The rate of sustainment may be unique to these early adopting pro

The rate of sustainment may be unique to these early adopting programs, and it is unknown whether these findings would generalize to later adopters. An additional limitation is sample attrition, which was examined through a series of bivariate multinomial logistic regression models. Associations between participation Trichostatin A chemical structure status at the follow-up (i.e., closure, hard refusal, or unable to be contacted, with participation as the reference category) and structural characteristics, smoking cessation medications, organizational barriers, and staff tobacco use were estimated for the 153 organizations with smoking cessation programs at baseline. There were no significant differences, but this may reflect the small cell sizes for the three types of nonparticipation.

Response bias was also examined for the full baseline sample of 897 organizations. At the bivariate level, participation status did vary by availability of a counseling-based smoking cessation program, profit status, sample type, organizational size, and administrator attitudes. These variables were entered into a multivariate model, which yielded only three significant differences. Publicly funded programs were less likely than privately funded programs to directly refuse to participate. Similar to prior research (Knudsen et al., 2005), larger programs were significantly less likely to close. Finally, having a counseling-based smoking cessation program was protective against closure. These differences suggest that some caution may still be warranted in interpreting the findings.

However, the finding that offering a counseling-based smoking cessation program protected against organizational closure suggests an additional benefit of offering this service. This study also provides the opportunity to consider the intersection of public policy and sustainment of clinical interventions. In 2008, New York was the first in the United States to institute a statewide policy requiring tobacco-free campuses and delivery of smoking cessation services by all licensed SUD treatment programs (Brown, Nonnemaker, Federman, Farrelly, & Kipnis, 2012; Eby, Sparks, Evans, & Selzer, 2012). Of the 10 New York SUD organizations that participated at follow-up, none discontinued their counseling-based smoking cessation programs, suggesting that state policy may play an important role in sustaining evidence-based practices. The majority of individuals who enter SUD treatment also use tobacco, placing them at heightened risk of SUD relapse, morbidity, and mortality. Nearly 40% of treatment organizations that Dacomitinib had adopted counseling-based smoking cessation programs discontinued this service over time.

The item was scored as: 1 = poor, 2 = fair, 3 = good, and 4 = exc

The item was scored as: 1 = poor, 2 = fair, 3 = good, and 4 = excellent; and (c) depression scale (nine items; Cronbach��s �� = .86), which assessed depressive symptoms (e.g., feeling low in energy or slowed down and trouble sleeping). The depression measure selleck chemicals Ganetespib has predictive validity (Lipman, Covi, & Shapiro, 1979). Each item was scored as: 1 = not at all, 2 = a little, 3 = somewhat, 4 = quite a bit, and 5 = extremely. Demographic characteristics were also included as covariates. These factors are gender (0 = female and 1 = male), age at T7, mean family income (T2 to T4), the highest level of parental education (T2�CT4), and the participant��s educational level at T7. Analysis Mplus software (L. K. Muth��n & Muth��n, 2007) was used to identify the developmental trajectories of cigarette use (N = 806).

For missing data (primarily due to individuals�� nonparticipation in waves of data collection), we applied the full information maximum likelihood approach (Schaefer & Graham, 2002). The dependent variable (smoking at each point in time) was treated as a censored normal variable. The independent variables predicting trajectory group membership were gender and age at T2. Each trajectory polynomial was set as cubic. The GMM analyses used a multinomial logistic regression model for unordered polytomous responses (B. Muth��n & Shedden, 1999). We used the minimum Bayesian information criterion (BIC) to determine the number of trajectory groups (G). To assure finding the maximum of the likelihood function, we used 50 random sets of starting values.

Each participant was assigned to a trajectory group with the largest Bayesian posterior probability (BPP). For each of the trajectory groups, an indicator variable was created, which had a value of 1 if the participant had the largest BPP for that group and 0 otherwise. The observed trajectory for a group was the average of tobacco use at each timepoint for participants assigned to the group (see Figure 1). Figure 1. Developmental trajectories of cigarette smoking extending from adolescence to age 32 (N = 806). Note. The smoking score categories are 5.00 = 1.5 packs a day or more, 4.00 = one pack per day, 3.00 = 1/2 pack per day, 2.00 = 1�C5 cigarettes/day … We reported the mean (SD) BMI for each of the trajectory groups, with and without statistically adjusting for the covariates cited above (i.e.

, gender, age at T7, family income at T2�CT4, parental education at T2�CT4, participant��s education at T7, age- and gender-adjusted BMI at T2, healthy habits at T6, physical health condition at T6, and depression at T6). SAS was then used to perform Drug_discovery logistic regression analyses to investigate the associations between the trajectory group membership and obesity (n = 584). The dependent variable was the indicator variable of obesity (BMI > 29.9) at T7.

Minor groove binders (MGBs)

Minor groove binders (MGBs) selleck products represent an interesting class of anticancer agents, which have been shown to be highly effective in in vitro and in vivo preclinical tumour models unresponsive to other antineoplastic agents (Martin et al, 1981; Li et al, 1982, 1992; Hartley et al, 1988; D’Alessio et al, 1994; D’Incalci, 1994; Colella et al, 1999; Marchini et al, 1999; Geroni et al, 2002). The main representatives of this class, which reached the clinic, are the antitumour agents derived from CC-1065, that is, adozelesin, carzelesin, and bizelesin, and the distamycin A derivative tallimustine.

These ��classical�� MGBs have been shown to be highly DNA sequence-specific (Lee et al, 1993; D’Incalci, 1994) and to exert their cytotoxic effect through the ability to per se directly alkylate DNA mainly at the N3 position of adenines exposed in (TA)-rich sequences in the DNA minor groove (Hurley et al, 1984; Reynolds et al, 1985; Broggini et al, 1995, 1991; Sun and Hurley, 1992; D’Incalci, 1994; Marchini et al, 1998), without the requirement to be activated by other pathways (e.g., enzymatic activation of the drug). The absence of significant antitumour activity for nonalkylating MGBs (Marchini et al, 1998) indicates that the N3 alkylation activity of these compounds is a prerequisite for their cytotoxicity. MGBs activity, however, has previously been reported (Colella et al, 1999) to be associated with reduced susceptibility to the cytotoxic effect in tumour cells with defects in DNA mismatch repair (MMR), similar to certain chemicals, including MNNG, which alkylates O6 of guanines, and anticancer agents such as doxorubicin and cisplatin (Branch et al, 1995; Drummond et al, 1996).

MMR proteins recognise mismatched base pairs in the DNA, arising either spontaneously during DNA metabolism or from modified nucleotides provoked by physical and chemical agents, and are thought to link DNA damage recognition to an apoptotic pathway, thereby preventing mutagenesis, tumorigenesis, and tumour progression (Modrich, 1991; Fink et al, 1998). Tumours resulting from MMR-deficiency include the hereditary nonpolyposis colon cancer (HNPCC) and some sporadic carcinomas such as mammary, ovarian, or endometrial cancers (Peltomaki, 2001). The development of novel MGBs able to overcome the involvement of MMR assumes great clinical importance with respect to the treatment of tumours deficient in MMR.

A novel ��-bromoacryloyl derivative of distamycin Brefeldin_A A, PNU-151807, which exhibits no alkylating activity per se, has been identified (Marchini et al, 1999). The cytotoxic effect has been shown to not depend on MLH1 in some tumour cells (Colella et al, 1999) and has been attributed to the ��-bromoacrylic moiety of the compound, which seems to interfere with cell cycle progression via yet unknown pathways (Cozzi, 2000; Geroni et al, 2002).

There are less than 100 cases described in the literature, so thi

There are less than 100 cases described in the literature, so this study could help to clarify the behavior of this neoplasm. Additionally, the successful management of severe evisceration that complicated the postoperative stay of the patient is analyzed. The incidence of this major postoperative complication is reported between 0.29 �C 2.3% (4,5). Evisceration is defined as the acute, complete disruption of the musculofascial layers, which results in herniation of the abdominal contents, usually the small bowel and omentum. Emergency surgical intervention is needed. This complication is potentially lethal and carries a mortality rate of approximately 25% (4). Cardiorespiratory failure accounts for 50% of deaths, while peritonitis has been reported as the cause in 15% of the cases (6).

Risk factors associated with death from acute wound failure are mechanical ventilation, female sex and advanced age. There are four main causes of wound evisceration: suture tearing through the fascia, knot failure, suture failure, and extrusion of abdominal contents between sutures placed too far apart. The most common and important factor is suture tearing through the fascia. Tissue healing is adversely affected by several factors, such as obesity, diabetes, renal failure, anemia, malignancy, postoperative increased intra-abdominal pressure, wound infection, glycocorticoids, antineoplastic agents or radiation. However, careful review would suggest that at least 50% of the cases are due to technical error (6).

Case report The patient, a nulliparous post-menopausal 76-years old Greek woman, was admitted to our Department because of abnormal findings during ultrasound examination of the pelvic organs. She had a history of hypertension and anxiety disorder under medical therapy. Her past surgical history was unremarkable. She was presented asymptomatic, but pelvic examination revealed bilateral non-motile ovarian masses and a second degree rectocele. Transvaginal ultrasound examination confirmed the diagnosis of bilateral ovarian masses, with a maximum diameter of 9 cm for the right and 7 cm for the left ovarian tumor. Their ultrasound characteristics were suggestive of cystic masses but with solid components. The ultrasound examination revealed also micropapillary elements into the tumor of the right ovary. The uterus was found normal with an endometrium thickness of 3 mm.

Cytological examination of cervical/vaginal smear (Papanikolaou examination) was negative for presence of malignant cells. The levels of serum cancer antigen CA-125 were elevated at 60.7 U/ml (normal ranges 0 �C 35 U/ml), while the others serum cancer antigen markers were into normal ranges. The appearance of the tumors at the computed tomography Entinostat (CT) examination was similar with that of the ultrasound examination. The possibility of ovarian malignant disease was high according to the results of CT.

Norberg, H Starkhammar, J-H Svensson Switzerland �C M Borner, R H

Norberg, H Starkhammar, J-H Svensson Switzerland �C M Borner, R Hermann, D K?berle, R Morant, O Pagani, C Sessa, R Stahel Thailand �C S Chakrapee-Sirisuk selleck Crizotinib United Kingdom �C N Bailey, F Daniel, D Dunlop, T Iveson, R James, E Levine, A Makris, A McDonald, L Samuel, M Soukop, W Steward, C Topham Uruguay �C IM Muse USA �C J Eckardt, G Gross, G Justice, L Kalman, R Kerr, CG Leichman, E Levine, V Malhotra, R Pelley, MC Perry, J Posey, M Saleh, J Salvatore, J Wooldridge
Cystic fibrosis (CF), the most common lethal inherited disease among Caucasians, is caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR). CFTR is a cAMP-activated low-conductance chloride channel localized in the apical plasma membrane of secretory epithelial cells (Crawford et al.

1991). The most frequent mutation in the CFTR protein is a deletion of the phenylalanine at position 508 (��F508). This mutation belongs to a class of mutation in which CFTR protein fails to be properly processed and trafficked to plasma membrane (Cheng et al. 1990; Kartner et al. 1992). ��F508 CFTR is retained in the endoplasmic reticulum�CGolgi intermediate compartment (ERGIC) (Gilbert et al. 1998), then degraded by the ubiquitin-proteasome pathway (Jensen et al. 1995). The severe reduction or absence of CFTR in the apical plasma membrane of epithelial cells impairs several intracellular processes, including ionic exchange, in particular with enhanced Na+ absorption (Boucher et al. 1988) and reduced HCO3 ? secretion in the intestine (Pratha et al. 2000) and pancreas (Kopelman et al.

1988; Smith and Welsh 1992; Lebenthal et al. 1993; Choi et al. 2001). Various studies using CF cells have demonstrated changes in the expression and/or intracellular trafficking of secreted or membrane proteins, Cilengitide including MRP8 and MRP14 (migration inhibitory factor-related proteins) (Fanjul et al. 1995), the Na+/H+ exchanger (NHE3) (Ahn et al. 2001), Cl?/HCO3 ? exchangers, such as the downregulated in adenoma (DRA) or the putative anion transporter (PAT1) (Greeley et al. 2001), and the carbonic anhydrase IV (CA IV) (Fanjul et al. 2002). Regarding CA IV, usually transported to plasma membranes via the Golgi complex (Mairal et al.

AIM: To evaluate and characterize

AIM: To evaluate and characterize selleck kinase inhibitor the patterns of disease progression of metastatic or unresectable gastrointestinal stromal tumor (GIST) treated with imatinib mesylate, and to determine the prognostic significance associated with disease progression. METHODS: Clinical data and computed tomography (CT) images were retrospectively reviewed in 17 GIST patients who were treated with imatinib mesylate from October 2002 to October 2006. Apart from using size measurement for evaluation of tumor response [Response Evaluation Criteria in Solid Tumors (RECIST) criteria], patterns of CT changes during treatment were evaluated and correlated with clinical data. RESULTS: There were eight non-responders and nine responders.

Five patterns of CT change during treatment were found: focal progression (FP), generalized progression (GP), generalized cystic change (GC), new cystic lesion (NC) and new solid lesion (NS). At the end of study, all non-responders showed GP, whereas responders showed cystic change (GC and NC) and response according to RECIST criteria. Overall survival was significantly better in patients with cystic change or response within the RECIST criteria compared with GP patients (P = 0.0271). CONCLUSION: Various patterns of CT change in patients with GIST who responded to imatinib mesylate were demonstrated, and might determine the prognosis of the disease. A combination of RECIST criteria and pattern of CT change are proposed for response evaluation in GIST.

Keywords: Computed tomography, Gastrointestinal stromal tumor, Imatinib mesylate INTRODUCTION Gastrointestinal stromal tumors (GISTs) are uncommon neoplasms that arise from mesenchymal cells in the walls of the gastrointestinal tract and account for 0.1%-3.0% of all gastrointestinal neoplasms and 5.7% of sarcomas[1,2]. GISTs arise most often from the stomach (60%-70%), followed by small intestine (20%-25%), but rarely from the rectum (5%), esophagus, colon or appendix[3]. GISTs differ from the other mesenchymal neoplasms histopathologically by immunohistochemical expression of CD 117 (c-kit proto-oncogene)[4]. Surgical resection is the standard initial treatment for non-resectable GISTs. However, locally advanced and metastatic tumors of the peritoneum or liver can effectively be treated with imatinib mesylate (known as Gleevec in the United States, Glivec in the rest of the world, and previously referred to as STI 571; Novartis Pharmaceuticals, Basel, Switzerland), a selective-tyrosine kinase inhibitor[5,6]. The drug acts as a c-kit blocker and is highly effective in patients with advanced disease[7], with nearly half of the patients responding to Entinostat treatment[8]. For optimal clinical outcome, the accurate assessment of tumor response to imatinib mesylate has become important.

All the 241 subjects who met the prescribed eligibility criteria

All the 241 subjects who met the prescribed eligibility criteria were invited to participate, of which 115 completed a telephone survey between March and June selleckchem Bosutinib 2008. The survey comprised 57 questions concerning participants�� preferences and practices related to smoke-free buildings policies, including perceived barriers and motivators of implementation among those with no current policy. Paper survey forms were subsequently sent to 70 subjects who were unable to be reached after five callback attempts and who had not previously refused to participate via telephone. Among these subjects, 12 completed and returned the paper survey form. In all, 127 subjects completed either a phone or paper survey, yielding a response rate of 62%, excluding 36 subjects for whom both phone and mail contact was unattainable.

All survey participants were provided with $50 compensation. Data analyses were conducted using SPSS version 14.0 (SPSS Inc., Chicago, IL). Descriptive analyses, including frequency counts, were assessed and reported for key measures, including policy implementation and interest. A binary logistic regression model was also constructed to identify significant predictors of these measures. Dependent variables included self-reported implementation of a policy restricting smoking inside all the living units within any one building (yes, no) and self-reported interest in implementing a smoke-free policy (very/somewhat/a little interested/not at all interested). Assessed predictors included participant smoking status (nonsmoker or smoker), quantity of units owned and/or managed (2�C49, 50�C99, 100�C149, or 150 units), U.

S. Department of Housing and Urban Development (HUD) subsidy status (no HUD units or HUD units), as well as average building age (��10, 11�C20, 21�C30, or >30 years), size (2�C4, 5�C9, or 10 units), and construction type (all masonry, all wood-frame, or other). Results When compared with those who completed the paper survey, participants who completed the telephone survey were significantly more likely to manage and/or own units subsidized through HUD (��2, p = .043). Method of survey completion was unrelated to participant smoking status, quantity of units owned/managed, or building age, construction type, and size. Prevalence of policy implementation and support A total of 9% of respondents reported that smoking was prohibited inside all the living units that they owned and/or managed, and an additional 2% reported smoking restrictions within at least one of their buildings. Cilengitide Among the 110 respondents who reported that there were currently no smoking restrictions in any of their buildings, 75% indicated an interest in implementing a smoke-free policy.

1 I) These findings demonstrate that S1pr1 expressed by the MK l

1 I). These findings demonstrate that S1pr1 expressed by the MK lineage intrinsically controls platelet homeostasis. Normal MK development, platelet life span, and serum TPO levels in S1pr1-deficient mice What could be the reason for the severe thrombocytopenia in the absence of S1pr1? First we selleck chemicals Vorinostat showed that the life spans of platelets from S1pr1+/+, S1pr1+/?, or S1pr1?/? chimaeras and between WT and S1pr1+/? mutant mice was similar, excluding a reduced life span as cause for the reduced platelet counts (Fig. 2 A). We also excluded a defect in the release of TPO, the principle regulator of thrombopoiesis (Kaushansky, 2005a), as cause for the thrombocytopenia in S1pr1-null mutants (Fig. 2 B). Finally, we also could not find evidence for a gross defect in MK development, as we found similar numbers of megakaryocytic progenitor cells in WT and S1pr1?/? FL cells populations (Fig.

2 C) and a normal differentiation of WT and S1pr1?/? precursor cells into MKs both in vitro (Fig. 2 D) and in vivo (Fig. 2, E and F). Figure 2. Loss of S1pr1 does not change platelet life span, serum TPO levels, and MK development. (A) Platelet life span assays in the indicated genotypes. n = 3�C5 per genotype. (B) Serum TPO levels. n = 3�C5 per genotype. (C) Quantification of CFU-MK … Loss of S1pr1 increases MK size but has no effect on positioning and motility of MKs in vivo Next we examined whether S1pr1 controls platelet biogenesis for example by modulating MK motility or their positioning within the BM compartment. To address this question, we performed MP-IVM of calvarian BM (Junt et al.

, 2007) of two different sets of S1pr1+/+ or S1pr1?/? chimaeras, in which MKs and their progeny were genetically marked: (a) S1pr1+/+ or S1pr1?/? CD41-YFPki/+ FL chimaeras, in which MKs and platelets express the YFP driven from the endogenous CD41 gene locus (Zhang et al., 2007) and (b) S1pr1+/+ or S1pr1?/? lenti-GpIb���Cenhanced GFP (EGFP) BM chimaeras, in which MKs and platelets express EGFP under the transcriptional control of the murine GpIb�� promoter (Lavenu-Bombled et al., 2007). The experiments revealed neither differences in MK size nor in their positioning or motility when we compared S1pr1+/+ CD41-YFPki/+ or S1pr1+/+ lenti-GpIb��-EGFP chimaeras and naive (nontransplanted) S1pr1+/+ CD41-YFPki/+ or platelet factor 4 (Pf4)�CEYFP transgenic mice, in which EYFP is driven by the MK-specific Pf4 promoter, which allowed excluding a major influence of irradiation and BM transplantation (Fig.

3, A�CD). As reported previously (Junt et al., 2007), S1pr1+/+ MKs were large, mostly Cilengitide sessile cells always located in close proximity to BM sinusoids (Fig. 3, A and D�CG). In S1pr1?/? chimaeras and S1pr1+/? mice, MKs were significantly larger compared with S1pr1+/+ chimaeras, whereas the position and motility of MKs was similar among all genotypes (Fig. 3, E�CG).

The main types of water sources for household chores and drinking

The main types of water sources for household chores and drinking Erlotinib HCl were similar in both arms as was the distance to the source (median distance 50 m and 30 m in the control and intervention arms, respectively). Storing water for longer than 2 d was more common among the intervention (26.8%) than the control arm (13.9%). Nearly 30% of all households reported treating water regularly before drinking. Boiling was the most common water treatment before the trial (20.2% in both arms). Table 1 Baseline community and household characteristics of a community-randomized trial of SODIS. Intervention and Attendance The NGO conducted 210 community events and 4,385 motivational household visits in intervention communities; 3,060 visits occurred in the households with children <5 y followed up and analysed for the study, and 1,325 household visits took place in homes that were not taking part in the study.

Study households attended a median of nine community events (IQR=5�C12) and were visited by the SODIS-programme team a median 11 times at home (IQR=7�C18). To ensure a sufficient number of PET bottles, the NGO provided as many SODIS-bottles as required by participants (mean 955 bottles/community). Diarrhoeal Illness in the Control and Intervention Arm Children in the SODIS-intervention arm reported a total of 808 episodes or a mean of 3.6 per child per year-at-risk (Table 2). In the control arm there were 887 episodes and an annual mean of 4.3 per child per year. In both arms median length of episodes was 3 d. The unadjusted relative rate (RR) estimate (0.81, 95% CI 0.59�C1.

12) suggested no statistically significant difference in the number of diarrhoea episodes between the SODIS and control arms of the study (Table 3). In an analysis of the longitudinal prevalence of diarrhoea we found no significant treatment effect (odds ratio [OR]=0.92, 95% CI 0.66�C1.29). Furthermore, no strong evidence was detected for the reduction of odds of severe diarrhoea cases (OR=0.91, 95% CI 0.51�C1.63) and dysentery (OR=0.80, 95% CI 0.55�C1.17). Table 2 Diarrhoea episodes, length of illness, and days ill with diarrhoea. Table 3 Effect of SODIS on diarrhoea episodes, longitudinal prevalence, severe diarrhoea, and dysentery episodes. A multivariable model adjusting for age, sex, baseline-existing water treatment practises, and child hand washing was consistent in its estimate of effect (RR=0.

74, 95% CI 0.50�C1.11). We repeated the analysis by including confounding covariates in the order of occurrence of the variables in Table 3 to confirm that the conclusions were not sensitive to the choice of covariates. Cilengitide None of the models yielded significant results for the effect of SODIS (all p-values>0.1) or resulted in meaningful changes in estimates of ORs. Figure 2 shows the relationship between study time and diarrhoea in the control and intervention arm.


TSA Therefore, in this case the ELISA that detect Ma2 autoantibodies can reliably identify about 47% of the SI-NET patients at the primary stage of the disease and the levels of autoantibodies correlate with the progression and recurrence free survival of the patients. Circulating levels of Ma2 autoantibodies did not seem to reflect the tumor mass per se as circulating levels for patients with lymph node or liver metastases with higher tumor load did not show significantly higher levels of autoantibodies. This supports the notion that Ma2 autoantibodies appear early during SI-NET development. These data pave the way for the possibility of using Ma2 autoantibodies as a reliable marker for tumor detection and progression of SI-NETs growth.

Furthermore, the identification of Ma2 as a target of the autoimmune response in patients with SI-NET may provide the first insights into the molecular mechanisms of paraneoplastic syndrome in patients with these tumors. We also presented preliminary results dealing with TLC and ALC. All blood and tumor samples of lung carcinoids tested so far by ELISA and immunohistochemistry on paraffin sections showed increased expression of Ma2 in comparison with normal internal tissues. This supports the view that Ma2 protein accumulation and the presence of Ma2 autoantibodies is closely associated with the development of several types of differentiated NETs. Our study shows that lower titer of Ma2 autoantibodies correlates to a lower probability of recurrence with longer survival of SI-NET patients. This finding contradicts those reported in other studies, for instance Graus et al.

detected autoantibodies, denoted anti-Hu antibodies, which recognize antigens expressed by neurons, in small-cell lung carcinoma that have been associated to patients’ longer survival [27]. Pujol et al. reported the presence of autoantibodies and spontaneous complete remission of a non-small cell lung cancer (SCLC) patient associated with anti-Hu syndrome. Moreover, like Graus et al, they concluded that the anti-Hu humoral immunology is associated to a positive tumor response [28]. However, a more recent study reported that onconeural antibodies, such as anti-Hu and anti-CV2/CRMP5 have a different behavior in different tumor types. Therefore, the prognosis of the same type of tumor may differ according to the type of analyzed onconeural antibodies [29].

The human immune system normally produces antibodies in response to foreign proteins, such those of pathogens, and ignores the body’s own cells proteins to avoid to trigger disease. Anacetrapib When the immune system fails to discriminate self from non-self, proteins start producing antibodies against self proteins denoted autoantibodies. A variety of theories have tried to explain why autoantibodies appear in different patient conditions. However, why humoral autoimmunity can cause diseases is not fully understood.