Support system for decision making in the identification of risk for body dysmorphic disorder: A fuzzy model

PurposeTo develop a fuzzy linguistic model to quantify the level of distress of patients seeking cosmetic surgery. Body dysmorphic disorder (BDD) is a mental condition related to body image relatively common among cosmetic surgery patients; it is difficult to diagnose and is a significant cause of morbidity and mortality. Fuzzy cognitive maps are an efficient tool based on human knowledge and experience that can handle uncertainty in identifying or grading BDD symptoms and the degree of body image dissatisfaction. Individuals who seek cosmetic procedures suffer from some degree of dissatisfaction with appearance.MethodsA fuzzy model was developed to measure distress levels in cosmetic surgery patients based on the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV), diagnostic criterion B for BDD. We studied 288 patients of both sexes seeking abdominoplasty, rhinoplasty, or rhytidoplasty in a university hospital.ResultsPatient distress ranged from “none” to “severe” (range = 7.5–31.6; cutoff point = 18; area under the ROC curve = 0.923). There was a significant agreement between the fuzzy model and DSM-IV criterion B (kappa = 0.805; p < 0.001).ConclusionThe fuzzy model measured distress levels with good accuracy, indicating that it can be used as a screening tool in cosmetic surgery and psychiatric practice.     

Novel engineered TRAIL-based chimeric protein strongly inhibits tumor growth and bypasses TRAIL resistance

Targeting of the TRAIL-DR4/5 pathway was proposed as a promising approach for specific induction of apoptosis in cancer cells. Clinical trials, however, showed inadequate efficiency of TRAIL as a monotherapy. It is a widely held view that the application of multifunctional molecules or combination therapy may lead to substantial improvement. Here, we demonstrate the effectiveness and safety of a novel chimeric protein, AD-O51.4, which is a TRAIL equipped with positively charged VEGFA-derived effector peptides. The study was performed in multiple cancer cell line- and patient-derived xenografts. A pharmacokinetic profile was established in monkeys. AD-O51.4 strongly inhibits tumor growth, even leading to complete long-term tumor remission. Neither mice nor monkeys treated with AD-O51.4 demonstrate symptoms of drug toxicity. AD-O51.4 exhibits a satisfactory half-life in plasma and accumulates preferentially in tumors. The cellular mechanism of AD-O51.4 activity involves both cytotoxic effects in tumor cells and antiangiogenic effects on the endothelium. The presence of DRs in cancer cells is crucial for AD-O51.4-driven apoptosis execution. The TRAIL component of the fusion molecule serves as an apoptosis inducer and a cellular anchor for the effector peptides in TRAIL-sensitive and TRAIL-resistant cancer cells, respectively. The FADD-dependent pathway, however, seems to be not indispensable in death signal transduction; thus, AD-O51.4 is capable of bypassing the refractoriness of TRAIL. AD-O51.4-driven cell death, which exceeds TRAIL activity, is achieved due to the N-terminally fused polypeptide, containing VEGFA-derived effector peptides. The high anticancer efficiency of AD-O51.4 combined with its safety has led to the entry of AD-O51.4 into toxicological studies.     

Structure-activity relationships at human and rat A2B adenosine receptors of xanthine derivatives substituted at the 1-, 3-, 7-, and 8-positions

In the search for improved selective antagonist ligands of the A2B adenosine receptor, which have the potential as antiasthmatic or antidiabetic drugs, we have synthesized and screened a variety of alkylxanthine derivatives substituted at the 1-, 3-, 7-, and 8-positions. Competition for 125I-ABOPX (125I-3-(4-amino-3-iodobenzyl)-8-(phenyl-4-oxyacetate)-1-propylxanthine) binding in membranes of stably transfected HEK-293 cells revealed uniformly higher affinity (<10-fold) of these xanthines for human than for rat A2B adenosine receptors. Binding to rat brain membranes expressing A1 and A2A adenosine receptors revealed greater A2B selectivity over A2A than A1 receptors. Substitution at the 1-position with 2-phenylethyl (or alkyl/olefinic groups) and at N-3 with hydrogen or methyl favored A2B selectivity. Relative to enprofylline 2b, pentoxifylline 35 was equipotent and 1-propylxanthine 3 was >13-fold more potent at human A2B receptors. Most N-7 substituents did not enhance affinity over hydrogen, except for 7-(2-chloroethyl), which enhanced the affinity of theophylline by 6.5-fold to 800 nM. The A2B receptor affinity-enhancing effects of 7-(2-chloroethyl) vs 7-methyl were comparable to the known enhancement produced by an 8-aryl substitution. Among 8-phenyl analogues, a larger alkyl group at the 1-position than at the 3-position favored affinity at the human A2B receptor, as indicated by 1-allyl-3-methyl-8-phenylxanthine, with a K(i) value of 37 nM. Substitution on the 8-phenyl ring indicated that an electron-rich ring was preferred for A2B receptor binding. In conclusion, new leads for the design of xanthines substituted in the 1-, 3-, 7-, and 8-positions as A2B receptor-selective antagonists have been identified.     

Bereavement-related cognitive impairment in an oldest-old community-dwelling Brazilian sample

As it is already known that depression can cause a demonstrable impact on cognition in elderly subjects, the objective of this study was to determine whether also the mourning process is associated with any cognitive impairment in this age range. A random and representative sample (a sample with 77 subjects/total county population of oldest-old with 219 subjects = 35%) aged 80 years or more was selected from the county of Veranópolis in the Brazilian rural southern region. Of this group, the cognitive function of subjects without grief and of subjects with the presence of grief were compared. Five neuropsychological tests (the Buschke-Fuld Selective Reminding Test, the word-list from the CERAD battery, the Verbal Fluency Test, and two subtests of the Wechsler memory scale), the Mini-Mental State Examination (MMSE) and two self-perceived memory impairment questionnaires were used. Presence of depressive symptomatology was identified by the Yesavage Geriatric Depression Scale (GDS). The prevalence rates of some psychiatric diagnoses (syndromic general anxiety disorder, major and minor depression) were compared between the bereaved group and the control group. There was not a statistically significant difference between the scores of controls and subjects with grief in the GDS. The frequency of affective disorders in both groups did not differ. However, the recently bereaved elderly subjects presented a mild cognitive impairment when evaluated with the MMSE, with the digit span test and with Word-list neuropsychological memory test. Likewise these bereaved octogenarian subjects presented more frequently a diagnosis of 'aging-associated cognitive decline' when compared with non-bereaved oldest-old. These results suggest that the normal sadness and/or the chronic stress of the grieving process, even without the presence of an identifiable syndromal-level depression, are associated with memory and cognitive differences among the bereaved oldest-old. Cause-effect relationships, however, cannot be established from this cross-sectional correlational study: Grief may influence cognitive functioning in the elderly, but mildly cognitively compromised elderly persons may be more likely to experience strong grief reactions after loss.     

Immortalization and characterization of human myometrial cells from term-pregnant patients using a telomerase expression vector

An examination of cellular processes involved in myometrial function has been greatly assisted by the use of human myometrial cells in primary culture. However, these cells can be used only for several passages before they senesce, and responses to various agents change with time in culture. The use of transformed cells is limited, as they can be polynucleated and can lose or gain chromosomes. We have developed three telomerase-immortalized cell lines from term-pregnant human myometrium to eliminate variability between passage numbers and allow genetic manipulations of myometrial cells to fully characterize signal pathways. These cells have a normal karyotype and were verified to be uterine smooth muscle by immunocytochemical staining for smooth muscle cell-specific alpha-actin and high affinity oxytocin antagonist binding sites. The three cell lines and the cells in primary culture from which they were derived were examined by cDNA microarray analysis. Of >10 000 expressed genes, there were consistent changes in the expression of approximately 1% in the three immortalized cell lines. We were unable to detect any significant differences between primary and immortalized cells in signal pathways such as epidermal growth factor-stimulated epidermal growth factor receptor phosphorylation, insulin-stimulated Akt phosphorylation, oxytocin and lysophosphatidic acid-stimulated extracellular signal-regulated kinase 1 and 2 phosphorylation, myosin light chain phosphorylation, and interleukin-1 induction of IkappaBalpha degradation. The immortalized cells should be useful for a range of studies, including high throughput analyses of the effects of environmental agents on the human myometrium.