Adult patients with histologically documented NSCLC who received ≥ 1 platinum-based chemotherapy regimen, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2, were potentially eligible for this study. Patients were excluded if they had a life expectancy of less than 1 month or had an indication for liver, renal, or heart failure. Thirty-four eligible patients

were enrolled in this study and PCI32765 asked for written informed consent. Information collected at baseline included sex, age, ECOG performance status, tumor size, histology, disease stage, lung tumor–related chest pain or dyspnea, time since last chemotherapy (interval from last chemotherapy to inclusion), times of CT-PFNECII, and platinum resistance. Protocol design, data collection, and analysis were solely the responsibility of the authors. Eligible patients were randomly assigned to receive either CT-PFNECII combined with second-line chemotherapy (standard pemetrexed or docetaxel dosing schedule) (combination group, n = 17) or second-line chemotherapy (standard pemetrexed or docetaxel dosing schedule) alone (chemotherapy

group, n = 17). If a patient received prior taxane treatment, such as docetaxel or paclitaxel, pemetrexed was given as second-line chemotherapy. Otherwise, docetaxel was given as second-line chemotherapy. Ethanol-cisplatin (5%) was freshly prepared with 10 mg (2 ml) of cisplatin (Qilu Pharmaceutical Co, Ltd, Shandong, China) dissolved into an ethanol solution BMS-354825 nmr of 20 to 30 ml Sirolimus in vitro with the final ethanol concentration of 5% (vol/vol). Next, the freshly prepared 20 to 30 ml of 5% ethanol-cisplatin solution was percutaneously injected into the lung tumor individually with a 22-gauge fine needle (Gallini Medical Devices, Via Frattini, Italy) under CT (GE Healthcare, Waukesha, WI) guidance, once a week. This procedure was performed weekly for two consecutive weeks, and a third week with no treatment completed one cycle. Single chemotherapy agent pemetrexed (Alimta; Eli Lilly and Company,

Indianapolis, IN) (500 mg/m2 as a 10-minute IV infusion on day 1 of a 21-day cycle) or docetaxel (Taxotere; Aventis Pharmaceuticals, Bridgewater, NJ) (75 mg/m2 as a 1-hour IV infusion on day 1 of a 21-day cycle) was administered IV 1 day after CT-PFNECII every 3 weeks as a cycle. Each patient in the combination group received one to two cycles of CT-PFNECII and four cycles of pemetrexed/docetaxel, and each patient in the chemotherapy group received four cycles of pemetrexed/docetaxel. Patients on the pemetrexed arm were instructed to take folic acid (350-1000 μg) orally daily beginning approximately 1 to 2 weeks before the first dose of pemetrexed and continuing daily until 3 weeks after the last dose of pemetrexed. A 1000-μg vitamin B12 injection was administered intramuscularly 1 week before the first dose of pemetrexed and was repeated approximately every 9 weeks until after discontinuation.

Dirigió más de 50 tesis doctorales con varios premios extraordinarios de doctorado. Sus estudios siempre tuvieron una clara aplicabilidad clínica, pues este era el objetivo final de todo su desarrollo científico. Fue sin duda un paradigma en nuestro medio del médico-científico que con base en unos sólidos conocimientos clínicos y fisiopatológicos pretendía trasladar su experimentación a la mejora de los procesos diagnósticos y terapéuticos en su especialidad. En el año 1992 fue nombrado jefe del servicio de Medicina learn more Interna del Hospital General Universitario de Alicante, en el que desempeñó una importante labor clínica e investigadora,

centrado principalmente en el desarrollo del área de Aparato Digestivo. Bajo su dirección el servicio de digestivo desarrolló diversas líneas de investigación que le han llevado a ser uno de los grupos más punteros del país en este ámbito. El desarrollo de su servicio

fue una de sus obsesiones. Miguel siempre tenía en mente nuevas maneras de fomentar el crecimiento de su gente, tanto en el aspecto asistencial como científico. En este sentido fue un jefe ejemplar, selleck monoclonal humanized antibody a él acudíamos en momentos de duda, y siempre encontramos un consejo o una acción con la que resolver nuestros problemas. Con él todo eran facilidades para el que quería crecer profesionalmente y no dudaba en ocuparse personalmente de todas las gestiones que fueran

precisas para el desarrollo del servicio o de sus adjuntos. Era un jefe sabio, también desde el punto de vista asistencial. Tenía un fino olfato clínico que le hacía adelantarse al diagnóstico más problemático, que llegó por desgracia hasta la sospecha de la propia enfermedad que ha acabado con su vida. Su calidad como médico era reconocida por todos los que le rodeaban y, especialmente, por sus pacientes, que sentían y sienten por él auténtica veneración. Era todo lo que un médico debe ser: inteligente, perspicaz, estudioso, educado, afable y con un magnífico trato personal. Entre los años 1999-2004 fue el primer presidente electo de la Asociación Española de Gastroenterología (AEG) y allí también RG7420 manufacturer dejó huella de su personalidad. Bajo su mandato la AEG inició el desarrollo que le ha llevado ha convertirse en una de las sociedades científicas más importantes y dinámicas del país. Su prudencia, inteligencia, y su magnífica mano izquierda para la resolución de problemas fueron conocidas por los principales colegas gastroenterólogos del país durante este periodo de tiempo. Su pérdida será sin duda muy sentida en la AEG, pero nos queda el recuerdo imborrable de un gran amigo y compañero. Con su marcha se va una importante figura de esta especialidad a nivel nacional.

G0900785 and by the Royal Society through the Paul Instrument Fund. The authors would

like to express appreciation to Clive Dixon, Mike Olsen, Ian Taylor, and Ian Thexton for fabrication of specialized glassware and equipment used in this work. The authors would like to also thank Prof. Ian Hall, and Prof. Peter Morris for useful discussions. A special thanks goes to Clémentine Lesbats for her assistance during the experiments. “
“By producing nuclear spin polarization far beyond that available at thermal equilibrium, hyperpolarization can provide improved sensitivity for NMR, enabling the detection of less concentrated molecules. In the area of molecular imaging, MRI has recently been used to study the distribution [1] and metabolism [2], selleck chemicals [3] and [4] of hyperpolarized substrates. For instance, multiple studies have reported on the conversion of hyperpolarized 13C-labeled pyruvate to its metabolic

products, alanine, lactate and carbonate in vivo [2], [3], [4], [5] and [6], in which higher lactate production is an important indicator of cancer. This technique is already being translated to the clinic and a first trial is ongoing [7]. Major hyperpolarization techniques include dynamic nuclear polarization (DNP) [8] and [9], spin exchange optical pumping polarization of noble gases [10] and parahydrogen induced polarization (PHIP) [11], [12], [13], [14], [15] and [16]. Parahydrogen is a spin isomer of hydrogen with an antisymmetric singlet spin state. By incorporating this pure spin state into a molecule through a hydrogenation reaction, LGK-974 purchase large signal enhancements have been observed in a variety of situations as first conceived by Bowers

and Weitekamp [12] and Pravica and Weitekamp [14]. In 2009, Duckett’s group developed a parahydrogen polarization technique that works without the need for the chemical modification of the substrate [17]. In this approach, Acetophenone the substrate and the parahydrogen bind to a catalyzing metal complex simultaneously, thus enabling polarization to be transferred to the substrate through the scalar coupling network. The polarized substrate is subsequently released, and replaced by new substrate which is polarized in turn. Such Signal Amplification By Reversible Exchange (SABRE) has already been applied to detect trace amounts of chemicals [18], [19] and [20] and used in conjunction with zero-field NMR spectroscopy [21]. According to a theoretical description of SABRE, the signal enhancement level depends on the binding kinetics and the magnetic field in which polarization transfer occurs [22]. In order to achieve better enhancement, new catalyst precursors have been developed to tune the binding kinetics. Enhancements can be boosted by using the bulky electron-donating phosphines of the Crabtree catalyst [23].

Natural breathing was emphasized and integrated into the practice

routine. The program was delivered by qualified instructors, trained by the first author. Five intervention classes were conducted in local senior centers, with 10–15 participants in each class. The intervention teaching protocol, including program fidelity, was monitored by the first author per criteria described previously (Li et al., 2013). Control: The control participants were asked to maintain their usual daily physical activities during the 14-week observational period. Baseline demographic descriptors and primary and secondary outcome measures were compared between study groups (Tai Ji Quan vs. control), using analysis of variance (ANOVA) for continuous PLX4032 order variables, chi-square test for categorical variables, or tests for proportions. The primary efficacy analysis used a repeated ANOVA model to determine differences between groups over time. The independent variable was intervention (Tai Ji Quan or Control), dependent variables were the primary and secondary outcome measures, and covariates were baseline values of outcome variables and other demographic factors, including age, gender, education, living conditions, and health status. When these demographic covariates were included in the models, the results did not change. Relationships between changes in MMSE and the

two physical performance and balance efficacy variables were evaluated diglyceride using Pearson’s correlation coefficient. All P values were 2-sided, and analyses were performed using SPSS 17.0 for Windows. The study flow chart INCB024360 is presented in Fig. 1. Baseline data on demographic, anthropometric, health status,

medical conditions, and habitual physical activity characteristics of the study participants by study conditions are shown in Table 1. Analyses assessing the comparability of the two groups indicated that they were well matched with regard to baseline descriptors. Further analyses on the level of leisure physical activity between the two groups over the 14 weeks also indicated no significant differences (P = 0.28). There was also no significant change in the level of physical activity reported by participants in the control condition. No participant dropped out of the study and all participants provided the outcome data. All Tai Ji Quan participants completed their 14-week training with a median class attendance of 22 sessions (range: 18–28 sessions). No adverse events or falls were observed during the course of intervention. At the end of the 14-week intervention, Tai Ji Quan participants exhibited significant pre-to-post-intervention improvements in MMSE scores (t = 8.9, P < 0.001). No within-group pre-to-posttest change was observed for the control group. Consequently, there was a difference in the improvements from baseline between the groups.

Twenty-seven of these areas had HGD/EAC, of which only 14 were detected by AFI, resulting in a sensitivity of 52% (14/27). Of the 93 areas with IM/LGD, 71 were normal on AFI, resulting in a specificity of 76% (71/93).

The overall accuracy of area-based analysis was marginally better than patient-based analysis at 71% (Fig. 4,Table 3). Of the 24 patients that were normal on AFI, 7 had HGD/EAC, 3 of whom were detected by irregular patterns on NBI (Fig. 3). Similarly, 84 areas seemed normal on AFI, of which 13 were HGD/EAC and 4 of them were detected Bcl-2 inhibitor by irregular patterns on NBI (Fig. 4). Under AFI imaging, 36 of a total of 120 areas appeared abnormal. When the 36 areas were further characterized with magnification NBI, 24 were found to have an abnormal mucosal pattern, of which 13 showed HGD/EAC and 11 showed IM/LGD on histology. Of the remaining 12 AFI abnormal areas that were found to have a normal pattern on NBI, only 1 area was found to have HGD/EAC (Fig. 4). In 84 areas that appeared normal on AFI, when further characterized by NBI, 17 were found to have irregular patterns, 4 of which were HGD/EAC. Thus, NBI was able to detect 4 additional areas that appeared normal

on AFI, increasing the cumulative sensitivity of tandem AFI/NBI on area-based analysis from 52% (14/27) to 67% (18/27). The accuracy of the 2 techniques used in tandem fashion and of AFI alone is shown in Table 2 (per-patient analysis) and in Table 3 (per-area analysis). Two of the 14 HGD/EAC patients (14.3%) were solely detected with AFI and Ruxolitinib research buy Liothyronine Sodium magnification NBI, after a negative examination under HD-WLE and negative random biopsy specimens. One of these 2 patients was detected with AFI and further

characterized with magnification NBI; the other one was detected with magnification NBI only after a negative AFI inspection. Thus, 2 of the 14 patients would have been missed if AFI and magnification NBI were not used. Of the 120 areas, 36 AFI images (17 HGD/cancer and 19 nondysplastic BE) and 44 magnification NBI images (21 HGD/cancer and 23 nondysplastic BE) of different areas were included in the testing set. The median score for the image quality for all examiners was 3 (good). The mean κ values for interobserver agreement for the patterns were, with AFI, 0.48 (95% CI, 0.40-0.57) and with magnification NBI 0.50 (95% CI, 0.42-0.58), and for the prediction of histology were, with AFI, 0.48 (95% CI, 0.39-0.57) and with magnification NBI, 0.50 (95% CI, 0.42-0.57). This prospective tandem study revealed a very modest overall accuracy of AFI and magnification NBI to detect HGD/EAC. In this study, on patient-based analysis, AFI alone had a sensitivity, specificity, and NPV of 50%, 61%, and 71%, respectively, and the overall accuracy for the detection of HGD/EAC patients was 57%.

We used microbiological and epidemiological surveillance data for England and Wales to estimate health outcomes attributable to influenza and other respiratory pathogens under the existing age- and risk-based national influenza vaccination programme. Our study shows that despite targeting vaccination at these vulnerable groups their disease burden is still disproportionately high compared with individuals in the same age group without co-morbidities, particularly in those under

65 years of age. Among 65+ year olds, the effect of underlying co-morbidities on hospitalisation and case fatality rates was less marked. Overall this age group contributed 93% all INCB018424 solubility dmso influenza-attributable deaths in hospital though only 29% of all admissions due to influenza (Table 3). Healthy children under 5 years of age had the highest influenza-attributable hospital admission rates, over 5 fold higher than 65+ year olds. Nearly 40% of the hospital admissions and consultations for influenza were in children under 15 years of age though annual mortality in this age group was low

at around 1.3/million population. Our study provides evidence to support the approach adopted in many developed countries Alectinib in vitro of targeting influenza vaccination at high-risk individuals and the

elderly. However, it also shows the limitation of such selective approaches in mitigating the consequences of disease in these vulnerable groups and suggests the need for additional prevention strategies. Vaccine coverage in England among those aged 65 years and over has been around 75% since 2005/6,17 meeting the target uptake recommended by the European Union Council for this age group.18 However, the relatively low vaccine efficacy in those aged 65 years and over19 limits its impact on morbidity and mortality 4-Aminobutyrate aminotransferase in this age group. Vaccine coverage in high-risk individuals under 65 years of age, such as those with cardiac, pulmonary or metabolic disorders, is low and has remained at around 50% since 2008/9 in England20 despite the recent experience with AH1N1 (2009) pandemic influenza which demonstrated the substantially higher morbidity and mortality in these groups.21 and 22 While vaccine uptake in these high-risk individuals needs to be improved, it is unlikely that this would be sufficient to abolish their morbidity and mortality differential given that vaccine efficacy against confirmed infection is only around 70% in a matched year in healthy adults23 and, if hospitalised with influenza, high-risk individuals have substantially higher case fatality rates (Table 3).

The spectrum from Complex I was always weak, and it was only observed at X-band frequencies; its intensity was too low to produce a spectrum at S-band frequencies.

However, it dominated the weak EPR spectra obtained with both the EGCG and GA in the slightly acidic pH range. The contributions from both Complexes II and III increased with increasing pH above pH 7, and above pH 12, only complex III was detected in the solutions which contained more than 2-fold excess of the poyphenols. At this high pH, the spectrum of a Cu(II) glycerol complex was observed from solutions with lower polyphenol concentrations. Thus Complex III might correspond to mixed polyphenol/glycerol complexes of Cu(II), but the formation of a complex between Cu(II) and EGCG with a similar spectrum to that of Complex III in Fig. 3d was observed using pure H2O as the solvent (i.e. without glycerol). All of the spectra from the Raf activation Cu(II) complexes are complicated by the presence of appreciable linewidth anisotropy; their analysis to produce estimates of rotational correlation Fulvestrant times is described below (after consideration of the frozen solution spectra). Representative frozen solution spectra from the Cu(II)/EGCG reaction at X-band and S-band frequencies are shown in Fig. 6 and Fig. 7

for a Cu:EGCG ratio of 1:5. The g// region in Fig. 6 is expanded to provide better clarity, since this represents the part of the spectrum where different complexes (indicated by stick

diagrams) can be discerned. The full range of X-band spectra is available as supplementary information (Figures S5-8). Very similar results were observed with the Cu:GA system and these are also available as supplementary information (Figures S9–12). The spectrum in Fig. 6a corresponds to the uncomplexed [Cu(H2O)6]2 + ion, and that in Fig. 6b belongs primarily to Complex I. Increasing the pH gave results that correspond to mixtures of all three complexes in different ratios (Fig. 6c and d) and at very high pH, Complex III was the major species detected (Fig. 6e). The “pepper” function in the Easyspin software package was used to simulate the spectra of the three mononuclear Cu-EGCG Lck complexes (Fig. 8), and their parameters are summarised in Table 1 along with the corresponding values derived by simulation of the Cu(II)/GA spectra. The various Cu-complexes are distinguished by a progressive shift in g// to lower values and A// to higher values from the uncomplexed ion through Complex I to Complex III (Table 1). Table 1 also includes the parameters for the Cu-glycerol complex, which can be formed at very high pH. However, since its g- and A-values differ significantly from those of Complex III, it can be concluded that polyphenol complexes dominate the spectra in high pH solutions with a Cu:EGCG ratio of 1:5.

Results with p-values of less than 0.05 were considered to be statistically significant. The size of all polystyrene particles was increased in DMEM + 10% FBS compared with distilled water (Table 1). The Epacadostat in vitro size increase of the amine-functionalized particles was larger than that of the carboxyl-functionalized particles and the size of smaller particles increased more than that of the larger particles. Sample heterogeneity for carboxyl-functionalized polystyrene particles, measured with the polydispersity index, was higher in DMEM + 10% FBS than in water, indicating a greater tendency for aggregate formation in protein-containing medium. The

opposite trends were seen for CNTs, in distilled water aggregates predominated and the polydispersity index was high, whereas in DMEM + 10% FBS sizes were much smaller and the polydispersity index lower. Zeta-potential values of carboxyl- functionalized polystyrene particles were negative when suspended in distilled water and positive for amine-functionalized ones. When suspended in DMEM + 10% FBS zeta-potential values of both polystyrene particle types were close to neutral.

Zeta-potential values of CNTs in distilled water and in DMEM + 10% FBS were in the slightly negative range. Transmission electron microscopical analysis showed that all CNTs were shorter than indicated by the producer with maximum length of 450 nm. CNT8, CNT20 and CNT50 had diameters of 4.7 ± 0.48, 18.9 ± 0.9 and 62.8 ± 5.7 nm, respectively.

To assess the influence ZD1839 datasheet MYO10 of nebulization on the particles, 20 and 200 nm carboxyl-functionalized polystyrene particles were also characterized in aerosols collected at the end of the glass tube. In addition to agglomerates predominant peaks at 46 nm for the 20 nm polystyrene particles and 234 nm for the 200 nm polystyrene particles were recorded, suggesting that the particles are stable in the aerosol. Cells cultured in ALI had a slightly lower viability (85 ± 8%) than those cultured in submersed culture, which may be due to a lower hydration of cells in ALI culture. The viability of ALI cultured cells exposed to solvent without particles from the VITROCELL PT/PARI BOY system was 110 ± 10% of the non-exposed cells in ALI culture and similar to cells cultured in submersed culture. Viability of cells exposed to aerosols without nanoparticles generated by MicroSprayer was 112 ± 7% of the non-exposed cells in ALI culture. TEER values were determined over two weeks to determine the stability of the ALI culture. Values increased during the first 13 days up to 230 ± 17.33  cm2 and subsequently decreased from day 16 on (Fig. 2a); cells were routinely used after 7–8 days of culture.

The hot plate was pre-heated and kept at a temperature of 55±0.5 °C. All rats were acclimated to the hot plate for 5 min, 24 h prior to testing, as, again, the novelty of the apparatus itself can induce antinociception (Netto et al., 2004). Rats were placed in glass funnels on the heated surface and the nociceptive Dabrafenib cell line threshold was assessed recording to the time taken to first response (foot licking, jumping, or rapidly removing paws), as described by Minami et al. (1994). Response was recorded in seconds (s) and a cutoff time of

20 s was used. After 11 weeks of chronic stress exposure, the rats of SN were subjected to a 20-min session of anodal tDCS every afternoon for 8 days. This period was established because tDCS has been shown to modify cortical excitability for up to 1 h after one session of stimulation (Nitsche and Paulus, 2000; Nitsche et al., 2003b). However, repetitive tDCS application has demonstrated better and longer-lasting effects on pain relief, and in recent study our group showed antihyperalgesic response in paw inflamed rats with this treatment period (Laste et al., 2012). The direct current was delivered from a battery-driven, trans-isomer in vivo constant current stimulator using ECG electrodes with conductive adhesive hydrogel. Rats’ heads were shaved for better adherence and the electrodes were trimmed to 1.5 cm2 for better fit. After placement, electrodes were fixed onto the head with adhesive tape (Micropore™)

and covered with a protective mesh to prevent removal (Fig. 5A). The anodal electrode was positioned between the ears, from the neck of the rat (parietal cortex) (Fig. 5B) (Takano et al., 2011 with modifications), so as to mimic anodal placement in human pain studies (Mendonca et al., 2011 and Dasilva

et al., 2012). The cathodal electrode was positioned at the midpoint of the lateral angle of the eyes (supraorbital area). The electrodes were placed on the skin in a similar manner to that used in human studies of tDCS for pain (Nitsche et al., 2008, Antal and Paulus, 2011, Rosen et al., 2009 and Fregni et al., 2006c). A constant current of 0.5 mA intensity was applied for 20 min (Fregni et al., Bcl-w 2006b, Dockery et al., 2011, Wachter et al., 2011 and Liebetanz et al., 2006). According to an earlier study (Liebetanz et al., 2009), a constant current of 1 mA intensity causes skin lesions, as current density is comparatively much higher than the traditional 1 mA tDCS using large pads in humans. We therefore chose to use 0.5 mA, an intensity that has also been used in other animal studies. In addition, in our study, electrodes were fixed onto the skin. We did not observe any lesions with montage and current intensity. An important point to consider was that this model required neither anesthesia nor surgery, unlike models used in the previous tDCS studies in rats (Dockery et al., 2011, Wachter et al., 2011 and Liebetanz et al., 2006).

Also, all sequences have a terminal Lys, but we do not know if they are removed

after post-translational processing as occurs in crotamine. All sequences described exhibited the characteristics of the β-defensin family, namely the six conserved Cys motif, small size (about 5 kDa), positive net charge, and high hydrophobicity ( Table 4). We analyzed three data sets by maximum parsimony: intronic sequences only, exonic sequences only, and the whole genes. In the case of snake β-defensin-like sequences, the best phylogenetic signal was obtained selleck screening library using the concatenated exonic and intronic sequences. In contrast, Luenser et al. (2005) analyzed caprine and ovine β-defensin-like sequences and found a phylogenetic signal only when intronic sequences were used to construct the phylogenetic tree. Phylogenetic analyses were done using parsimony and probabilistic approaches obtaining

three topologies (Fig. 3, Fig. 4 and Fig. 5). The best substitution model obtained using TreeFinder resulted in two models, TVM for intron 1 and HKY for the other partitions (intron 2, exons 1, 2 and 3) and they were used for both maximum likelihood and Bayesian analyses. All topologies showed three branches including non-β-defensins and β-defensin-like sequences of Crotalus and Lachesis and two lineages of Bothrops. check details The lineages were jararaca (B.jararaca_defensinB_01 and _02, B.atrox_defensinB_01, B.erythromelas_defensinB_01, B.pauloensis_defensinB_01, B.diporus_defensinB_03) and jararacussu (B.jararacussu_defensinB_01, B.leucurus_defensinB_01, B.neuwiedi_defensinB_02, B.mattogrossensis_defensinB_02 and 03), and the β-defensin-like genes of ‘neuwiedi’ (B. erythromelas, B. pauloensis, B. diporus, B. neuwiedi and B. mattogrossensis) and ‘atrox’ (B. atrox and B. leucurus) groups were recovered in Amrubicin both branches. Maximum parsimony and Bayesian analyses recovered B.neuwiedi_defensinB_02 together with B.matogrossensis_defensinB_01 and 02, both of the ‘neuwiedi’ group, though without support. The lineage jararaca which showed polytomy in Bayesian analysis, had low support in other analyses. The two paralogous β-defensin-like genes jararaca_01 and jararaca_02 may

have duplicated before the speciation of the ‘neuwiedi’, ‘jararacussu’ and ‘jararaca’ groups. The sequences B.mattogrossensis_defensinB_02 and _03 seem to be polymorphic sequences and not duplicated genes. In all trees, the low support of branches was probably due to lack of sequence sampling from other snake species groups as well in the same species and due to gene duplications. Thus, an increase in the number of sequences of the same species, and also a larger sampling in β-defensin-like sequences from other snake species, may improve the tree topology and branch support in future studies. The great number of gaps and only one sequence in that gap did not seem to affect the parsimony or Bayesian analyses but it seemed to be spurious in likelihood analysis.