Genotype-phenotype relationships in fragile X syndrome: a family study.
Relationships between the measures of intellectual and physical status in the fragile X syndrome and the size of amplification of the fragile X-specific fragment, equivalent to the number of CCG repeats within the FMR1 locus, were studied by a maximum-likelihood scoring technique for analysis of pedigree data. This allows for estimation of random effects (genetic and environmental variance) concurrently with other (fixed) effects in a quantitative trait. FMR1 expression is usually shut down in males penetrant for the fragile X syndrome who have hypermethylated CCG amplifications of > or = 0.6 kb. The assumption of the step versus curvilinear function representing this relationship was tested by the likelihood-ratio criterion. The maximum-likelihood parameters were based on the most appropriate model for each measure. The results were indicative of the presence of a curvilinear relationship between the amplification size and the two intellectual scores, the Peabody Picture Vocabulary Test and Block Design Test, measuring verbal and spatial abilities, respectively. Reasons for the unexpected curvilinear regression between the amplification size and intellectual scores were explained further by methylation analysis of fragile X males with amplifications of 0.6 < delta < or = 1.2 kb who appeared to be responsible for the curvilinearity of the relationship. Four of these showed unmethylated status of the amplified bands in lymphocytes, which were presumably transcriptionally active. Removal of the aberrant individuals led to the anticipated step function between amplification and intellectual scores. For the combined anthropometric score, as well as for several single physical measures, the step function was the most appropriate model regardless of the inclusion or omission of the aberrant individuals in the pedigree sample.


Efficacy of kinesio taping in early stage breast cancer associated lymphedema: A randomized single blinded study.
This study was designed to evaluate the effectiveness of kinesio taping compared to compression garment in treatment of early stage breast cancer-associated lymphedema (BCAL). Patients between 18-70-years old who had unilateral stage 1 BCAL were randomized into group I kinesio taping (KT) and group II compression garment (CG) for this single blinded study. KT was applied with a lymphatic correction technique in three-four day intervals for four weeks. At the end of the fourth week, patients were suggested to wear CGs. Patients in group II were treated daily for 23-hours in CGs. Education, preventive measures, and exercises were given to both groups. All patients were evaluated before the treatment (T0), immediate post treatment (T1), and three months after treatment (T2). Circumference differences were measured between the extremities with a nonelastic tape at five levels. Additionally, shoulder range of motion (ROM) was measured, and pain, heaviness, and sensation of tightness were evaluated with a visual analog scale (VAS). Thirty-five patients with stage 1 BCAL were included and randomized to the KT (n= 16) and CG (n= 19) groups. Demographic data and baseline clinical characteristics were similar. Both groups had reductions in all levels of arm circumference differences at immediate post-treatment and three months after treatment. Pain, tightness, and heaviness scores significantly decreased for both groups at immediate post-treatment and third month. Patients in the KT group had significantly lower pain sores than patients in the CG group. Results demonstrated that both modalities had similar effects in the treatment of early stage BCAL. For patients with early stage BCAL, KT can be an alternative treatment to CG for patients who have difficulties in obtaining and wearing CGs.


[Surgery for metastatic lung tumor from malignant tumor of liver, biliary duct and pancreas].
Resection of lung metastasis from malignant tumor of liver, biliary duct and pancreas has various controversial problems. These problems are that many patients have a progressive disease and there are few patients who can have resectable lesion. Generally the prognosis of these diseases is poor. In addition, the effect of pulmonary resection for lung metastasis from malignant tumor of liver, biliary duct and pancreas is unclear. We set out to investigate the outcome and usefulness of surgery in this group. From January 1999 to November 2012, 18 patients underwent a total of 21 surgeries. There were 11 men and 7 women with mean age of 66.6±10( range, 43 to 78). Primary diseases of these patients were hepatocellular carcinoma in 5, cholangiocellular carcinoma in 1, cholangiocarcinoma in 2 and pancreatic cancer in 10 patients. Disease-free interval from 1st local therapy such as surgical treatment for primary lesion was 50.8±28.7(range, 19 to 107) months. Numbers of lung metastasis were 1 in 15, 2 in 4 patients and 3 in 1 patient. Many metastasis were in right lower lobe. Numbers of wedge resection were 13, segmentectomy were 4, lobectomy were 2 in these patients. Average of total survival time was 38±34 months. Four patients were dead. The 14 patients are alive and 7 patients had no recurrence. Adjuvant therapy such as chemotherapy was important. One-year all over survival rate after 1st pulmonary resection was 88%, 3 or 5-years was 73%. We think that it's was good result. There is a possibility that surgery for metastatic lung tumor from malignant tumor of liver, biliary duct and pancreas is useful by control of primary lesion and selecting of patients and adjuvant therapy such as chemotherapy.


No gain in pain: psychological well-being, participation, and wages in the BHPS.
Accounting for endogeneity, unobserved heterogeneity, and sample selection in an unified framework, we investigate the effect of psychological well-being on wages and labour market participation using a panel from the British Household Panel Survey. We find the effect of psychological well-being on labour market outcomes to differ across gender. In particular, psychological distress significantly reduces participation across genders, but, conditional on participation, has a significant negative effect on hourly wages only in the female sample.


Oxygen free radicals in erythrocytes during open heart operation.
This study was performed to observe the effect of myocardial ischemia on the patients undergoing cardiopulmonary bypass (CPB) operation. For this aim, superoxide dismutase (SOD) activities, reduced glutathione (GSH) and lipid peroxide (LP) levels were determined in blood samples which were obtained from the coronary sinus. Sampling times were as follows: (1) Before CPB. (2) Immediately after CPB. (3) Fifteen minutes after the second specimen. (4) Thirty minutes after the second specimen. SOD activities of these groups were 5135.10 +/- 278.51 U/g Hb, 3505.64 +/- 302.09 U/g Hb, 4206.55 +/- 272.25 U/g Hb, 4707.20 +/- 270.91 U/g Hb respectively. Also the LP levels were 1.90 +/- 0.29 nmol MDA/ml, 4.37 +/- 0.52 nmol MDA/ml, 4.09 +/- 0.39 nmol MDA/ml, 2.74 +/- 0.30 nmol MDA/ml respectively. GSH levels were slightly increased during ischemia and reperfusion; 103.27 +/- 5.18 mg/dl, 125.00 +/- 10.36 mg/dl, 125.00 +/- 6.61 mg/dl, 111.18 +/- 8.22 mg/dl respectively. SOD activities were reduced significantly in second group (p < 0.001), in third and fourth groups (p < 0.01) as compared with control group. Also LP levels were increased significantly in all groups (p < 0.001) as compared with controls. Our results confirm the generation of oxygen free radicals from ischemia and reperfusion of heart during CPB. Also it appears that oxygen free radical generation exceeds the capacity of intracellular SOD, which is the most important scavenger of free radical in the cell.


Effects of epinephrine, benzalkonium chloride, and intraocular miotics on corneal endothelium.
Drugs formulated for use both inside and outside of the eye were tested for their potential toxic effects on the corneal endothelium. Commercially available epinephrine 1:1000 was toxic to the corneal endothelium, but solutions diluted fivefold caused no endothelial damage. The toxic agent was the sodium bisulfite 0.1% preservative. Benzalkonium chloride is highly toxic to corneal endothelium in its commonly used concentration of 0.01% and had to be diluted one thousand times to prevent endothelial damage. Ophthalmic medications for extraocular use should never be used intracamerally. Miotics commonly used in surgery during intraocular lens implantation are generally nontoxic to the cornea, though caution is advised in the use of carbachol in patients with preexisting endothelial disease and in patients having procedures in which substantial mechanical trauma to the endothelium may occur.


[Heart rate variability and pulmonary infections after myocardial revascularization].
heart rate variability (HRV) is a noninvasive diagnostic method used in the assessment of the autonomic modulation of the heart. The assessment of HRV using nonlinear dynamics methods in the preoperative period of surgical myocardial revascularization could be predictive of morbidity such as pulmonary infections in the postoperative period. to evaluate the behavior of HRV using nonlinear dynamics in the preoperative period of surgical myocardial revascularization and its relation to the occurrence of pulmonary infections in the in-hospital postoperative period. a total of 69 patients with coronary artery disease (mean age of 58.6 ± 10.4 years) and indication for elective surgical myocardial revascularization were studied. In order to quantify the nonlinear dynamics of HRV, the following procedures were performed: detrended fluctuation analysis (DFA); analysis of the short (α1) and long-term (α2) components of DFA; approximate entropy (ApEn); Lyapunov exponent (LE); and Hurst exponent (HE) of time series of RR intervals of the ECG, as captured by the Polar S810i instrument on the day before surgery. at the cut-off levels set by the ROC curve, there was a significant difference between the groups with and without pulmonary infections in the postoperative period of myocardial revascularization for total DFA, approximate entropy and Lyapunov exponent with p = 0. 0309, p = 0.0307 and p = 0.0006, respectively. the nonlinear dynamics methods, at their respective cut-off levels, allowed for the identification of patients developing pulmonary infection in the postoperative period of surgical myocardial revascularization, thus suggesting that these methods may have a prognostic value for this group of patients.


Cardiac Kinetophagy Coincides with Activation of Anabolic Signaling.
Growing evidence has shown that endurance exercise is a strong inducer of autophagy in various tissues. Thus, we define here endurance exercise-induced autophagy as "kinetophagy" derived from the Greek terms "kineto" (movement), "auto" (self), and "phagy" (eating). Currently, the exact cellular mechanisms responsible for kinetophagy remain unclear; hence, we examined kinetophagy signaling transduction pathways occurring during acute endurance exercise (AEE). C57BL/6 mice were randomly assigned to either AEE (n = 7) or control sedentary group (CON, n = 7). After 5 d of treadmill running acclimation, mice performed 60 min of a single bout of treadmill running at 12 m · min(-1) on a 0% grade. Hearts were excised immediately 1 h after exercise and homogenized for Western blot analyses. Our data showed that AEE promoted kinetophagy flux (an increase in LC3-II to LC3-I ratio and LC3-II levels and a reduction in p62 levels) with Beclin-1 levels suppressed but Atg7 levels elevated compared with those in the sedentary group. We also observed that AEE increased lysosome-associated membrane protein and cathepsin L, linked to the termination process of autophagy, and that AEE augmented potent autophagy inducers (i.e., adenosine monophosphate kinase phosphorylation, BNIP3, and HSP70). Moreover, we found that exercise-mediated BNIP3 upregulation is associated with hypoxia-inducing factor 1α rather than FoxO3a. Intriguingly, we found for the first time that kinetophagy parallels with anabolic signaling activation (Akt and mammalian target of rapamycin). Our findings provide evidence that AEE results in kinetophagy without a time-associated elevation in Beclin-1 but with the presence of Akt-mTOR activation and that AEE-induced activation of anabolic signaling is not associated with kinetophagy promotion.


Guidelines for diagnosis and treatment of depression in patients with medical illness.
Many medically ill people report depressed mood. Differentiating a true depressive syndrome from the expectable mood change due to the presence of the medical illness is problematic. The author describes criteria potentially useful in making this diagnostic differentiation and reviews predictors of treatment response in primary depression, with the implication that use of these criteria is clinically appropriate until more data on secondary depression are available. It is often necessary to formulate treatment for medically ill depressed patients on the basis of empirical observations, that is, to use a treatment trial for diagnostic as well as therapeutic purposes. In such treatment circumstances, it is imperative to use unambiguous criteria to define a therapeutic response and to stop or change treatment if these criteria are not met.


Arg-Gly-Asp-containing domains of fibrillins-1 and -2 distinctly regulate lung fibroblast migration.
Development of the extracellular matrix is a critical feature of alveolar formation and actively involves pulmonary interstitial fibroblasts. The elastic fiber network is an interconnected system of load-bearing fibers that also influences the behavior of adjacent cells, particularly the interstitial lung fibroblasts (LF). We hypothesized that discrete domains of fibrillins-1 and -2 interact with LF integrins and direct their migration in the presence of platelet-derived growth factor (PDGF)-A. Surfaces coated with recombinant peptides lacking or including an arginine-glycine-aspartic acid (RGD) motif were used to study LF migration across porous filters and on protein-coated glass. Exon 24 of fibrillin-2 (Fib2 24), which encodes for an RGD-containing transforming growth factor-beta-binding (TB) domain, stimulated migration with greater directional persistence and more effectively stimulated trans-filter migration at low concentrations. Exons 36-44 of fibrillin-1 (Fib1 36-44), which include epidermal growth factor-like domains and an RGD-containing TB domain, induce more lamlellipodia and more widespread remodeling of the leading edge, resulting in greater migration velocity than did Fib2 24. Distinct structural features in regions that surround the RGD motifs may differentially regulate how the PDGF receptor-alpha promotes integrin distribution and actin filament remodeling at the cell's leading edge. Understanding how fibrillins regulate LF migration may help elucidate how the elastic fiber system could be restored as an interconnected unit, which fails to occur in emphysematous lungs.


[Adaptive transformation of rat myometrium with the progression of pregnancy and after parturition].
The myometrium of various parts of uterine wall was studied in 40 albino rats--non-pregnant animals, rats at different stages of pregnancy and after parturition. The methods of immunocytochemistry (detection of apoptotic cells with the help of antibodies against the tumor necrosis factor receptor), complex morphometic and cytochemical analysis of DNA content in the nuclei and of total protein in the cytoplasm of isolated smooth-myocytes (SM). The regularities of structural reconstruction of SM population in the uterine wall at various physiological periods were detected. The realization of basic mechanisms of myometrial transformation during the pregnancy, such as hyperplasia and hypertrophy are different in various uterine parts because of their specialized functional load. At the early stages of pregnancy, small SM were found to prevail in SM populations of all the uterine part, proliferative potential was increased. By the end of gestation, the fraction of large-sized SM was increased in the horns, the synthetic processes in the cytoplasm were activated, while the fraction of medium-sized SM was increased in the corpus and the cervix. The structure of SM population in the horns on Day 7 of postpartum involution was similar to that of non-pregnant rats, in the corpus and the cervix the increase of small SM number was observed.


Ab initio calculations of mechanical properties of bcc W-Re-Os random alloys: effects of transmutation of W.
To examine the effect of neutron transmutation on tungsten as the first wall material of fusion reactors, the elastic properties of W1-x-y Re x Os y (0 ⩽ x, y ⩽ 6%) random alloys in body centered cubic (bcc) structure are investigated systematically using the all-electron exact muffin-tin orbitals (EMTO) method in combination with the coherent-potential approximation (CPA). The calculated lattice constant and elastic properties of pure W are consistent with available experiments. Both Os and Re additions reduce the lattice constant and increase the bulk modulus of W, with Os having the stronger effect. The polycrystalline shear modulus, Young's modulus and the Debye temperature increase (decrease) with the addition of Re (Os). Except for C 11, the other elastic parameters including C 12, C 44, Cauchy pressure, Poisson ratio, B/G, increase as a function of Re and Os concentration. The variations of the latter three parameters and the trend in the ratio of cleavage energy to shear modulus for the most dominant slip system indicate that the ductility of the alloy enhances with increasing Re and Os content. The calculated elastic anisotropy of bcc W slightly increases with the concentration of both alloying elements. The estimated melting temperatures of the W-Re-Os alloy suggest that Re or Os addition will reduce the melting temperature of pure W solid. The classical Labusch-Nabarro model for solid-solution hardening predicts larger strengthening effects in W1-y Os y than in W1-x Re x . A strong correlation between C' and the fcc-bcc structural energy difference for W1-x-y Re x Os y is revealed demonstrating that canonical band structure dictates the alloying effect on C'. The structural energy difference is exploited to estimate the alloying effect on the ideal tensile strength in the [0 0 1] direction.


Competition in Biofilms between Cystic Fibrosis Isolates of Pseudomonas aeruginosa Is Shaped by R-Pyocins.
Pseudomonas aeruginosa is an opportunistic pathogen and the leading cause of morbidity and mortality in cystic fibrosis (CF) patients. P. aeruginosa infections are difficult to treat due to a number of antibiotic resistance mechanisms and the organism's propensity to form multicellular biofilms. Epidemic strains of P. aeruginosa often dominate within the lungs of individual CF patients, but how they achieve this is poorly understood. One way that strains of P. aeruginosa can compete is by producing chromosomally encoded bacteriocins, called pyocins. Three major classes of pyocin have been identified in P. aeruginosa: soluble pyocins (S types) and tailocins (R and F types). In this study, we investigated the distribution of S- and R-type pyocins in 24 clinical strains isolated from individual CF patients and then focused on understanding their roles in interstrain competition. We found that (i) each strain produced only one R-pyocin type, but the number of S-pyocins varied between strains, (ii) R-pyocins were generally important for strain dominance during competition assays in planktonic cultures and biofilm communities in strains with both disparate R- and S-pyocin subtypes, and (iii) purified R-pyocins demonstrated significant antimicrobial activity against established biofilms. Our work provides support for a role played by R-pyocins in the competition between P. aeruginosa strains and helps explain why certain strains and lineages of P. aeruginosa dominate and displace others during CF infection. Furthermore, we demonstrate the potential of exploiting R-pyocins for therapeutic gains in an era when antibiotic resistance is a global concern.IMPORTANCE A major clinical problem caused by Pseudomonas aeruginosa, is chronic biofilm infection of the lungs in individuals with cystic fibrosis (CF). Epidemic P. aeruginosa strains dominate and displace others during CF infection, but these intraspecies interactions remain poorly understood. Here we demonstrate that R-pyocins (bacteriocins) are important factors in driving competitive interactions in biofilms between P. aeruginosa strains isolated from different CF patients. In addition, we found that these phage-like pyocins are inhibitory against mature biofilms of susceptible strains. This highlights the potential of R-pyocins as antimicrobial and antibiofilm agents at a time when new antimicrobial therapies are desperately needed.


A randomized, placebo-controlled trial of Ginkgo biloba L. in treatment of premenstrual syndrome.
During the reproductive years, most of menstruating women experience symptoms of premenstrual syndrome (PMS), which is incapacitating in up to 10% of cases. According to complicated etiology, various therapeutic approaches have been proposed. Because PMS is a chronic situation, special attention should be paid to the side-effects of pharmacological interventions. Herbal medicine is a recent favorable therapeutic approach owing to fewer side-effects. We aimed to determine the effect of Ginkgo biloba L. on the symptoms of PMS. This was a single-blind, randomized, placebo-controlled trial conducted from November 2007 to April 2008. The students with PMS, living in dormitories of a medical university (Tehran), who met the inclusion criteria entered the study. The students filled out the daily symptom rating forms in two consecutive menstrual cycles. After we verified the PMS diagnosis in 90 students, the participants were randomly assigned to experiment and placebo groups and took G. biloba L. tablets (containing 40 mg leaf extracts) or placebo three times a day from the 16th day of the menstrual cycle to the 5th day of the next cycle. Data were collected using daily symptom rating forms. Eighty-five (85, 94.4%) participants completed the study. The two groups were similar in terms of demographic characteristics and baseline overall severity of symptoms. After the intervention, there was a significant decrease in the overall severity of symptoms and physical and psychologic symptoms in both Ginkgo (23.68%) and placebo (8.74%) groups (p < 0.001). However, the mean decrease in the severity of symptoms was significantly more in the Ginkgo group compared to the placebo group (p < 0.001). G. biloba L. can reduce the severity of PMS symptoms. Further research on active ingredients and also the efficacy and safety of various doses and treatment durations of Ginkgo are required.


Receptors on target cells. Receptors on airway smooth muscle.
Airway smooth muscle is a complex tissue that, in common with most other cell types, possesses a multitude of specific binding proteins that are coupled usually via guanine nucleotide regulation proteins to intracellular effector mechanisms. The development of sophisticated probes and biochemical approaches should allow an in-depth characterization of receptor subtypes, expression, regulation, and coupling to effector mechanisms that are activated as a consequence of ligand/receptor interaction. To date, most receptors in airway smooth muscle appear to be coupled via G proteins to these effector systems: PI turnover, adenylate cyclase, or phospholipase C. Qualitative and quantitative estimates of receptor proteins and the nature and efficiency of coupling to these effector mechanisms need to be linked to physiologic function and the regulation of airway smooth muscle response in health and disease.


Floral Scents and Fruit Aromas: Functions, Compositions, Biosynthesis, and Regulation.
Floral scents and fruit aromas are crucial volatile organic compounds (VOCs) in plants. They are used in defense mechanisms, along with mechanisms to attract pollinators and seed dispersers. In addition, they are economically important for the quality of crops, as well as quality in the perfume, cosmetics, food, drink, and pharmaceutical industries. Floral scents and fruit aromas share many volatile organic compounds in flowers and fruits. Volatile compounds are classified as terpenoids, phenylpropanoids/benzenoids, fatty acid derivatives, and amino acid derivatives. Many genes and transcription factors regulating the synthesis of volatiles have been discovered. In this review, we summarize recent progress in volatile function, composition, biosynthetic pathway, and metabolism regulation. We also discuss unresolved issues and research perspectives, providing insight into improvements and applications of plant VOCs.


Role of Hydroxysteroid Dehydrogenase-Like 2 (HSDL2) in Human Ovarian Cancer.
BACKGROUND Ovarian cancer is a common type of malignant neoplasm. Its prognosis is poor because the disease is not well understood. Abnormal lipometabolism in peroxisomes is involved in tumor progression and hydroxysteroid dehydrogenase-like 2 (HSDL2), localized in peroxisomes, might be a regulatory factor in lipometabolism. However, the role of HSDL2 in ovarian cancer progression remains unknown. MATERIAL AND METHODS HSDL2 expression was detected by qPCR and immunohistochemistry in ovarian tumor samples and qPCR in human ovarian cancer cell lines. Cell proliferation was measured by Celigo and MTT assay. Cell cycle distribution and apoptosis were determined using flow cytometry. Giemsa staining was used for analyzing colony formation. Cell motility was performed using Transwell migration and invasion assays. Tumorigenesis in nude mice was also detected. RESULTS HSDL2 expression was upregulated in human ovarian cancer samples and in 3 human ovarian cancer cell lines: SKOV3, HO8910, and OVCAR-3. Higher expression of HSDL2 in ovarian tumor samples was associated with more progressed tumors (P=0.03) and lymphatic metastases (P=0.03). HSDL2 down-regulation by lentiviral-mediated HSDL2 knockdown suppressed cell proliferation, colony formation, and cell motility, while it promoted cell apoptosis and resulted in cell cycle arrest at the G0/G1 phase in human ovarian cancer cell lines OVCAR-3 and SKOV3. HSDL2 knockdown also inhibited tumorigenesis in mouse models. CONCLUSIONS This study shows that HSDL2 upregulation is associated with ovarian cancer progression. HSDL2 knockdown inhibited cell proliferation, colony formation, motility, and tumorigenesis. It induced apoptosis and cell cycle arrest and might therefore serve as a potential target for ovarian cancer therapy.


A decision-tree approach to cost comparison of newborn screening strategies for cystic fibrosis.
Because cystic fibrosis can be difficult to diagnose and treat early, newborn screening programs have rapidly developed nationwide but methods vary widely. We therefore investigated the costs and consequences or specific outcomes of the 2 most commonly used methods. With available data on screening and follow-up, we used a simulation approach with decision trees to compare immunoreactive trypsinogen (IRT) screening followed by a second IRT test against an IRT/DNA analysis. By using a Monte Carlo simulation program, variation in the model parameters for counts at various nodes of the decision trees, as well as for costs, are included and applied to fictional cohorts of 100 000 newborns. The outcome measures included the numbers of newborns given a diagnosis of cystic fibrosis and costs of screening strategy at each branch and cost per newborn. Simulations revealed a substantial number of potential missed diagnoses for the IRT/IRT system versus IRT/DNA. Although the IRT/IRT strategy with commonly used cutoff values offers an average overall cost savings of $2.30 per newborn, a breakdown of costs by societal segments demonstrated higher out-of-pocket costs for families. Two potential system failures causing delayed diagnoses were identified relating to the screening protocols and the follow-up system. The IRT/IRT screening algorithm reduces the costs to laboratories and insurance companies but has more system failures. IRT/DNA offers other advantages, including fewer delayed diagnoses and lower out-of-pocket costs to families.


Hypoparathyroidism in beta-thalassemia major. Clinical and laboratory observations in 24 patients.
In the last 18 years, we have observed 24 cases of hypoparathyroidism (HPT) in beta-thalassemia major. At present, 4.5% of patients followed regularly in our department have this complication. HPT is thought to be mainly the consequence of iron deposition in the parathyroid glands. The age of our patients when HPT was diagnosed ranged from 11 to 24 years (mean 16.5 years). Their serum ferritin levels ranged from 810 to 15,200 ng/ml (mean 3,772 ng/ml). The severity of HPT varied widely. In only 3 patients was hypocalcemia severe with signs of tetany, seizures or cardiac failure. The onset of HPT was preceded or followed in most patients by other endocrine and/or cardiac complications. We found no clear relationship between HPT and serum ferritin levels in our patients, suggesting either an individual sensitivity to iron toxicity or early damage of the parathyroid gland before chelation had reduced the iron overload. However, the diagnosis of no new cases of HPT in the last 3 years coinciding with the much improved regime of chelation therapy suggests that chelation may have helped to prevent the development of HPT.


Study of chemical changes produced in virgin olive oils with different phenolic contents during an accelerated storage treatment.
Chemical changes produced in an extra virgin olive oil sample in the presence (EVOO) and absence (EVOOP) of its phenolic fraction during an accelerated storage treatment at 60 degrees C up to 7 weeks were studied. Modifications in phenol content, as well as changes in several quality parameters (free acidity, peroxide value, UV absorbance, fatty acid composition, oxidative stability index, and tocopherol content) were also evaluated under the same storage conditions and compared to those of the same sample deprived of phenolic compounds. When the phenolic extract of the EVOO was studied, a decrease of the antioxidants first present in the sample and an increase of the oxidized products were observed. In addition, oxidation seemed to produce the transformation of such phenolic compounds as secoiridoids and the appearance of oxidized forms of them. These latter compounds could be used as molecular markers of the lack of extra virgin olive oil freshness.


[Economic effectiveness of conservative and surgical methods of treatment of duodenal ulcer in young patients].
The work evaluates the results of treatment of duodenal ulcer in 152 young patients. The state's financial losses connected with their treatment by various methods are counted up. Prolonged nonoperative treatment was applied in 52 patients (group I), organ-preserving operations were carried out in 100 patients (group II). Group I patients felt much worse, most of them suffered from annual recurrences of the disease, 21% underwent various operative interventions later due to the development of complications. Good and excellent results were recorded in 86% of group II patients. It was established that not only are the clinical results better in group II patients, but the economical losses in timely performance of organ-preserving operations are half those in prolonged nonoperative therapy.


Implementation of a quality assurance program for computerized treatment planning systems.
In the present investigation, the necessary tests for implementing a quality assurance program for a commercial treatment planning system (TPS), recently installed at Sao Paulo University School of Medicine Clinicas Hospital-Brazil, was established and performed in accordance with the new IAEA publication TRS 430, and with AAPM Task Group 53. The tests recommended by those documents are classified mainly into acceptance, commissioning (dosimetric and nondosimetric), periodic quality assurance, and patient specific quality assurance tests. The recommendations of both IAEA and AAPM documents are being implemented at the hospital for photon beams produced by two linear accelerators. A Farmer ionization chamber was used in a 30 x 30 x 30 cm3 phantom with a dose rate of 320 monitor unit (MU)/min and 50 MU in the case of the dosimetric tests. The acceptance tests verified hardware, network systems integration, data transfer, and software parameters. The results obtained are in good agreement with the specifications of the manufacturer. For the commissioning dosimetric tests, the absolute dose was measured for simple geometries, such as square and rectangular fields, up to more complex geometries such as off-axis hard wedges and for behavior in the build up region. Results were analysed by the use of confidence limit as proposed by Venselaar et al. [Radio Ther. Oncol. 60, 191-201 (2001)]. Criteria of acceptability had been applied also for the comparison between the values of MU calculated manually and MU generated by TPS. The results of the dosimetric tests show that work can be reduced by choosing to perform only those that are more crucial, such as oblique incidence, shaped fields, hard wedges, and buildup region behavior. Staff experience with the implementation of the quality assurance program for a commercial TPS is extremely useful as part of a training program.


Non-viral risk factors for nasopharyngeal carcinoma in the Philippines: results from a case-control study.
In a case-control study of NPC conducted in the Philippines, 104 predominantly non-Chinese (< 10% ethnically Chinese) cases of nasopharyngeal carcinoma (NPC) and 205 hospital and community controls were recruited. Risk factor information was obtained through personal interview. The occupational history of each subject was reviewed "blind" by an industrial hygienist to determine estimates of exposure to formaldehyde, solvents, dusts, exhaust and pesticides. After control for confounding, subjects who were first exposed to formaldehyde 25 or more years prior to diagnosis/interview or wo were first exposed before the age of 25 were found, in relation to those never exposed, to be at a 4.0-fold excess risk of disease. Similarly, those first exposed to dust and/or exhaust 35 or more years prior to diagnosis/interview were at a 4.4-fold excess risk of disease and those first exposed before the age of 20 were at a 3.5-fold excess risk of disease. Salted fish consumption was not associated with risk, while consumption of processed meats protected against NPC. Smoking was positively associated with NPC, but only when cases were compared to community controls. Relative to non-smokers, subjects reporting more than 30 years of smoking were at an adjusted 7.2-fold excess risk of disease. Herbal medicine use and burning of anti-mosquito coils were both independently associated with risk of NPC, with ever-users of herbal medicines being at a 2.5-fold excess risk of disease and those reporting daily use of anti-mosquito coils being at a 5.9-fold excess risk of disease relative to never users. Exposure to solvents, pesticides, or use of betel nuts were not associated with NPC risk.


Does Tourniquet Use in TKA Increase Postoperative Pain? A Systematic Review and Meta-analysis.
Although tourniquets are commonly used during TKA, that practice has long been surrounded by controversy. Quantifying the case for or against tourniquet use in TKA, in terms of patient-reported outcomes such as postoperative pain, is a priority. The purpose of this study was to meta-analyze the available randomized trials on tourniquet use during TKA to determine whether use of a tourniquet during TKA (either for the entire procedure or some portion of it) is associated with (1) increased postoperative pain; (2) decreased ROM; and (3) longer lengths of hospital stay (LOS) compared with TKAs performed without a tourniquet. We completed a systematic review and meta-analysis using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guidelines to assess the impact of tourniquet use on patients after TKA. We searched the following databases from inception to February 1, 2015, for randomized controlled trials meeting prespecified inclusion criteria: PubMed, Embase, and Cochrane Central Register of Controlled Trials. Postoperative pain was the primary outcome. Secondary outcomes were postoperative ROM and LOS. The initial search yielded 218 studies, of which 14 met the inclusion criteria. For our primary analysis on pain and ROM, a total of eight studies (221 patients in the tourniquet group, 219 patients in the no-tourniquet group) were meta-analyzed. We also performed a subgroup meta-analysis on two studies that used the tourniquet only for a portion of the procedure (from osteotomy until the leg was wrapped with bandages) and defined this as half-course tourniquet use (n = 62 in this analysis). The Jadad scale was used to ascertain methodological quality, which ranged from 3 to 5 with a maximum possible score of 5. Statistical heterogeneity was tested with I and chi-square tests. A fixed-effects (inverse variance) model was used when the effects were homogenous, which was only the case for postoperative pain; the other endpoints had moderate or high levels of heterogeneity. Publication bias was assessed using a funnel plot, and postoperative pain showed no evidence of publication bias, but the endpoint of LOS may have suffered from publication bias or poor methodological quality. We defined the minimum clinically important difference (MCID) in pain as 20 mm on the 100-mm visual analog scale (VAS). We found no clinically important difference in mean pain scores between patients treated with a tourniquet and those treated without one (5.23 ± 1.94 cm versus 3.78 ± 1.61 cm; standardized [STD] mean difference 0.88 cm; 95% confidence interval [CI], 0.54-1.23; p < 0.001). None of the studies met the MCID of 20 mm in VAS pain scores. There was also no clinically important difference in ROM based on degrees of flexion between the two groups (49 ± 21 versus 56 ± 22; STD mean difference 0.8; 95% CI, 0.4-1.1; p < 0.001). Similarly, we found no difference in mean LOS between groups (5.8 ± 4.4 versus 5.9 ± 4.6; STD mean difference -0.2; 95% CI, -0.4 to 0.1; p = 0.25). A subgroup meta-analysis also showed no clinically important difference in pain between the full-course and half-course tourniquet groups (5.17 ± 0.98 cm versus 4.09 ± 1.08 cm; STD mean difference 1.31 cm; 95% CI, -0.16 to 2.78; p = 0.08). We found no clinically important differences in pain or ROM between patients treated with and without tourniquets during TKA and no differences between the groups in terms of LOS. In the absence of short-term benefits of avoiding tourniquets, long-term harms must be considered; it is possible that use of a tourniquet improves a surgeon's visualization of the operative field and the quality of the cement technique, either of which may improve the long-term survivorship or patient function, but those endpoints could not be assessed here. We recommend that the randomized trials discussed in this meta-analysis follow patients from the original series to determine if there might be any long-term differences in pain or ROM after tourniquet use. Level I, therapeutic study.


Cartilage regeneration in zebrafish depends on Nrg1/ErbB signaling pathway.
Objective: Cartilage, as the majority of adult mammalian tissues, has limited regeneration capacity. Cartilage degradation consecutive to joint injury or aging then leads to irreversible joint damage and diseases. In contrast, several vertebrate species such as the zebrafish have the remarkable capacity to spontaneously regenerate skeletal structures after severe injuries. The objective of our study was to test the regenerative capacity of Meckel's cartilage (MC) upon mechanical injury in zebrafish and to identify the mechanisms underlying this process. Methods and Results: Cartilage regenerative capacity in zebrafish larvae was investigated after mechanical injuries of the lower jaw MC in TgBAC(col2a1a:mCherry), to visualize the loss and recovery of cartilage. Confocal analysis revealed the formation of new chondrocytes and complete regeneration of MC at 14 days post-injury (dpi) via chondrocyte cell cycle re-entry and proliferation of pre-existing MC chondrocytes near the wound. Through expression analyses, we showed an increase of nrg1 expression in the regenerating lower jaw, which also expresses Nrg1 receptors, ErbB3 and ErbB2. Pharmacological inhibition of the ErbB pathway and specific knockdown of Nrg1 affected MC regeneration indicating the pivotal role of this pathway for cartilage regeneration. Finally, addition of exogenous NRG1 in an in vitro model of osteoarthritic (OA)-like chondrocytes induced by IL1β suggests that Nrg1/ErbB pathway is functional in mammalian chondrocytes and alleviates the increased expression of catabolic markers characteristic of OA-like chondrocytes. Conclusion: Our results show that the Nrg1/ErbB pathway is required for spontaneous cartilage regeneration in zebrafish and is of interest to design new therapeutic approaches to promote cartilage regeneration in mammals.


Statins Reduces the Risk of Dementia in Patients with Late-Onset Depression: A Retrospective Cohort Study.
Patients with late-onset depression (LOD) have been reported to run a higher risk of subsequent dementia. The present study was conducted to assess whether statins can reduce the risk of dementia in these patients. We used the data from National Health Insurance of Taiwan during 1996-2009. Standardized Incidence Ratios (SIRs) were calculated for LOD and subsequent dementia. The criteria for LOD diagnoses included age ≥65 years, diagnosis of depression after 65 years of age, at least three service claims, and treatment with antidepressants. The time-dependent Cox proportional hazards model was applied for multivariate analyses. Propensity scores with the one-to-one nearest-neighbor matching model were used to select matching patients for validation studies. Kaplan-Meier curve estimate was used to measure the group of patients with dementia living after diagnosis of LOD. Totally 45,973 patients aged ≥65 years were enrolled. The prevalence of LOD was 12.9% (5,952/45,973). Patients with LOD showed to have a higher incidence of subsequent dementia compared with those without LOD (Odds Ratio: 2.785; 95% CI 2.619-2.958). Among patients with LOD, lipid lowering agent (LLA) users (for at least 3 months) had lower incidence of subsequent dementia than non-users (Hazard Ratio = 0.781, 95% CI 0.685-0.891). Nevertheless, only statins users showed to have reduced risk of dementia (Hazard Ratio = 0.674, 95% CI 0.547-0.832) while other LLAs did not, which was further validated by Kaplan-Meier estimates after we used the propensity scores with the one-to-one nearest-neighbor matching model to control the confounding factors. Statins may reduce the risk of subsequent dementia in patients with LOD.


[Changes in corticosterone and aldosterone concentrations in various tissues of Xenopus laevis tadpoles during the metamorphosis].
During the metamorphosis of Xenopus laevis tadpoles, tissue concentrations of corticosterone and aldosterone did not change significantly in forelegs and hindlegs; they increased in tail, liver, skin and intestine. The rise of corticosteroid concentrations appeared in tissues which were deeply transformed during the first part of the climax, when plasma levels of corticosteroids also increased. Highest tissue levels, attained at the mid-climax, were maintained at least until the end of metamorphosis although plasma concentrations of two steroids were then abruptly fallen. Tissues able to retain corticosteroids reacted as Vertebrate "target tissues" and transformations which took place in them could be dependent, at least partially, on corticosteroids.


Quality of life in age-related macular degeneration: a review of the literature.
The Age-related Macular Degeneration Alliance International commissioned a review of the literature on quality of life (QoL) in macular degeneration (MD) with a view to increasing awareness of MD, reducing its impact and improving services for people with MD worldwide. A systematic review was conducted using electronic databases, conference proceedings and key journal hand search checks. The resulting 'White Paper' was posted on the AMD Alliance website and is reproduced here. MD is a chronic, largely untreatable eye condition which leads to loss of central vision needed for tasks such as reading, watching TV, driving, recognising faces. It is the most common cause of blindness in the Western world. Shock of diagnosis, coupled with lack of information and support are a common experience. Incidence of depression is twice that found in the community-dwelling elderly, fuelled by functional decline and loss of leisure activities. Some people feel suicidal. MD threatens independence, especially when comorbidity exacerbates functional limitations. Rehabilitation, including low vision aid (LVA) provision and training, peer support and education, can improve functional and psychological outcomes but many people do not receive services likely to benefit them. Medical treatments, suitable for only a small minority of people with MD, can improve vision but most limit progress of MD, at least for a time, rather than cure. The White Paper considers difficulties associated with inappropriate use of health status measures and misinterpretation of utility values as QoL measures: evidence suggests they have poor validity in MD. There is considerable evidence for the major damage done to QoL by MD which is underestimated by health status and utility measures. Medical treatments are limited to a small proportion of people. However, much can be done to improve QoL by early diagnosis of MD with good communication of prognosis and continuing support. Support could include provision of LVAs, peer support, education and effective help in adjusting to MD. It is vital that appropriate measures of visual function and QoL be used in building a sound evidence base for the effectiveness of rehabilitation and treatment.


Controlling acute rheumatic fever and rheumatic heart disease in developing countries: are we getting closer?
To describe new developments (2013-2014) in acute rheumatic fever (ARF) and rheumatic heart disease (RHD) relevant to developing countries. Improved opportunities for the primary prevention of ARF now exist, because of point-of-care antigen tests for Streptococcus pyogenes, and clinical decision rules which inform management of pharyngitis without requiring culture results. There is optimism that a vaccine, providing protection against many ARF-causing S. pyogenes strains, may be available in coming years. Collaborative approaches to RHD control, including World Heart Federation initiatives and the development of registers, offer promise for better control of this disease. New data on RHD-associated costs provide persuasive arguments for better government-level investment in primary and secondary prevention. There is expanding knowledge of potential biomarkers and immunological profiles which characterize ARF/RHD, and genetic mutations conferring ARF/RHD risk, but as yet no new diagnostic testing strategy is ready for clinical application. Reduction in the disease burden and national costs of ARF and RHD are major priorities. New initiatives in the primary and secondary prevention of ARF/RHD, novel developments in pathogenesis and biomarker research and steady progress in vaccine development, are all causes for optimism for improving control of ARF/RHD, which affect the poorest of the poor.


A phase I trial of pan-Bcl-2 antagonist obatoclax administered as a 3-h or a 24-h infusion in combination with carboplatin and etoposide in patients with extensive-stage small cell lung cancer.
Bcl-2 family genes are frequently amplified in small cell lung cancer (SCLC). A phase I trial was conducted to evaluate the safety of obatoclax, a Bcl-2 family inhibitor, given in combination with standard chemotherapy. Eligible patients (3-6 per cohort) had extensive-stage SCLC, measurable disease, ≤ 1 before therapy, Eastern Cooperative Oncology Group performance status 0 or 1, and adequate organ function. Patients were treated with escalating doses of obatoclax, either as a 3- or 24-h infusion, on days 1-3 of a 21-day cycle, in combination with carboplatin (area under the curve 5, day 1 only) and etoposide (100 mg m(-2), days 1-3). The primary endpoint was to determine the maximum tolerated dose of obatoclax. Twenty-five patients (56% male; median age 66 years) were enrolled in three dose cohorts for each schedule. Maximum tolerated dose was established with the 3-h infusion at 30 mg per day and was not reached with the 24-h infusion. Compared with the 24-h cohorts, the 3-h cohorts had higher incidence of central nervous system (CNS) adverse events (AEs); dose-limiting toxicities were somnolence, euphoria, and disorientation. These CNS AEs were transient, resolving shortly after the end of infusion, and without sequelae. The response rate was 81% in the 3-h and 44% in the 24-h infusion cohorts. Although associated with a higher incidence of transient CNS AEs than the 24-h infusion, 3-h obatoclax infusion combined with carboplatin-etoposide was generally well tolerated at doses of 30 mg per day. Though patient numbers were small, there was a suggestion of improved efficacy in the 3-h infusion group. Obatoclax 30 mg infused intravenously over 3 h on 3 consecutive days will be utilised in future SCLC studies.


The prevalence of psychiatric disorders in elderly residents of public housing.
This study estimates lifetime and one-month prevalence of psychiatric disorders among elderly public housing residents. Nine hundred forty-five residents of six public housing developments for the elderly were administered the General Health Questionnaire (GHQ), the Mini-Mental State Examination (MMSE), and the CAGE by lay interviewers. Residents screening positive and a 10% random sample of screen negatives were administered the Structured Clinical Interview for DSM-III-R (SCID) and a DSM-III-R derived algorithm for dementia and delirium. Prevalence rates were estimated based on weighted data from 298 subjects. Thirty-six percent of participants screened positive on at least one instrument. Based on the case identification interview, estimated lifetime prevalence of psychiatric disorders was 57.6%, and one-month prevalence was 27.9%. Cognitive disorder (10.5%), mood disorder (8.0%), psychotic disorder (4.6%), and substance abuse/dependence (4.4%) were the most common current disorders. Mood disorders (26.6%) and substance abuse/dependence (23.0%) were the most prevalent lifetime disorders. Compared to data from the Epidemiologic Catchment Area, public housing residents have higher current rates of mood disorder, schizophrenia, and substance use disorder. Elderly residents of public housing suffer higher rates of psychiatric morbidity than older people living independently in the community. The high prevalence of psychiatric disorders in this growing population of low-income elderly presents a challenge to the delivery of mental health service.


Safety and efficacy of rituximab biosimilar (CT-P10) in systemic sclerosis: an Italian multicentre study.
Recent data have shown a significant efficacy of rituximab (RTX) in SSc. An RTX biosimilar (RTX-B) is a more affordable option. We assessed the safety and efficacy of an RTX-B (CT-P10) in SSc. SSc patients treated with RTX-B with at least 6 months of follow-up were retrospectively identified from six Italian referral centres. SSc patients naïve to RTX-B (RTX-Bn) or already treated with RTX originator and switched to an RTX-B (RTX-Bs) were evaluated. A comprehensive assessment of disease characteristics and organ involvement at baseline and after 6 months was obtained. Thirty-three SSc patients were selected: 29 (87.9%) females, mean age 51.6 years (s.d. 14.2), mean disease duration 9.8 years (s.d. 8.1); 21 (64.5%) with dcSSc, 20 (60.1%) anti-topoisomerase I, 7 (21.2%) anti-RNA polymerase III and 6 (18.2%) anti-centromere positive. Seventeen (51.5%) were RTX-Bn and 16 were on RTX-Bs (48.5%). RTX was introduced because of skin progression in 18 patients (54.5%), interstitial lung disease (ILD) worsening in 11 (33.3%) and arthritis in 12 (36.4%). All patients were previously treated with immunosuppressants. At RTX-B introduction, 21 (63.6%) patients were on concomitant immunosuppressants: 15 (71.4%) on MMF and 6 (28.6%) on MTX. Twenty-three (69.7%) were on low-dose steroids. After 6 months, a significant reduction of the modified Rodnan skin score (mRSS), 28-joint DAS and CRP was observed (P = 0.002, 0.005 and 0.008, respectively); the mRSS significantly improved both in RTX-Bn (P < 0.024) and RTX-Bs patients (P < 0.031). No significant changes were observed for lung function tests, either in the entire cohort or in the subgroup of ILD patients. Only one RTX-Bs patient experienced transient neutropenia. Our data suggest that RTX-B can represent a cheaper option in SSc patients, as it is effective in improving skin and joint involvement and in stabilizing lung function.


Secondary structure of the self-cleaving RNA of hepatitis delta virus: applications to catalytic RNA design.
A model for the secondary structure of the self-cleaving RNA from hepatitis delta virus was tested. Specific base changes were introduced in each of four regions with the potential for base-pairing (stems I-IV), and for each variant sequence, a rate constant for cleavage was determined. In each stem, mutations that would interfere with Watson-Crick base-pairing also reduced the first-order rate constants by 10-10(4)-fold relative to the unmodified version. Within stems I and II and a shortened form of stem IV, compensatory changes resulted in rates of cleavage equal to or greater than the unaltered ribozyme sequence. Stem III compensatory mutants cleaved faster than the uncompensated mutants although they were not as active as the natural sequence, suggesting additional sequence-dependent requirements within this region. Structure probing of RNA containing the stem II mutations provided an independent confirmation of stem II in the ribozyme. The predictive value of the model was tested by designing two trans-acting ribozymes which were circularly permuted composites of genomic, antigenomic, and unique sequences. The core of these two catalytic RNAs was the same, but they otherwise differed in that, in one of them, a constraining tetraloop sequence was added to stem II. Both ribozymes catalyzed the trans cleavage of a substrate oligoribonucleotide, thus providing additional evidence for stem II and the proposed structure in general.


Translocation and enhancement of phosphotransferase activity of protein kinase C following exposure in mouse epidermal cells to oxidants.
We have studied changes in intracellular localization and phosphorylating activity of protein kinase C (PKC) in mouse epidermal JB6 cells treated with oxidants. Exposure to hydrogen peroxide, reagent grade or generated enzymatically by glucose/glucose oxidase, at concentrations known to result in elevated intracellular free Ca2+ resulted in an increase in binding of [3H]phorbol dibutyrate to intact cells. Ca2+ chelation, either intracellularly by quin 2 or extracellularly by ethylene glycol bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid, abolished the increase in radioligand binding. In contrast to H2O2, superoxide generated extracellularly by xanthine/xanthine oxidase or intracellularly by menadione was inactive. Scatchard plot analysis revealed that the enhancement in binding resulted from both increased receptor affinity and increased maximal binding capacity. Treatment of cells with superoxide, generated extracellularly by xanthine/xanthine oxidase or intracellularly by menadione, diminished the [3H]phorbol dibutyrate-binding capacity of the cytosol fractions prepared at low Ca2+ concentration. This decrease was not accompanied by a compensatory increase in the binding to membrane components. In contrast to superoxide, reagent H2O2, H2O2 produced by glucose/glucose oxidase, and the Ca2+ ionophore A23187 had no significant effect on the [3H]phorbol dibutyrate-binding capacities of either cellular fraction. Exposure of cells to low concentrations of extra- or intracellular superoxide resulted in an increase in the Ca2+- and phospholipid-dependent phosphorylating activity of cytosolic extracts towards adenosine diphosphoribose transferase which has been reported to be a specific substrate for PKC. The increase in phosphorylation could be diminished by the extracellular addition of copper-zinc-containing superoxide dismutase but not catalase suggesting that superoxide rather than H2O2 represents the active oxygen species in this reaction. The observation that reagent H2O2 or glucose/glucose oxidase failed to increase the phosphorylating activity of cytosolic preparations supports this conclusion. Treatment of cells or cytosolic extracts with the sulfhydryl reagent diamide stimulated the Ca2+/phospholipid-dependent phosphorylating activity toward adenosine diphosphoribose transferase. In a reconstituted system containing purified PKC, diamide induced a 25-30% increase in phospholipid-dependent phosphorylation of H1 whereas no change in activity was observed with the reducing agent dithiothreitol. It is concluded that H2O2 but not superoxide induces an increase in the phorbol ester binding, presumably to PKC, of intact JB6 cells. On the other hand


[Long-term outcome of Swanson prosthesis management of the rheumatic wrist joint].
Silicone-wrist arthroplasty has dominated reconstructive surgery of the rheumatoid wrist for a long time. Silicone interposition wrist arthroplasty yielded good clinical results in short and midterm studies. The durability and longevity of the prosthesis however is limited and progressive X-ray deterioration and silicone synovialitis are the main shortcomings. We present the ten-year follow-up results of 102 rheumatoid wrists operated between 1984 and 1992. 72 patients with 82 wrist arthroplasties were clinically and radiologically examined. The mean age at operation was 56.9 years. The average onset of R.A. was 16.1 years. Each wrist was rated on a 100-point scale, with points based on wrist balance, range of motion, pain relief and extensor strength. The postoperative Clayton score averaged 69.4 points. Including revision cases, 51% of the Swanson implants were rated good or excellent, 16% fair, and 33% were judged poor because of pain or prosthesis breakage. Patient satisfaction and pain relief were achieved in 68.2%. Active motion with unrevised implants was 21 degrees extension and 31 degrees flexion. We noticed a moderate increase (7 degrees) for ulnar-radial deviation. There was a progressive deterioration in the radiographic appearance. Implant fracture occurred in 31% of the patients. Subsidence of the implant and significant reduction of carpal height was noticed in 82.5% of the prosthesis. Revision procedures were performed in eleven cases. We conclude that the clinical and radiological results of Swanson silicone interposition arthroplasty will deteriorate with the passage of time. Beyond the potential deleterious effects of silicone, long-term radiological complications such as implant fracture, subsidence and carpal collapse are the main disadvantages of Swanson arthroplasty of the wrist. We therefore currently recommend the MPH-total wrist design in patients with rheumatoid arthritis.


A comprehensive meta-regression analysis on outcome of anatomic resection versus nonanatomic resection for hepatocellular carcinoma.
It remains unclear whether hepatectomy for hepatocellular carcinoma should be performed as an anatomic resection (AR) or a nonanatomic resection (NAR). Because no randomized controlled trials are currently available on this topic, a meta-regression analysis was performed on available observational studies to control for confounding variables. A systematic review of studies published from 1990 to 2011 in the PubMed and Embase databases was performed. Patient and disease-free survival (DFS), postoperative mortality, and morbidity were considered as outcomes. Results are expressed as relative risk (RR) or weighted mean differences with 95 % of confidence interval. Eighteen observational studies involving 9,036 patients were analyzed: 4,012 were in the AR group and 5,024 in the NAR group. Meta-analysis suggested that AR provided better 5-year patient survival (RR 1.14; P = 0.001) and DFS than NAR (RR 1.38; P = 0.001). However, patients in the NAR group were characterized by a higher prevalence of cirrhosis (RR 1.27; P = 0.010), more advanced hepatic dysfunction (RR 0.90 for Child-Pugh class A; P = 0.001) and smaller tumor size (weighted mean difference 0.36 cm; P < 0.001) compared with patients in the AR group. Meta-regression analysis showed that the different proportion of cirrhosis in the NAR group significantly affected both 5-year patient survival (RR 1.28; P = 0.016) and DFS (RR 1.74; P = 0.022). Tumor size only slightly affected DFS (RR 1.72; P = 0.076). Postoperative mortality and morbidity were unaffected (P > 0.05 in all cases). Patient survival and DFS after AR seem to be superior to NAR because the worse liver function reserve in the NAR group significantly affects prognosis.


Capitalizing on Insights from Human Genetics to Identify Novel Therapeutic Targets for Coronary Artery Disease.
Coronary artery disease (CAD) is a major cause of morbidity and mortality. Unfortunately, despite decades of research focused on disease pathogenesis, we still lack a sufficient pharmacopeia for preventing CAD. The failure of many novel cardiovascular drugs to improve clinical outcomes reflects the major substantial challenge of drug development: identifying causal mechanisms that can be therapeutically manipulated to lower disease risk. Identifying genetic variants that are associated with risk of CAD has emerged as a clear path toward improving our understanding of the underlying mechanisms that lead to disease and to the development of new therapies. Here, we review the potential utility and limitations of using human genetics to guide the identification of therapeutic targets for CAD.


To move or not to move? Skull and lower jaw morphology of the blindsnake Afrotyphlops punctatus (Leach, 1819) (Serpentes, Typhlopoidea, Typhlopidae) with comments on its previously advocated cranial kinesis.
"Scolecophidians" are traditionally known for their several skull and lower jaw autapomorphies, being conspicuously different from alethinophidian snakes in terms of skull shape and function. Although typically known for the absence of any kinetic joint in the skull dermatocranium and neurocranium-mostly due to an adaptation to fossorial habit, literature data have previously suggested a possible cranial kinesis for individuals of Afrotyphlops punctatus based on observations of live and preserved individuals. Given such observations, herein we aim to describe in detail the skull of A. punctatus based on CT-scan images of five specimens, evaluating the skull morphology and inferred function, and also providing valuable discussion on the skull osteology of the genus. Our results suggest that the skull of A. punctatus is similar to other blindsnakes in lacking any trace of snout, or even a frontal-parietal articulation. We also discuss possible osteological data that might be systematically relevant for Typhlopidae both interspecifically and intergenerically.


Primary Melanoma Histologic Subtype: Impact on Survival and Response to Therapy.
Two primary histologic subtypes, superficial spreading melanoma (SSM) and nodular melanoma (NM), comprise the majority of all cutaneous melanomas. NM is associated with worse outcomes, which have been attributed to increased thickness at presentation, and it is widely expected that NM and SSM would exhibit similar behavior once metastasized. Herein, we tested the hypothesis that primary histologic subtype is an independent predictor of survival and may impact response to treatment in the metastatic setting. We examined the most recent Surveillance, Epidemiology, and End Results (SEER) cohort (n = 118 508) and the New York University (NYU) cohort (n = 1621) with available protocol-driven follow-up. Outcomes specified by primary histology were studied in both the primary and metastatic settings with respect to BRAF-targeted therapy and immunotherapy. We characterized known driver mutations and examined a 140-gene panel in a subset of NM and SSM cases using next-generation sequencing. All statistical tests were two-sided. NM was an independent risk factor for death in both the SEER (hazard ratio [HR] = 1.55, 95% confidence interval [CI] = 1.41 to 1.70, P < .001) and NYU (HR = 1.47, 95% CI = 1.05, 2.07, P = .03) cohorts, controlling for thickness, ulceration, stage, and other variables. In the metastatic setting, NM remained an independent risk factor for death upon treatment with BRAF-targeted therapy (HR = 3.33, 95% CI = 1.06 to 10.47, P = .04) but showed no statistically significant difference with immune checkpoint inhibition. NM was associated with a higher rate of NRAS mutation (P < .001), and high-throughput sequencing revealed NM-specific genomic alterations in NOTCH4, ANK3, and ZNF560, which were independently validated. Our data reveal distinct clinical and biological differences between NM and SSM that support revisiting the prognostic and predictive impact of primary histology subtype in the management of cutaneous melanoma.


Optical Coherence Tomography Angiography to Quantify Choroidal Neovascularization in Response to Aflibercept.
To investigate the microvascular changes in choroidal neovascularization (CNV) using optical coherence tomography angiography (OCTA) during anti-vascular endothelial growth factor (VEGF) therapies. We retrospectively collected data on consecutive treatment-naïve eyes with typical age-related macular degeneration that initially received 3 aflibercept injections. OCTA was performed at baseline and at 1, 2, and 4 months of follow-up. The CNV images were analyzed using open-source software to assess vessel area and junction density. Fifteen eyes of 15 patients were included. The mean vessel area at baseline was 0.50 ± 0.33 mm2; at 1, 2, and 4 months, the ratios of change in vessel area from baseline were 66.6 ± 38.8%, 80.5 ± 25.5%, and 94.0 ± 29.3%, respectively. The vessel area was significantly reduced at 1 month from that at baseline (p = 0.0015) but significantly increased at 4 months from that at 1 month (p = 0.011). The mean junction density was also significantly reduced from 4.70 ± 1.30/mm at baseline to 3.82 ± 1.06/mm at 1 month (p = 0.00084). However, junction density did not continue to decrease at 2 and 4 months. OCTA quantification revealed that CNV rebounded after repeat aflibercept injections despite shrinking in response to the first injection.


[Neurocysticercosis--5 years' experience at the Clinic for Infectious Diseases].
Neurocysticercosis (NCC) is the most common parasitic disease with wide distribution which is caused by larval forms of Taenia Solium. Our aim was to: show the most common clinical manifestations of patients with NCC and their importance in diagnosing this disease; examine the value of serologic diagnostic methods in blood and cerebrospinal fluid; to emphasize the value of radiological diagnostic methods--CT and MRI of the brain, in relation to the applied protocol of therapy, as well as the impact of anti-parasitic therapy on the outcome of this disease. 13 patients with NCC (from 35 to 63 years of age, median age 49; 61.5% male and 38.5% female) were treated at the Clinic of Infectious Diseases in Novi Sad during a five-year period. Two patients had a positive epidemic data of parasitic diseases of the intestinal tract in childhood. The most common clinical manifestation was headache in 61.5% of patients, and generalized convulsions and hemiparesis in 46.2%. Meningeal inflammation was present in 27.3% of patients. Two of five patients had positive ELISA test for cysticercosis in the serum and cerebrospinal fluid. CT and MRI findings confirmed parenchimal form of NCC in 30.8% of patients, while calcifications were found in 69.2% of patients. All patients were treated with Albendazole, 800 mg a day, in two doses, 30.76% of patients had a favorable outcome of the disease, 53.7% of patients were discharged with complications, and one patient died. The most common manifestation of NCC in our patients was headache, followed by general convulsions and hemiparesis. Radiological diagnostic methods--CT and MRI--proved to be most valuable both in diagnostics and follow-up of lesions. All our patients were treated with Albendazole; Dexamethasone was applied in patients with severe inflammatory reaction, and anti-convulsive drugs in patients with convulsions.


[Studies on the rare earth content in food and its daily intake in man].
The rare earth content of major food in China, they are distributed over 17 provinces and cities were examined by three-wavelength spectrophotometry. The rare earth contents were as follows: 0.41 +/- 0.35 mg/kg in grain, 0.23 +/- 0.18 mg/kg in vegetables, 0.19 +/- 0.11 mg/kg in fruits, 0.83 +/- 0.73 mg/kg in beans, 0.66 +/- 0.50 mg/kg in potato, 1.76 +/- 0.23 mg/kg in tea, 0.07 +/- 0.05 mg/kg in meat, birds, domestic fowls and eggs, 0.52 +/- 0.12 mg/kg in aquatic animals, 5.11 +/- 8.68 micrograms/L in drinking water. The possible daily intake of rare earth for a person from common foodstuffs was about 2.10-2. 50 mg/person.day, which was about one tenth to one sixth of ADI allowable daily intake of rare earths for a person.


Thermodynamics of Fe3O4-Co3O4 and Fe3O4-Mn3O4 spinel solid solutions at the bulk and nanoscale.
High temperature oxide melt solution calorimetry has been performed to investigate the enthalpies of mixing (ΔmixH) of bulk and nanophase (1 -x)Fe3O4-xM3O4 (M = Co, Mn) spinel solid solutions. The entropies of mixing (ΔmixS) were calculated from the configurational entropies based on cation distributions, and the Gibbs free energies of mixing (ΔmixG) were obtained. The ΔmixH and ΔmixG for the (1 -x)Fe3O4-xCo3O4 system are negative over the complete solid solution range, for both macroscopic and nanoparticulate materials. In (1 -x)Fe3O4-xMn3O4, the formation enthalpies of cubic Fe3O4 (magnetite) and tetragonal Mn3O4 (hausmannite) are negative for Mn3O4 mole fractions less than 0.67 and slightly positive for higher manganese content. Relative to cubic Fe3O4 and cubic Mn3O4 (stable at high temperature), the enthalpies and Gibbs energies of mixing are negative over the entire composition range. A combination of measured mixing enthalpies and reported Gibbs energies in the literature provides experimental entropies of mixing. The experimental entropies of mixing are consistent with those calculated from cation distributions for x > 0.3 but are smaller than those predicted for x < 0.3. This discrepancy may be related to the calculations, having treated Fe(2+) and Fe(3+) as distinguishable species. The measured surface energies of the (1 -x)Fe3O4-xM3O4 solid solutions are in the range of 0.6-0.9 J m(-2), similar to those of many other spinels. Because the surface energies are relatively constant, the thermodynamics of mixing at a given particle size throughout the solid solution can be considered independent of the particular particle size, thus confirming and extending the conclusions of a recent study on iron spinels.


The possible influence of noise frequency components on the health of exposed industrial workers--a review.
Noise is a common occupational health hazard in most industrial settings. An assessment of noise and its adverse health effects based on noise intensity is inadequate. For an efficient evaluation of noise effects, frequency spectrum analysis should also be included. This paper aims to substantiate the importance of studying the contribution of noise frequencies in evaluating health effects and their association with physiological behavior within human body. Additionally, a review of studies published between 1988 and 2009 that investigate the impact of industrial/occupational noise on auditory and non-auditory effects and the probable association and contribution of noise frequency components to these effects is presented. The relevant studies in English were identified in Medknow, Medline, Wiley, Elsevier, and Springer publications. Data were extracted from the studies that fulfilled the following criteria: title and/or abstract of the given study that involved industrial/occupational noise exposure in relation to auditory and non-auditory effects or health effects. Significant data on the study characteristics, including noise frequency characteristics, for assessment were considered in the study. It is demonstrated that only a few studies have considered the frequency contributions in their investigations to study auditory effects and not non-auditory effects. The data suggest that significant adverse health effects due to industrial noise include auditory and heart-related problems. The study provides a strong evidence for the claims that noise with a major frequency characteristic of around 4 kHz has auditory effects and being deficient in data fails to show any influence of noise frequency components on non-auditory effects. Furthermore, specific noise levels and frequencies predicting the corresponding health impacts have not yet been validated. There is a need for advance research to clarify the importance of the dominant noise frequency contribution in evaluating health effects.


Practical Guide to the Identification and Diagnosis of Asthma-COPD Overlap (ACO).
Chronic obstructive pulmonary disease (COPD) is one of the leading causes of mortality around the world. COPD is characterised by a heterogeneous clinical presentation and prognosis which may vary according to the clinical phenotype. One of the phenotypes of COPD most frequently studied is the asthma-COPD overlap (ACO), however, there are no universally accepted diagnostic criteria for ACO. It is recognised that the term ACO includes patients with clinical features of both asthma and COPD, such as more intense eosinophilic bronchial inflammation, more severe respiratory symptoms and more frequent exacerbations, but in contrast, it is associated with a better prognosis compared to COPD. More importantly, ACO patients show better response to inhaled corticosteroid treatment than other COPD phenotypes. The diagnosis of ACO can be difficult in clinical practice, and the identification of these patients can be a challenge for non-specialized physicians. We describe how to recognise and diagnose ACO based on a recently proposed Spanish algorithm and by the analysis of three clinical cases of patients with COPD. The diagnosis of ACO is based on the diagnosis of COPD (chronic airflow obstruction in an adult with significant smoking exposure), in addition to a current diagnosis of asthma and/or signficant eosinophilia.


Immunization with recombinant class 1 outer-membrane protein from Neisseria meningitidis: influence of liposomes and adjuvants on antibody avidity, recognition of native protein and the induction of a bactericidal immune response against meningococci.
The porA gene from Neisseria meningitidis was cloned into the pRSETA vector and recombinant class 1 outer-membrane protein expressed at high levels in Escherichia coli. The protein was readily purified by affinity chromatography on a Ni2+ matrix and used for immunization of mice with conventional AI(OH)3 adjuvant, with experimental adjuvants which have the potential for human use, and with liposomes. The resulting sera were analysed for the magnitude, subclass distribution and antigenic specificity of the immune response. In addition, surface plasmon resonance (SPR) was used to quantify antibody avidity by analysis of the kinetics of binding to native class 1 protein. Immunization with conventional and experimental adjuvants induced antibodies of low avidity that did not recognize native class 1 protein. In contrast, immunization with recombinant protein in liposomes induced antibodies of high avidity which recognized native class 1 protein, as measured by their ability to label meningococcal cells in immunofluorescence assays and to inhibit the binding of a protective mAb. These properties were associated with the presence in sera of high levels of antibodies with the ability to induce complement-mediated killing of meningococci. These data show that liposomes containing recombinant class 1 protein represent a potential basis of future vaccines, of defined composition, designed for the prevention of group B meningococcal infections.


Sarcopenia, sarcopenic obesity, and functional impairments in older adults: National Health and Nutrition Examination Surveys 1999-2004.
The Foundation for the National Institutes of Health Sarcopenia Project validated cutpoints for appendicular lean mass (ALM) to identify individuals with functional impairment. We hypothesized that the prevalence of sarcopenia and sarcopenic obesity would be similar based on the different Foundation for the National Institutes of Health criteria, increase with age, and be associated with risk of impairment limitations. We identified 4984 subjects at least 60 years of age from the National Health and Nutrition Examination Surveys 1999-2004. Sarcopenia was defined using ALM (men <19.75 kg, women <15.02 kg) and ALM adjusted for body mass index (BMI; men <0.789 kg/m2, women <0.512 kg/m2). Sarcopenic obesity is defined as subjects fulfilling the criteria for sarcopenia and obesity by body fat (men ≥25%, women ≥35%). Prevalence rates of both sarcopenia and sarcopenic obesity were evaluated with respect to sex, age category (60-69, 70-79, and >80 years) and race. We assessed the association of physical limitations, basic and instrumental activities of daily living and sarcopenia status. The mean age was 70.5 years in men and 71.6 years in women. Half (50.8%; n = 2531) were female, and mean BMI was 28 kg/m2 in both sexes. Appendicular lean mass was higher in men than in women (24.1 vs. 16.3; P < .001), but fat mass was lower (30.9 vs. 42.0; P < .001). In men, sarcopenia prevalence was 16.0% and 27.8% using the ALM and ALM/BMI criteria. In women, prevalence was 40.5% and 19.3% using the ALM and ALM/BMI criteria. Sarcopenia was associated with a 1.10 (0.86-1.41) and 0.93 (0.74-1.16), and 1.46 (1.10-1.94), and 2.13 (1.41-3.20) risk of physical limitations using the ALM and ALM/BMI definitions in men and women, respectively. Prevalence of sarcopenia and sarcopenic obesity varies greatly, and a uniform definition is needed to identify and characterize these high-risk populations.


Autologous bone marrow transplantation in patients with AML in first complete remission. Results of two different conditioning regimens after the same induction and consolidation therapy.
Thirty-nine patients with acute myeloblastic leukemia (AML) in first complete remission (CR) were treated by autologous bone marrow transplantation. All patients received the same induction and consolidation chemotherapy consisting of a combination of daunorubicin (DNR) and cytarabine (Ara-C) followed by four courses of DNR, Ara-C and 6-thioguanine (6-TG). Two different conditioning regimens were used; 25 patients were submitted to the BAVC regimen (BCNU, amsacrine, VP-16 (etoposide) and Ara-C) and 14 to a cyclophosphamide/total body irradiation (CY + TBI) regimen. Six patients (one treated with BAVC and five treated with CY + TBI) died in aplasia. Twelve of the 25 BAVC treated patients and one of the nine CY + TBI treated patients relapsed; 12 (48%) of the BAVC treated patients are in CR with a median follow-up of 45 months and eight (57%) of the CY + TBI treated patients are in CR with a median follow-up of 50 months. All patients in CR have survived for more than 2 years since transplant.


Characterization of swine leucocyte antigen alleles in a crossbred pig to be used in xenotransplant studies.
We have characterized swine leucocyte antigen (SLA) classes I and II molecules of a domestic pig as a model for use in our xenotransplant program. Molecular characterization of the SLA classes I and II genes is critical to understanding the adaptive immune responses between swine and humans in the event of xenotransplantation. Seven swine leucocyte antigen genes (SLA-1, SLA-2, SLA-3, DQB1, DRB1, DQA and DRA) were analyzed and 15 alleles were identified. A novel DRA*w04re01 is reported for this limited polymorphic class II gene. The heterozygous haplotypes, Hp-32.0/35.0 and Hp-0.13/0.23 were deduced for our IU-pig model, for SLA classes I and II regions, respectively.


Phase II clinical trial results involving treatment with low-dose daily oral cyclophosphamide, weekly vinblastine, and rofecoxib in patients with advanced solid tumors.
Preclinical studies indicate that conventional chemotherapeutic agents given continuously at low doses (metronomic chemotherapy) may provide an improved therapeutic index. Cyclophosphamide and vinblastine have been best studied in experimental models, where tumor growth inhibition is achieved, at least in part, through antiangiogenic mechanisms. Fifty patients with advanced solid tumors were enrolled in this phase II trial, 43 of whom had received at least one prior chemotherapy regimen. Patients were required to have Eastern Cooperative Oncology Group performance status of < or = 2, a life expectancy of >3 months, and at least one measurable lesion. All patients received oral cyclophosphamide (50 mg) and rofecoxib (25 mg) daily in addition to weekly injections of vinblastine (3 mg/m2). Half of the patients also received minocycline (100 mg) orally twice daily with the intent of further inhibiting tumor angiogenesis. The primary end point of the study was clinical benefit, defined as the percentage of patients experiencing an objective response or exhibiting stable disease for at least 6 months. For the 47 eligible patients, there were two (4%) complete responses and four (9%) partial responses, for an overall objective response rate of 13%. An additional eight patients achieved disease stabilization (stable disease > or = 6 months) (17%). The primary end point of clinical benefit was therefore 30%, (95% confidence interval, 16-44%). The median progression-free survival for all patients was 103 days and 289 days for patients experiencing clinical benefit. The incidence of patients experiencing grade 3/4 toxicities were as follows: neutropenia (10/2), anemia (2/0), and thrombocytopenia (1/0). No patients developed grade 3 or 4 nausea, vomiting, mucositis, or alopecia. This low-dose regimen consisting of daily oral cyclophosphamide and weekly vinblastine injections given concurrently with rofecoxib is associated with minimal toxicity and provides significant clinical benefit to patients with advanced solid tumors. These results are particularly encouraging given the nature of the study population and indicate that this approach merits further investigation in specific disease site studies.


A case of severe hyperammonemia and unconsciousness following sodium valproate intoxication.
Although valproic acid has gradually gained its popularity in the treatment of various seizure disorders, overdose of valproate is not common. An 18-y-old man with a history of epilepsy controlled by sodium valproate and clonazepam attempted suicide with an ingestion of 45 g sodium valproate. He presented to our service with drowsiness and irritability. Extremely high serum ammonia (623 ug/dL) and elevated serum valproate concentration (575 ug/mL) were found on admission. Several metabolic abnormalities, including hypernatremia, hypocalcemia and metabolic acidosis, as well as, increased serum transaminase levels were also recorded. With supportive measures, he became clear 24 h later and was discharged 6 d after ingestion. Serial follow-up of his serum valproate and ammonia levels disclosed a close relationship between these 2 measurables. After acute overdose of valproic acid, patients usually present with mild and generally reversible depression of the central nervous system. However, impairment of liver function, hyperammonemia, fluid-electrolyte disturbances, coma, seizures, hypotension and even death may occur following valproate overdose. Symptomatic and supportive measures are the mainstay in the treatment of valproic acid overdose. With prompt diagnosis and early institution of treatment, a complete recovery should be anticipated.


Spatio-Temporal Dynamics of Foraging Networks in the Grass-Cutting Ant Atta bisphaerica Forel, 1908 (Formicidae, Attini).
Foraging networks are a key element for ant colonies because they facilitate the flow of resources from the environment to the nest and they allow the sharing of information among individuals. Here we report the results of an 8-month survey, extending from November 2009 to June 2010, of the foraging networks of four mature colonies of Atta bisphaerica, a species of grass-cutting ant which is considered as a pest in Brazil. We found that the distribution of foraging effort was strongly influenced by the landscape features around the nests, in particular by the permanently wet parts of the pasture in which the nests were located. The foraging networks consisted of underground tunnels which opened on average at 21.5m from the nests and of above-ground physical trails that reached on average 4.70m in length. The use of the foraging networks was highly dynamic, with few sections of the networks used for long periods of time. Three different phases, which could be linked to the seasonal change in the local rainfall regime, could be identified in the construction and use of the foraging networks. The first phase corresponded to the beginning of the rainy season and was characterized by a low foraging activity, as well as a low excavation and physical trail construction effort. The second phase, which began in February and extended up to the end of the humid season at the end of March, was characterized by an intense excavation and trail construction effort, resulting in an expansion of the foraging networks. Finally, in the third phase, which corresponded to the beginning of the dry season, the excavation and trail construction effort leveled off or decreased while foraging activity kept increasing. Our hypothesis is that ants could benefit from the underground tunnels and physical trails built during the humid season to maintain their foraging activity at a high level.


Targeting NF-κB pathway for the therapy of diseases: mechanism and clinical study.
NF-κB pathway consists of canonical and non-canonical pathways. The canonical NF-κB is activated by various stimuli, transducing a quick but transient transcriptional activity, to regulate the expression of various proinflammatory genes and also serve as the critical mediator for inflammatory response. Meanwhile, the activation of the non-canonical NF-κB pathway occurs through a handful of TNF receptor superfamily members. Since the activation of this pathway involves protein synthesis, the kinetics of non-canonical NF-κB activation is slow but persistent, in concordance with its biological functions in the development of immune cell and lymphoid organ, immune homeostasis and immune response. The activation of the canonical and non-canonical NF-κB pathway is tightly controlled, highlighting the vital roles of ubiquitination in these pathways. Emerging studies indicate that dysregulated NF-κB activity causes inflammation-related diseases as well as cancers, and NF-κB has been long proposed as the potential target for therapy of diseases. This review attempts to summarize our current knowledge and updates on the mechanisms of NF-κB pathway regulation and the potential therapeutic application of inhibition of NF-κB signaling in cancer and inflammatory diseases.


Family contexts: parental experiences of discrimination and child mental health.
Research on the mental health correlates of discrimination traditionally has been intra-individual, focusing exclusively on the individual directly experiencing discrimination. A small number of studies have begun to consider the links between parental experiences of discrimination and child mental health, but little is known about potential underlying mechanisms. The present study tested the independent mediating effects of parent mental health and household socioeconomic status on the associations between parental experiences of discrimination (past-year perceived discrimination and perceptions of being unaccepted culturally) and child mental health (internalizing and externalizing symptoms) using a bootstrapping analytic approach. Data were drawn from racial/ethnic minority (n = 383) and White (n = 574) samples surveyed in an urban Midwestern county. For all measures of discrimination and child mental health, findings supported an association between parental experiences of discrimination and child mental health. Whereas parent mental health served as a significant mediator in all analyses, socioeconomic status did not. Mediation findings held for both the White and racial/ethnic minority samples. Results suggest that parental experiences of discrimination and mental health may contribute to child mental health concerns, thus highlighting the role of family contexts in shaping child development.


Probing the effects of conjugation path on the electronic transmission through single molecules using scanning tunneling microscopy.
A systematic study of the relationship between the molecular structure of a series of thiol end-capped oligo-phenylenevinylenes (OPVs) and the coherent electronic transmission at the single molecule level was measured by scanning tunneling microscopy (STM). This reveals a significant change in the electronic transparency of various OPV derivatives due to the insertion of a methylene spacer group or due to nitro group substitution. Apparently, changes in the conjugation path through the central benzene ring from para to meta substitution does not have a profound effect on the electronic transparency of the molecules.


Bioactive-Tissue-Derived Nanocomposite Hydrogel for Permanent Arterial Embolization and Enhanced Vascular Healing.
Transcatheter embolization is a minimally invasive procedure that uses embolic agents to intentionally block diseased or injured blood vessels for therapeutic purposes. Embolic agents in clinical practice are limited by recanalization, risk of non-target embolization, failure in coagulopathic patients, high cost, and toxicity. Here, a decellularized cardiac extracellular matrix (ECM)-based nanocomposite hydrogel is developed to provide superior mechanical stability, catheter injectability, retrievability, antibacterial properties, and biological activity to prevent recanalization. The embolic efficacy of the shear-thinning ECM-based hydrogel is shown in a porcine survival model of embolization in the iliac artery and the renal artery. The ECM-based hydrogel promotes arterial vessel wall remodeling and a fibroinflammatory response while undergoing significant biodegradation such that only 25% of the embolic material remains at 14 days. With its unprecedented proregenerative, antibacterial properties coupled with favorable mechanical properties, and its superior performance in anticoagulated blood, the ECM-based hydrogel has the potential to be a next-generation biofunctional embolic agent that can successfully treat a wide range of vascular diseases.


[30 years animal welfare legislation: where are the problems of application?].
The contribution deals with legal structure, organization and problems of application of the Swiss animal welfare legislation of 1978. Besides positive effects considerable problems with the application of the legislation occurred, in particular in housing of bovines, swine and laying hens. Punishable acts of animal protection in companion and pet animals were markedly increasing in the last years, particularly in dogs. There were also loopholes in the legislation, which could be filled by the new animal welfare law of 2005 and the animal welfare ordinance of 2008 with only a few exceptions.


Inhibition of PQS signaling by the Pf bacteriophage protein PfsE enhances viral replication in Pseudomonas aeruginosa.
Quorum sensing, a bacterial signaling system that coordinates group behaviors as a function of cell density, plays an important role in regulating viral (phage) defense mechanisms in bacteria. The opportunistic pathogen Pseudomonas aeruginosa is a model system for the study of quorum sensing. P. aeruginosa is also frequently infected by Pf prophages that integrate into the host chromosome. Upon induction, Pf phages suppress host quorum sensing systems; however, the physiological relevance and mechanism of suppression are unknown. Here, we identify the Pf phage protein PfsE as an inhibitor of Pseudomonas Quinolone Signal (PQS) quorum sensing. PfsE binds to the host protein PqsA, which is essential for the biosynthesis of the PQS signaling molecule. Inhibition of PqsA increases the replication efficiency of Pf virions when infecting a new host and when the Pf prophage switches from lysogenic replication to active virion replication. In addition to inhibiting PQS signaling, our prior work demonstrates that PfsE also binds to PilC and inhibits type IV pili extension, protecting P. aeruginosa from infection by type IV pili-dependent phages. Overall, this work suggests that the simultaneous inhibition of PQS signaling and type IV pili by PfsE may be a viral strategy to suppress host defenses to promote Pf replication while at the same time protecting the susceptible host from competing phages.


Proteasome modulator 9 gene is linked to diabetic and non-diabetic retinopathy in T2D.
Diabetic retinopathy is a long-term complication of type 2 diabetes (T2D). Non-diabetic retinopathy may be present in T2D patients as well and non-T2D patients with hypertension and/or atherosclerosis. The aim of this study was to identify linkage of the proteasome modulator 9 (PSMD9) T2D risk variants IVS3+nt460, IVS3+nt437, E197G to diabetic retinopathy and retinopathy including also atherosclerotic or hypertensive retinopathy in Italian T2D families. A total of 126 siblings of our 200 T2D siblings/families were characterized for diabetic retinopathy or retinopathy. The clinical characterization is based on a fundus oculi exam and on fluorangiography of the participating subjects. Diabetic retinopathy includes both pre-proliferative and proliferative retinopathy. The common gene variants were directly amplified by PCR and by fluorescent-based automation. A parametric and non-parametric linkage study of the gene variants with diabetic retinopathy and retinopathy was then performed using Merlin software. Finally, 1000 simulation analyses were performed to test for the statistical power of the significant results (P-value ≤ 0.05). This study shows a linkage of the PSMD9 IVS3+nt460 (rs74421874), IVS3+nt437 (rs3825172) and E197G (rs14259) single nucleotide polymorphisms (SNPs) to diabetic and non-diabetic retinopathy by using the non-parametric as well as the parametric linkage analysis. The strongest signal is present for the PSMD9 variants with the diabetic retinopathy, in particular under the additive model. The 1,000 simulations performed for each significant test confirmed that the results are not due to random chance. In summary, the PSMD9 IVS3+nt460, IVS3+nt437, E197G SNPs are linked to diabetic retinopathy and non-diabetic retinopathy in Italians.


Phytomedicines prepared from Arnica flowers inhibit the transcription factors AP-1 and NF-kappaB and modulate the activity of MMP1 and MMP13 in human and bovine chondrocytes.
Arnica preparations have long been used for the symptomatic treatment of rheumatic complaints and recent clinical trials have demonstrated the beneficial effects of Arnica preparations in the treatment of osteoarthritis (OA). The efficacy of Arnica is presumed to be mainly due to its anti-inflammatory properties and inhibition of the transcription factor NF-kappaB. Here we provide further insights into its molecular mode of action. Arnica preparations suppress MMP1 and MMP13 mRNA levels in bovine and human articular chondrocytes in a concentration-dependent manner and in a low concentration range. This suppression may be due to inhibition of DNA binding of the transcription factors AP-1 and NF-kappaB. Interestingly, sesquiterpene lactones present in the preparations were always more active than the pure compounds, demonstrating the advantage of using plant preparations.