloid nucleus and posterior basomedial amygdaloid nucleus, but only the MeAV and MeAD target the amygdalostriatal transition area. On the other hand, MeAV projections to the main olfactory system are less dense and widespread than those from the MeAD or MePV. 4) Projections from the MeAV and MePV to the core region of the ventromedial hypothalamic nucleus have a similar distribution and density (Fig. 7). However, in contrast to the MeAV, the MePV innervates very robustly the shell of the ventromedial hypothalamic nucleus, the

intermediate periventricular nucleus and the tuberal nucleus (Fig. 7B). 5) The MeAD and MePV provide considerably denser inputs to the medial preoptic and ventral premammillary nuclei, key components of the reproductive hypothalamic network (Simerly, 2002 and Swanson, 2000) than does the MeAV (Figs. 3B, C, 7C, D). To confirm second the present anterograde tracing observations, injections of FG were placed in regions which were found to be substantially labeled in MeAV case 565 or in regions which, albeit sparingly labeled in MeAV case 565, are known to receive major inputs from other Me parts. The injection sites of representative cases of the different prosencephalic regions that were explored in the present work are illustrated in Fig. 8. One injection (case 181) was located in the caudal half of the lateral amygdaloid nucleus and did not spread over the amygdalostriatal transition area. Two injections (cases 737 and 738) were restricted to the posterior basomedial amygdaloid nucleus. One injection (case 740) encompassed the amygdalostriatal transition area and the lateral part of the central amygdaloid nucleus, infringing minimally on the medial part. Two injections were placed in the medial BST, one (case 752) in the anterior division, involving peripherally the lateral septal nucleus, and the other (case 762) in the posterior division.

It has been studied in 2 phase 2 randomized, double-blind, placeb

It has been studied in 2 phase 2 randomized, double-blind, placebo-controlled trials in Crohn’s disease. This article reviews the clinical efficacy and safety data of ustekinumab in Crohn’s disease in anticipation of the final results of the phase III development program in moderate to severe Crohn’s disease. Index 631 “
“In the caption to Fig. 4, the first sentence labels the Happy and Angry tasks incorrectly. The sentence should read:

“Mean dRT for facial expressions in Experiment 3 on Happy (dark circles; solid regression line) and Angry (light circles; dashed regression line) tasks (first task completed only). “
“The investigation of how intelligence and sex differences are manifested in the brain’s structure has become an exciting research question in the differential psychological approach in the last decade. Although there are no sex differences in general intelligence, sex differences in the relationship between general intelligence and brain structure have been observed. One of the earliest reports goes back to Haier, Jung, Yeo, Head, and Alkire (2005). selleck products In an MRI study using voxel-based morphometry (VBM), they demonstrated that, in women, intelligence is positively related to white matter volume in the frontal lobe, whereas men show positive intelligence-gray matter correlations in

frontal and parietal lobes. Thus, although the sexes do not differ in general intelligence, the neuroanatomical structures of intelligence are different for women and men. Burgaleta et al. (2012) tested the relationship between general intelligence and global brain features, like total and tissue-specific volumes, related to sex differences. Interestingly, their

findings are not in line with Haier’s results. Women showed a positive intelligence-gray matter volume relationship but no significant intelligence-white matter volume correlation was found. For men, no significant correlations between general intelligence and total volumetric measures were observed. The discrepant findings could in part be the result from different analysis methods. While Haier et al. (2005) explored the relationship on a regional level, Burgaleta’s study analyzed total Tacrolimus (FK506) volumetric measures. These studies provide first evidence that the correlation between intelligence and the brain structure is moderated by sex. While the focus of earlier studies lies mainly on volumetric differences using VBM, more recent studies investigated neural fiber tracts using diffusion tensor imaging (DTI) to analyze the white matter microstructure. Specifically, fractional anisotropy (FA), radial diffusivity (RD), and axial diffusivity (AD) provide estimates of the integrity and density of fibers and the degree of myelination. Even though there exists no sex difference in general intelligence on a behavioral level, it becomes apparent from the literature reviewed above that the relationship between intelligence and brain structure varies between the sexes.

Inclusion criteria were age >18 years, single stroke of ≥3 months

Inclusion criteria were age >18 years, single stroke of ≥3 months duration, unilateral upper limb weakness, completed

upper limb rehabilitation, and the presence of motor-evoked potentials in response to transcranial magnetic stimulation with the muscles either at rest or preactivated (to ensure potential for functional improvement14). Exclusion criteria were contraindications to transcranial magnetic stimulation (eg, epilepsy or seizures), cardiac pacemakers or metal implants in the head, severe spasticity (≥4 on the Modified Ashworth Scale [MAS]15), wheelchair-bound, or presence of dysphasia or cognitive dysfunction sufficient to limit the ability to provide SGI-1776 informed consent. All participants received 12 sessions (4wk) of TST with an experienced neurophysiotherapist

(S.F.R.L.). Each 30-minute session was divided into 6 sections of 5 minutes: stretching and warm-up, Small molecule library price grasp, grip, pinch, gross movements, and patient choice. The tasks were based around those required for the Action Research Arm Test (ARAT)16 and were practiced in a pseudo-randomized order in each session.10 Demographic and clinical variables were chosen that are commonly assessed in survivors of stroke in clinical and/or research settings and could be logically thought to have a potential influence on the amount of paretic arm use. Data were obtained from the assessments of the RCT. These variables included age, time since stroke (chronicity), Barthel Index,17 MAS,15 baseline ARAT,18 baseline upper CHIR-99021 order limb Fugl-Meyer Assessment (FMA),19 and change in ARAT and FMA 3 months after TST. The ARAT and FMA are standardized measures of upper limb function.16, 18 and 19 The ARAT is formed of 4 subsections: grasp, grip, pinch, and gross. Each task is scored out of 3 (high score means good function, maximum of 57). The FMA is formed of 4 subsections: shoulder, wrist, hand, and coordination. Each task is scored out of 2

(high score means good function, maximum of 66). The subsection scores were also included as potential predictors. The dependent variables were the average baseline MAL amount of use and the change 3 months after TST. The MAL requires participants to report how much (amount of use) they use their affected arm for a selection of daily activities. Ratings are from 0 (arm not used at all) to 5 (used as much as before the stroke). After confirmation that the 2 baseline assessments were not statistically different (paired t tests), mean values were used for the ARAT, FMA, and MAL. Spearman correlations were performed to determine whether clinical and demographic factors ( table 1) correlated with baseline MAL amount of use rating. Forward stepwise multiple linear regression analysesa were conducted to explore the variables that predicted baseline MAL amount of use and change in the amount of use 3 months after TST.

The atlas loop segment (V3) is created by a curved course of the

The atlas loop segment (V3) is created by a curved course of the artery around the atlas. The intracranial segment V4 is the section of the vertebral artery after penetrating the atlantooccipital membrane, dura mater and arachnoidea. At the clivus the right and left vertebral artery merge to form the basilar artery, which is a part of the intracranial posterior circulation. The diameter of vertebral arteries varies from 1.5 to 5.0 mm. Identical width of VA occurs in 25% of the population, in 65% the left vertebral artery is wider, whereas in the remaining 10% the

right vertebral artery is larger selleck chemicals [3]. Khan et al. found dominance of the left vertebral artery in 50%, and of the right vertebral artery in 25% in regard to the diameter

of the vessel [4]. The following congenital anatomic variations of the vertebral artery are described in the literature: vertebral artery aplasia and vertebral artery hypoplasia (VAH). Epigenetics inhibitor Aplasia of VA occurs in about 1% of the population [5]. Vertebral artery hypoplasia (VAH) is classified as a vessel with a diameter in the entire course of less than 2 mm [6], respectively less than 3 mm [7], or with a side difference equal or greater than 1:1.7 [8]. Additionally to the vessel diameter, another criterion contains reduced blood flow velocity and increased resistance index values in the ultrasonographic findings [1] and [9]. There is a tendency of compensatory increase in the vessel diameter of the contralateral vertebral artery of more than 5 mm [1]. These various definitions of the incidence of VAH are based on subsequent characteristics: a diameter of less than 2 mm was observed by the method of duplex ultrasonography by the authors Delcker and Diener in 1.9% of the population [6], a diameter of less than 3 mm was described by Touboul et al. in 6% of the

population [7]. Trattnig et al. set a side asymmetry in the ratio 1:1.7 for more than 10% of patients examined by ultrasonography [8]. Frequency of VAH (diameter equal or less than 2 mm) in the general population is 26.5% in unilateral and 1.6% in bilateral hypoplasia of the vertebral artery [10]. In terms of side difference, the right hypoplastic vertebral artery occurs in 6.2% of the population, while left vertebral hypoplasia is present less frequently in 4.5% PRKACG [2]. Visualization of vertebral artery is possible by ultrasonographic examination, by invasive or non-invasive angiography (MRA, CTA), and also by autopsy findings. As mentioned previously, a more narrow vessel lumen is present in the ultrasonographic image in vertebral artery hypoplasia, and additionally, blood flow parameters are defined by a reduced diastolic flow velocity associated with higher peripheral resistance. The resistance index (RI) is equal to or greater than 0.75. The peak systolic velocity (PSV) is usually less than 40 cm/s [1] and [5].

This result was supported by a separate analysis, which found tha

This result was supported by a separate analysis, which found that the median number of consecutive days with undetectable

HCV-RNA level before transplantation was 5.5 days (range, 0–88 days) for patients with observed recurrence compared with 99.5 days (range, 1–473 days) for patients with pTVR (P < .001, 2-sided Wilcoxon rank sum test). Outcomes did not appear to correlate with donor age or other donor characteristics, although given the small numbers of patients with recurrence and incomplete donor information for all patients, this observation is Bortezomib preliminary. Baseline population sequencing detected the presence of 2 variants associated with resistance to nucleotide inhibitors: L159F in 4 patients and N142T in 1 patient. Resistance analysis by deep sequencing was performed for 29 of

61 patients who showed virologic failure before transplantation or recurrence after transplantation with HCV-RNA level greater than 1000 IU/mL. 17-AAG purchase No NS5B mutant S282T was detected in any patient samples analyzed. Twelve of 29 patients developed other nucleoside inhibitor resistance–associated variants and only as minor subpopulations (<10% of population) in 11 of 12 patients (Table 4). All 4 patients with L159F at baseline relapsed and had the L159F variant at the time of relapse. The patient enough with N142T at baseline achieved SVR12. Phenotypic testing of the patient samples and site-directed mutants of the variants (N142T, L159F, V321A, and L320F) did not show any change in susceptibility to sofosbuvir (sofosbuvir fold-change, <2.0; data not shown). Observed minor variants, S282R and S282G, also were introduced by site-directed mutagenesis in replicons but failed to replicate in vitro precluding phenotypic analysis. No ribavirin treatment-associated mutations, M390I or F415Y, developed in patients who qualified for resistance testing. Eighty-nine percent of the 61 patients

receiving at least 1 dose of drug reported an adverse event (Table 3). The most common events were fatigue (38% of patients), headache (23% of patients), anemia (21% of patients), nausea (16% of patients), and rash (15% of patients). Two subjects discontinued treatment because of adverse events (pneumonitis and sepsis/acute renal failure). Eleven patients (18%) experienced serious adverse events; 3 of those events occurred in more than 1 patient: progression of hepatocellular carcinoma, obstructive umbilical hernia, and pyrexia (Supplementary Table 5 shows the full list of treatment-emergent serious adverse events). One treatment-emergent death as a result of sepsis occurred 15 days after the last dose of study drug.