When co-incubated with infected alveolar epithelial cells in vitro, neutrophils from infected lungs strongly induced NETs generation, and augmented PF-00299804 concentration endothelial damage. NETs induction was abrogated by anti-myeloperoxidase antibody and an inhibitor of superoxide dismutase, thus implying that NETs generation is induced by redox enzymes in influenza pneumonia. These findings support the pathogenic effects of excessive neutrophlls in acute lung injury of influenza pneumonia by instigating alveolar-capillary damage. (Am J Pathol 2011, 179:199-210; DOI: 10.1016/j.ajpath.2011.03.013)”
“Induction

of inducible nitric oxide synthase (iNOS) may be involved in carcinogenesis of the stomach, because nitric oxide (NO) derived from iNOS can exert DNA damage Selleck BMS-777607 and post-transcriptional modification of target proteins. In the present study, we investigated the correlation between endoscopic findings and iNOS mRNA expression/NO-modified proteins in the gastric

mucosa.\n\nFifty patients were prospectively selected from subjects who underwent upper gastrointestinal chromoendoscopy screening for abdominal complaints. The Helicobacter pylori (H. pylori) status of patients was determined by anti-H. pylori IgG antibody levels. We classified the mucosal area of the fundus as F0, fine small granules; F1, edematous large granules without a sulcus between granules; F2, reduced-size granules with a sulcus between granules; and F3, irregular-sized granules with extended sulcus between granules. Gastritis was graded using the visual analog scale of the 123 Updated Sydney System. The expression of interleukin (IL)-8 and iNOS mRNA was assayed in gastric biopsy specimens by reverse transcription-polymerase chain reaction. NO-modified proteins were analyzed by Western blotting using novel monoclonal antibodies against nitrotyrosine.\n\nA total of 91.7% (11/12) of the F0 group was H. pylori-negative, whereas 94.7% (36/38) of the F1-3 groups was H. pylori-positive. Spearman’s analysis showed good correlation between the endoscopic grading and the score of chronic inflammation (r = 0.764) and glandular atrophy (r = 0.751). The

expression of IL-8 mRNA was significantly increased in F1, F2, and F3 cases compared with the F0 group, with no significant differences among them. iNOS mRNA was significantly increased in the F3 group compared with the other HDAC inhibitor groups, with increased nitration of tyrosine residues of proteins.\n\nThe proposed classification by chromoendoscopy is useful for screening patients for atrophic and iNOS-expressing gastric mucosa with NO-modified proteins in H. pylori-associated atrophic gastric mucosa.”
“In the present study, the role of kainate (KA) receptors in hypnosis and analgesia induced by emulsified inhalation anesthetics was investigated. A mouse model of hypnosis and analgesia was established by an intraperitoneal injection of emulsified enflurane, isoflurane or sevoflurane.

In contrast, recent ethnopharmacological studies suggested that many of the reported uses of several other palms do not

appear to have a strong physiological basis. This study has provided a useful assessment of the ethnobotanical and pharmacological data available on palms.”
“Objective. To examine the relationship between changes in time spent walking since middle age and incident functional disability. Method. In 2006, we conducted a prospective cohort study of 7177 disability-free Japanese individuals aged bigger than = 65 years who lived in Ohsaki City, Miyagi Prefecture, Japan. Participants were categorized into four groups according to changes in time spent walking based on two questionnaire surveys conducted in 1994 and in 2006. Incident functional IPI-145 purchase disability was 4 retrieved from the public Long-term Care Insurance database, and the subjects were followed up for 5 years. The Cox proportional hazards model was used to investigate the association between changes in time spent walking and the risk of incident functional disability. Results. Compared

with subjects who remained sedentary, the multivariate-adjusted hazard ratios (95% confidence intervals) were 0.69 (0.49-0.98) among those who became active and 0.64 (0.50-0.82) among those who remained active. These results did not alter when analyses were stratified by gender, age and motor function status. Conclusion. An increase in time www.selleckchem.com/products/prt062607-p505-15-hcl.html spent walking among sedentary adults is significantly associated with a lower risk of incident functional disability. (C) 2013 Elsevier Inc. All rights reserved.”
“An increase in ploidy (polyploidization) causes genomic instability in cancer. However, the

determinants for the increased DNA content of cancer cells have not yet been fully elucidated. In the present study, we investigated whether adhesion induces polyploidization in human selleck kinase inhibitor U87MG glioblastoma cells. For this purpose, we employed expression vectors that reported transcriptional activation by signaling networks implicated in cancer. Signaling activation induced by intercellular integrin binding elicited both extracellular signal-regulated kinase (ERK) and Notch target transcription. Upon the prolonged activation of both ERK and Notch target transcription induced by integrin binding to adhesion protein, cell cultures accumulated polyploid cells, as determined by cell DNA content distribution analysis and the quantification of polynucleated cells. This linked the transeriptional activation induced by integrin adhesion to the increased frequency of polyploidization. Accordingly, the inhibition of signaling decreased the extent of polyploidization mediated by protease-driven intracellular invasion. Therefore, the findings of this study indicate that integrin adhesion induces polyploidization through the stimulation of glioblastoma cell invasiveness.

These results also provide evidence that pacing may be related to positive outcomes after treatment.”
“ObjectivesTo (1) report a modified transfixation pin cast technique, using dorsal recumbency for fracture reduction, distal positioning of the pins in the epiphysis and distal metaphysis, and a hybrid cast, combining plaster AZD0530 order of Paris (POP) and fiberglass casting, and (2) report outcome

in 11 adult horses.\n\nStudy DesignCase series.\n\nAnimalsAdult horses (n=11) with comminuted phalangeal fractures.\n\nMethodsHorses were anesthetized and positioned in dorsal recumbency. The phalangeal fracture was reduced by limb traction using a cable attached to the hoof. Screw fixation in lag fashion of fracture fragments was performed when possible. Transfixation casting was performed using two 6.3mm positive profile centrally threaded pins with the 1st pin placed in the epiphysis of the metacarpus/tarsus at the center of, or slightly proximal to, the condylar fossa and the 2nd one 3-4cm proximal. A

hybrid cast was applied.\n\nResultsForelimbs were involved in 9 horses and the hind limb in 2. Pins were maintained for a minimum of 6 weeks. No pin loosening was observed at the time of removal (6-8 weeks). A pony fractured the distal aspect of the metacarpus at see more the proximal pin. Nine horses survived (82%); none of the horses developed septic arthritis despite the distal location of the distal pin, close to the fetlock joint.\n\nConclusionThis modified transfixation pin casting technique was associated with good pin longevity and could reduce the risk of secondary pin hole fractures and pin loosening.”
“123 Background: Taking into account Lazertinib cell line our rapidly ageing population, older people are of particular interest in studying health inequalities.

The aim of the present study is to examine the relation between socio-economic status and health-related functioning in older people and to find out how material factors (e.g. the lack of basic goods) and psychosocial factors (e.g. low self-efficacy) compare regarding the explanation of these socio-economic differences. Methods: Data came from 5061 Dutch men and women aged epsilon 55 years who participated in the longitudinal Study on Medical Information and Lifestyles Eindhoven (SMILE) study. Baseline data were collected between November 2002 and May 2004 and respondents were followed until May 2009 (follow-up range: 0-5 years). Multilevel analyses were used to study the association between educational level and longitudinal changes in physical and mental functioning (i.e. two subscales of the SF-36) and to study the relative contribution of material and psychosocial factors to this relation. Results: Low educational level was associated with poor initial physical and mental functioning. However, no further widening of these gradients was found during follow-up.

Methods: A cohort study was conducted RG7321 from over 5 years. A total of 59187 EMS transports of an Advanced Life Support (ALS) ambulance service were studied. Results: One hundred and three patient transports for allergic complaints were

analyzed. Fifteen patients received EMS epinephrine, and epinephrine was recommended for 2 additional patients who refused, for a total of 17 (17%) patients for whom epinephrine was administered or recommended. Emergency medical system epinephrine administration or recommendation was associated with venom as a trigger (29% vs 8%; odds ratio [OR], 4.70; 95% confidence interval [CI], 1.28-17.22; P = . 013), respiratory symptoms (88% vs 52%; OR, 6.83; 95% CI, 1.47-31.71; P = .006), and fulfillment of anaphylaxis diagnostic criteria (82% vs 49%; OR, 3.50; 95% CI, 0.94-13.2; P = .0498). Four (4%) patients received epinephrine after ED

arrival. Conclusion: Low rates of epinephrine administration were observed. The association of EMS administration of epinephrine ARN-509 cell line with respiratory symptoms, fulfillment of anaphylaxis diagnostic criteria, and low rate of additional epinephrine administration in the ED suggest that ALS EMS administered epinephrine based on symptom severity. Additional studies of EMS anaphylaxis management including ED management and outcomes are needed. (C) 2014 Elsevier Inc. All rights reserved.”
“Cell death in the germ line is controlled by both positive and negative mechanisms that maintain the appropriate number of germ cells and that prevent the possible formation of germ cell tumors. In the mouse embryo, Steel/c-Kit signaling is required to prevent migrating primordial germ cells (PGCs) from undergoing Bax-dependent apoptosis. In our current study, PXD101 solubility dmso we show that migrating PGCs also undergo apoptosis in Nanos3-null embryos. We assessed whether the Bax-dependent apoptotic pathway is responsible

for this cell death by knocking out the Bax gene together with the Nanos3 gene. Differing from Steel-null embryos, however, the Bax elimination did not completely rescue PGC apoptosis in Nanos3-null embryos, and only a portion of the PGCs survived in the double knockout embryo. We further established a mouse line, 4 Nanos3-Cre-pA, to undertake lineage analysis and our results indicate that most of the Nanos3-null PGCs die rather than differentiate into somatic cells, irrespective of the presence or absence of Bax, In addition, a small number of surviving PGCs in Nanos3/Bax-null mice are maintained and differentiate as male and female germ cells in the adult gonads. Our findings thus suggest that heterogeneity exists in the PGC populations and that Nanos3 maintains the germ cell lineage by suppressing both Bax-dependent and Bax-independent apoptotic pathways. (C) 2008 Elsevier Inc. All rights reserved.

Family, adoption and twin studies show that genetics influences suicidal behaviour. The serotonin transporter (5HTT) plays an important role in the pathophysiology of mood disorders and may also be involved in suicidal behaviour since 5HTT SIS3 inhibitor binding is decreased in the brain of suicide completers. Because the effect of genomic imprinting in the 5HTT gene on suicidal behaviour has not been investigated, we analysed the parent-of-origin effect (POE) of four 5HTT markers and the 3 differential expression of the 5HTT G2651T (rs1042173) alleles in suicide attempters affected by bipolar disorder. We performed a family based association study and ETDT/QTDT

analyses of the rs25531, HTTLPR, VNTR-2 and G2651T polymorphisms in 312 nuclear families with at least one subject affected by bipolar check details disorder. The main outcomes investigated in this study are bipolar disorder diagnosis, suicide attempts, suicidal behaviour severity and age at onset of bipolar disorder. We also compared the allele-specific

mRNA levels in lymphoblastoid cells from 13 bipolar suicide attempters and 8 bipolar non-suicide attempters. Allele 2651T was transmitted significantly more often to bipolar patients (P = 0.042). There was no significant difference between maternal and paternal transmission ratios. Furthermore, there was no significant difference in the ratio of T/G-specific mRNA expression between bipolar Selleckchem Lonafarnib attempters and non-attempters. These data do not support a role for differential allelic expression of 5HTT for suicidal behaviour in bipolar disorder. Small sample size and the fact that RNA was obtained from lymphoblastoid cell lines were some of the limitations of this study.”
“Little is known whether trabecular bone matrix mineralization is altered at the site of osteoporotic vertebral fractures. Bone mineralization density distribution (BMDD) was assessed in trabecular bone of acute, single-level compression fractures of the spine at various stages of fracture repair using

quantitative backscattered electron imaging (qBEI). The grading of the repair stage was performed by histological methods. From 20 patients, who underwent either kyphoplasty (n?=?18) or vertebroplasty (n?=?2), a vertebral bone biopsy was taken prior to cement augmentation. Six patients took bisphosphonates (BP) prior to fracture. Three study groups were formed: N1?=?early-, N2?=?late-healing and B?=?BP treatment at late healing stage. In general, all groups had an altered BMDD when compared to historical normative reference data. Mean matrix mineralization (CaMean) was significantly (p?<?0.001) lower in all groups (N1: -5%, N2: -16%, and B2: -16%). In N2, CaMean was -13.1% (p?<?0.001) lower than N1. At this stage, deposition of new bone matrix and/or formation of woven bone are seen, which also explains the more heterogeneous matrix mineralization (CaWidth).

“
“Formononetin is a novel herbal isoflavonoid isolated from Astragalus membranaceus and possesses anti-tumorigenic properties. In the present study, we investigated the anti-proliferative effects of formononetin on human non-small cell

lung cancer (NSCLC), and further elucidated the molecular mechanism Selleckchem Pfizer Licensed Compound Library underlying the anti-tumor property. MTT assay showed that formononetin treatment significantly inhibited the proliferation of two NSCLC cell lines including A549 and NCI-H23 in a time-and dose-dependent manner. Flow cytometric analysis demonstrated that formononetin induced G1-phase cell cycle arrest and promoted cell apoptosis in NSCLC cells. On the molecular level, we observed that exposure to formononetin altered the expression levels of cell cycle arrest-associated proteins p21, cyclin A and cyclin D1. Meanwhile, the apoptosis-related proteins cleaved caspase-3, bax and bcl-2

were also changed following treatment with formononetin. In addition, the expression level of p53 was dose-dependently upregulated after administration with formononetin. We also found that formononetin treatment increased the phosphorylation of p53 at Ser15 and Ser20 and enhances its transcriptional activity in a dose-dependent manner. Collectively, these VX-770 results demonstrated that formononetin might be a potential chemopreventive drug for lung cancer therapy through induction of cell cycle arrest and apoptosis in NSCLC cells.”
“Brown fat is specialized for energy expenditure, a process that is principally controlled by the transcriptional coactivator PGC-1 alpha. Here, we describe a molecular network important for PGC-1 alpha function and brown fat metabolism. We find that twist-1 is selectively expressed in adipose tissue, interacts with PGC-1 alpha, and is recruited to the promoters of PGC-1 alpha’s target genes to suppress mitochondrial metabolism and uncoupling. In vivo, transgenic mice expressing twist-1 in the adipose tissue are prone to high-fat-diet-induced obesity, whereas twist-1 heterozygous knockout mice are obesity resistant. These phenotypes are attributed

AZD5582 to their altered mitochondrial metabolism in the brown fat. Interestingly, the nuclear receptor PPAR delta not only mediates the actions of PGC-1 alpha but also regulates twist-1 expression, suggesting a negative-feedback regulatory mechanism. These findings reveal an unexpected physiological role for twist-1 in the maintenance of energy homeostasis and have important implications for understanding metabolic control and metabolic diseases.”
“The present study investigated the pharmacokinetics of meropenem and biapenem in bile and estimated their pharmacodynamic target attainment at the site. Meropenem (0.5 g) or biapenem (0.3 g) was 123 administered to surgery patients (n = 8 for each drug). Venous blood samples and hepatobiliary tract bile samples were obtained at the end of infusion (0.

Thereby two aspects are neglected, the income effects on micro level, and the integration ASP2215 datasheet of traditional firewood production systems for comparison. To fill this gap, an Environmentally Extended Social Accounting Matrix (ESAM) at the village level is developed and applied to a rural village in Tanzania. The objective is first to explore the integration of agroforestry systems in rural smallholder systems and second to analyze income effects of agricultural biomass production for bioenergy

purposes in comparison to firewood production. In order to distinguish the use of firewood from public and private tree resources, environmental accounts for changes in tree stocks (public and private) are included. Findings indicate the importance of including common firewood BMS-754807 production as a reference point The highest income effect for the poorest households derives from agroforestiy, which households

use as a source of firewood and fruits for sale or home consumption, followed by J. curcas, sugarcane and finally cassava. Agroforestry in general has been also found to substantially release the pressure on public forest reserves. (C) 2014 Elsevier B.V. All rights reserved.”
“The long gonadotrophin releasing-hormone agonists (GnRH-a) protocol of pituitary down regulation was widely used in controlled ovarian hyperstimulation (COH). Some clinicians prefer to use one cycle of oral contraceptives (OC) pretreatment

before the traditional long GnRH-a protocol. This study was aimed to investigate whether such pretreatment could reduce the incidence of ovarian hyperstimulation syndrome (OHSS) for patients with different ovarian responses in IVF/ICSI treatment. Participants undergoing IVF/ICSI treatment with long GnRH-a protocol of pituitary down regulation in luteal phase were recruited by their potential risk of OHSS into one group of SIS3 nmr suspected high responders (227 participants) and the other group of suspected normal responders (665 participants). As for the suspected high responders, pretreatment with OC could lower the serum LH level, LH/FSH ratio and E-2 level right after 14 days of pituitary down regulation. It could also lower the serum E-2 level before oocytes retrieval and the count of oocytes collected. The incidence of severe OHSS was also significantly decreased. Such effect of OC on hormone profile, follicular dynamics and incidence of OHSS was not discovered in the group of suspected normal responders.”
“OBJECTIVE. A few studies have reported on short-term outcomes of patients receiving imaging-guided injections into the foot articulations, but none have compared patient responses depending on the anatomic site injected. This study includes a large sample size facilitating the investigation of postinjection pain reduction overall and by specific articulation.\n\nMATERIALS AND METHODS.

Consistent with this, VEGF-B treatment rescued neurons from apoptosis in the retina and brain in mouse models of ocular neurodegenerative disorders and stroke, respectively. Interestingly, VEGF-B treatment at the dose effective for neuronal survival selleck compound did not cause retinal neovascularization, suggesting that VEGF-B is the first member of the VEGF family that has a potent antiapoptotic effect while lacking a general angiogenic activity. These findings indicate that VEGF-B may potentially offer a new therapeutic option for the treatment of neurodegenerative diseases.”
“The recent development of gamma-ray probes makes it possible to perform radioguided surgery for

primary hyperparathyroidism (PHPT). There have only been a few reports, however, regarding the use of a handheld gamma camera to detect parathyroid adenoma intraoperatively. The aim of this preliminary study was to assess the efficiency of a semiconductor Selleck GW4869 gamma camera (eZ-SCOPE AN) in navigation surgery for PHPT. The eZ-SCOPE is designed to be used as a handheld, regional diagnostic imaging device. Eleven consecutive patients with documented

primary hyperparathyroidism underwent surgery using this compact camera. Scintigraphy images of the neck by eZ-SCOPE were acquired: 1) before skin incision; 2) after adenoma location; 3) after adenoma excision; and 4) ex vivo imaging of the specimen. In scan-positive cases by preoperative Tc-MIBI, the eZ-SCOPE revealed parathyroid adenoma in all cases

(100%), whereas ultrasound and CT showed a single adenoma in 63.6 and 72.7 per cent of cases, respectively. Navigation surgery for PHPT using the eZ-SCOPE permitted intraoperative identification and removal of parathyroid adenoma in all cases. Scintigraphy images of the neck by eZ-SCOPE also revealed a single adenoma even before skin incision. Our results suggest that Tc-MIBI scintigraphy with the eZ-SCOPE is useful for navigation surgery for PHPT. The eZ-SCOPE is useful for skin marking and could be easily applied for minimally invasive radioguided parathyroidectomy in scan-positive cases.”
“The use of 1,4-dioxane or pyridine as solvents Caspase inhibitor clinical trial for the polymerization of isoprene mediated by the acid-functional SG1-based alkoxyamines N-(2-methylpropyl)-N-(1-diethylphosphono-2,2-dimethylpropyl)-O-(2-carboxylprop-2-yl)hydroxylamine (BlocBuilder MA) and N-(2-methylpropyl)-N-(1-diethylphosphono-2,2-dimethylpropyl)-O-(2-carboxyleth-2-yl)hydroxylamine results in an increase in the rate of consumption of the initiator and narrower molecular weight distributions of the resulting polymer. In pyridine, an improved control of the polymerization was also obtained for a non-acid-functional initiator, and the overall rate of polymerization increased.

\n\nResults and conclusion: Significant differences in genotype, allele and haplotype frequencies of PRNP 1368 polymorphism were not observed between AD and normal controls. There were no significant differences

in the 432 genotype and allele frequencies of the PRNP 1368 polymorphism between Korean VaD patients MK-2206 mw and normal controls. However, in the haplotype analysis, haplotype Ht5 was significantly over-represented in Korean VaD patients. This was the first genetic association study of a polymorphism outside the coding region of PRNP in relation to AD and VaD.”
“Manganese superoxide dismutase (leMnSOD) cDNA was cloned from the Antarctic bivalve Laternula elliptica. The full-length cDNA of leMnSOD is 1238 bp in length and contains an open reading frame of 681 bp encoding 226 amino acid residues including a putative mitochondrial

targeting peptide of 26 amino acids in the N-terminal region. The calculated molecular mass is 24.8 kDa with an estimated isoelectric point of 6.75. leMnSOD signatures from 185 to 192 (DVWEHAYY) and four conserved amino acids (H52, H11, D185, and H192) responsible for binding manganese were observed. Sequence comparison showed that leMnSOD had high levels of identity with MnSOD from Haliotis discus discus, Mizuhopecten yessoensis, and Crassostrea gigas (68%, 66%, and 59%, respectively). RT-PCR analysis revealed the presence of leMnSOD transcripts in all tissues examined. Quantitative real-time click here RT-PCR assay indicated that treatment with polychlorinated biphenyls (PCBs) significantly increased leMnSOD mRNA expression in an organ-, time-, and dose-dependent manner. The mRNA expression with exposure to PCBs at 0.1

and 10 ppb reached the highest level at 6 h and then recovered slightly from 6 to 48 h in the gill. In contrast, the expression of leMnSOD mRNA showed a see more different expression pattern related to PCB concentration in the digestive gland. The mRNA expression at 0.1 ppb PCBs increased up to 12 h and then decreased by 48 h, but increased immediately at 10 ppb PCBs. The leMnSOD was overproduced in Escherichia coli and purified. The recombinant leMnSOD showed maximum activity at pH 9.0, and it retained more than 50% of its original activity after incubation for 30 min at 40 degrees C. (C) 2009 Elsevier Ltd. All rights reserved.”
“This study was performed to test whether children born small for gestational age (SGA) with catch-up growth (CUG) could be associated with the early development of insulin resistance and the beta-cell dysfunction and to explore the impacts of height CUG and weight CUG on the insulin resistance in a Chinese population.

“
“Bisphosphonates are widely prescribed and highly effective at limiting the bone loss that occurs In many disorders characterized by Increased GSK1838705A in vitro osteoclast-mediated bone resorption, Including senile osteoporosis

In both men and women, glucocorticoid-associated osteoporosis, and malignancies metastatic to bone. Although they are generally well tolerated, potential adverse effects may limit bisphosphonate use In some patients. Optimal use of bisphosphonates for osteoporosis requires adequate calcium and vitamin D Intake before and during therapy. The World Health Organization fracture risk assessment algorithm Is currently available to determine absolute fracture risk in patients with low bone mass and Is a useful tool for clinicians In Identifying patients most likely to benefit from pharmacological 432 Intervention to limit fracture risk. This fracture risk estimate may facilitate shared decision making, especially when patients are wary of the rare but serious adverse effects that have recently been described for this class of drugs. Mayo Clin Proc. 2009;84(7):632-638″
“Objectives: The aim of this study is to identify the prognostic factors predicting remission and subsequent disease relapse in patients with differentiated thyroid cancer (DTC)

greater than 60 years of age. Materials and Methods: The institute thyroid cancer database had 4370 patients with DTC, of which 447 (10%) were aged bigger than 60. However, 9 patients were excluded www.selleckchem.com/products/BEZ235.html due to follow-up less than 1 year. The prognostic factors selleckchem in the remaining 438 patients were studied. Results: Among the 438 patients, 311 (71%) had only loco-regional disease (M-0) and 127 (29%) had distant metastases (M-1) at the time of initial presentation. The host factors predictive of distant metastases at presentation were female gender, primary tumor size ( bigger than 4 cm), follicular histology, and extra-thyroidal extension. Among M-0 patients, 195 (63%) achieved complete remission while only 12 (9%) M-1 patients did so. Average number of radioactive iodine (I-131) doses administered

to achieve complete remission was 2.3 (range, 1-6) and the mean cumulative dose was 3404 MBq (range, 925-46,250 MBq). In multivariate logistic regression among M-0 patients, follicular histology, nodal metastases, and surgical treatment lesser than total/near-total thyroidectomy and among M-1 patients, site of distant metastases (skeletal and multiple sites) were independent factors predicting non-remission. Among the patients (both M-0 and M-1) who achieved remission, factors associated with disease recurrence were primary tumor size ( bigger than 4 cm), nodal metastases, pulmonary metastases, and non-remission after first dose of radioactive iodine and were associated with greater chances of disease relapse.