Functional characterization of the tumor suppressor CMTM8 and its association with prognosis in bladder cancer.
Previous research revealed that CMTM8 acts as a tumor suppressor gene in variety cancers. However, the role of CMTM8 in bladder cancer has never been reported. In this study, the expression profile of CMTM8 was examined in bladder cancer tissues and bladder cancer cell lines. The effects of CMTM8 on bladder cancer cell proliferation, apoptosis, migration, and invasion were examined. Bladder tumor tissues from 84 cases were examined for CMTM8 expression by immunohistochemistry. Disease-specific survival was investigated using a Kaplan-Meier analysis, and Cox proportional hazards analysis was assessed. Our results showed that upregulation of CMTM8 in the T24 cell line could suppress T24 cells proliferation, migration and invasion and enhance the sensitivity to Epirubicin. Kaplan-Meier analysis revealed that the expression of CMTM8 was correlated with the survival time of bladder cancer patients. Altogether, our data suggested that CMTM8 is an important tumor suppressor gene in human bladder cancer and qualified as a useful prognostic indicator for patients with bladder cancer.


Differences in lipoprotein (a) and apolipoprotein (a) levels in men and women with advanced coronary atherosclerosis.
This study was designed to evaluate whether differences between sexes exist in serum-lipoprotein (a) [Lp(a)] and arterial-wall-apolipoprotein (a) [Apo(a)] levels in patients with advanced coronary artery disease. The concentrations of Lp(a) in serum and Apo(a) in aortic biopsies were studied in 76 men and 20 women undergoing coronary artery bypass graft surgery. The severity of coronary artery disease was determined by a coronary atherosclerosis score that used quantitative coronary angiography. Serum-Lp(a) and tissue-Apo(a) do not correlate with the severity of coronary artery disease as expressed by the coronary atherosclerosis score (r = 0.09 and r = 0.14, respectively). Women were older (65 +/- 8 versus 57 +/- 8 years, P < 0.001) and had higher mean Lp(a) and higher mean Apo(a) levels (47 +/- 41 versus 32 +/- 40 mg/dl and 33 +/- 34 versus 19 +/- 24 micrograms/g wet weight, P < 0.05) than men with identical coronary atherosclerosis score (35 +/- 8 versus 33 +/- 8, P > 0.05). The serum levels of cholesterol, triglycerides, and high-density lipoprotein were similar in both groups. Men and women undergoing coronary artery bypass graft surgery had very similar severity of coronary artery disease as expressed by the coronary atherosclerosis score. Women were 8 years older and had 1.5 times higher mean serum-Lp(a) levels and 1.75 times higher mean tissue Apo(a) levels higher than the men. Sixty per cent of the women but only 39% of the men had serum Lp(a) levels higher than 25 mg/dl. Lp(a) level seems to be an additional risk factor for coronary artery disease confined to postmenopausal women.


Pneumonectomy for Non-Small Cell Lung Cancer.
Lung cancer is the leading cause of cancer deaths and its incidence continues to increase. Emerging therapies as part of a multimodal approach are making more patients eligible for surgical resection. As more surgeons are treating locally advanced non-small cell lung cancer they find themselves recommending pneumonectomy as the surgical component of the multidisciplinary plan. Performing a pneumonectomy is technically demanding and is associated with many potential perioperative comorbidities. With the proper preparation, experience, and attention to perioperative care, pneumonectomy can be carried out safely with excellent outcomes and a good quality of life.


Moderate concordance was found between case-only and parallel group designs in systematic comparison.
To empirically evaluate the concordance of effect estimates between case-only and parallel group designs and to identify predictors of discrepancies. MEDLINE and EMBASE databases were searched through June 31, 2013. Studies that used both a case-only (case crossover or self-controlled case series) and a parallel group design (cohort or case-control) were identified. Spearman correlation coefficient was used to evaluate the concordance between designs. Z-scores were used to assess whether differences in the effect estimates were common, using an absolute threshold value of 1.96. A prediction model was built to identify predictors of discrepancies. The search identified 1,367 articles of which 53 were included for analysis. In total, 519 comparisons were made. The correlation coefficient between case-only vs. parallel group studies was 0.64 (P < .001). In 221 of the 519 comparisons (43%), the difference between both study designs was larger than the predetermined threshold. The following predictors of discrepancy were found: intermittent exposure, rare event, acute outcome, length of hazard period, type of case-only design, and sample size (C statistic of 0.783). The concordance between effect estimates of case-only and parallel group designs is moderate. Such discrepancies could be predicted by failure to meet assumptions of case-only designs.


Revisiting the "July Effect" in Plastic Surgery: New Data to Support Resident Autonomy.
The "July Effect" represents a topic of considerable interest across residency programs. This study investigated the frequency of postoperative complications following procedures with plastic surgery resident participation (all postgraduate year [PGY] levels) during the first (quarter 3, July-September) and last academic quarters. The American College of Surgeons National Surgical Quality Improvement Program database was used to calculate complication rates from 2006 to 2010. Resident involvement was analyzed as a categorical variable consisting of "juniors" (PGY1-PGY3), and "seniors" (PGY4-PGY6). Outcomes from procedures during Q3 were compared with all quarters. Propensity score matching and adjustment enabled logistic regression identifying the effect of resident involvement and admission. Among all cosmetic and reconstructive procedures (n = 6625), mean operative time was not significantly greater in Q3 compared with all other quarters (P = 0.069); no significant differences in complication rates were observed between Q3 and all other quarters, though superficial surgical site infection (SSI) approached significance (3.3% of procedures in Q3 vs 2.5% in all other quarters, P = 0.063). Among reconstructive procedures only (n = 5677), mean operative time was not significantly greater in Q3 compared with all other quarters (P = 0.119); the same held true for cosmetic procedures only (P = 0.275). Surgical site infection, however, was significantly more likely to occur with reconstructive procedures only, in Q3 compared with all other quarters (3.5% of cases vs 2.3%, P = 0.024). When adjusting for PGY status and matching populations, superficial SSI and return to the operating room were not significantly more common in Q3. When adjusting for quarter of admission, however, superficial SSI was significantly more common among the overall and noncosmetic cases with participation by junior residents (P = 0.013 and 0.020, respectively). This may represent the first fully reproducible, transparent National Surgical Quality Improvement Program study in plastic surgery that demonstrates the absence of a clinically significant "July Effect," and suggests that an appropriate degree of resident autonomy may pose minimal risk during both cosmetic and reconstructive procedures in residency training. Additionally, the findings encourage the development a plastic surgery-specific database to remedy inherent difficulties with larger, more comprehensive surgical databases.


Determination of ursodeoxycholic acid in pharmaceutical preparations by capillary electrophoresis with indirect UV detection.
A simple and rapid capillary electrophoretic method, with indirect UV detection, for the quantification of ursodeoxycholic acid (UDCA) in pharmaceutical preparations was developed in this study. Sodium p-hydroxy benzoate was used as background electrolyte (BGE) (5 mM, pH 8.0) and visualization agent. Separation was carried out on a fused-silica capillary (50 microm x 72 cm) at a potential of 25 kV under ambient temperature and detected at 250 nm. Glycocholic acid was used as internal standard for quantification. Both run-to-run repeatability and day-to-day reproducibility of migration time were below 0.1% relative standard deviation (R.S.D.). Repeatability and reproducibility of relative peak height were 3.3 and 3.8% R.S.D., respectively. Accuracy was tested by spiking two pharmaceutical tablets with standards and the recoveries were 101.9+/-9.87 and 99.6+/-9.60% (n=3), respectively. Linearity of relative peak height was tested in the range 20-100 microg/ml. Limit of detection (LOD) was 3 microg/ml. The method could be used to assay UDCA raw materials and formulation products.


Retinoid- and sodium-butyrate-induced decrease in heat shock protein 70 membrane-positive tumor cells is associated with reduced sensitivity to natural killer cell lysis, growth delay, and altered growth morphology.
Human tumors frequently present heat shock protein 70 (Hsp70) on their cell membranes, whereas corresponding normal tissues fail to do so. Therefore, an Hsp70 membrane-positive phenotype provided a tumor-specific marker. Moreover, membrane-bound Hsp70 provides a target structure for the cytolytic attack mediated by natural killer (NK) cells. Vitamin A derivatives 13-cis retinoic acid (13-RA) and all-trans retinoic acid (ATRA) and sodium-butyrate (SBU) are known for their redifferentiating capacity. Therefore, we asked the question whether loss in tumorigenicity might be associated with a reduced Hsp70 membrane expression. For our studies we used epithelial colon (CX+/CX-) and thyroid (ML-1) cancer cells, with initially different Hsp70 cell surface expression pattern. After treatment up to 7 weeks with freshly prepared 13-RA, ATRA, and SBU at nonlethal concentrations of 10 microM, 1 microM, and 0.5 mM, respectively, growth morphology, Hsp70 levels, and sensitivity toward Hsp70-specific NK cells were compared with that of untreated tumor cells. Significant growth delay was determined in CX+ tumor cells after 6 weeks treatment with 13-RA. Concomitantly, growth morphology changed from spheroid cell clusters to monolayers. Despite a weak increase in cytosolic Hsp70, the percentage of Hsp70 membrane-positive cells dropped significantly after repeated treatments with 13-RA and ATRA in CX+ and ML-1 but not in CX- tumor cells. Similar results were observed with SBU. Functionally, the decrease in Hsp70 membrane-positive CX+ and ML-1 cells correlated with a reduced sensitivity to lysis mediated by NK cells. In summary, redifferentiating agents predominantly affected Hsp70 membrane-positive tumors. The decrease in Hsp70 membrane positivity correlated with a lower sensitivity to NK lysis, growth delay, and altered growth morphology.


Impact of the European Randomized Study of Screening for Prostate Cancer (ERSPC) on prostate-specific antigen (PSA) testing by Dutch general practitioners.
To determine the impact of the European Randomized Study of Screening for Prostate Cancer (ERSPC) publication in 2009 on prostate-specific antigen (PSA) level testing by Dutch general practitioners (GPs) in men aged ≥40 years. Retrospective study with a Dutch insurance company database (containing PSA test claims) and a large district hospital-laboratory database (containing PSA-test results). The difference in primary PSA-testing rate as well as follow-up testing before and after the ERSPC was tested using the chi-square test with statistical significance at P < 0.05. Decline in PSA tests 4 months after ERSPC publication, especially for men aged ≥60 years. Primary testing as well as follow-up testing decreased, both for PSA levels of <4 ng/mL as well as for PSA levels of 4-10 ng/mL. Follow-up testing after a PSA level result of >10 ng/mL moderately increased (P = 0.171). Referral to a urologist after a PSA level result of >4 ng/mL decreased slightly after the ERSPC publication (P = 0.044). After the ERSPC publication primary PSA testing as well as follow-up testing decreased. Follow-up testing seemed not to be adequate after an abnormal PSA result. The reasons for this remain unclear.


Comparative effects of hydroxocobalamin and cyanocobalamin on plasma homocysteine concentrations in end-stage renal disease.
End-stage renal disease (ESRD) is associated with marked hyperhomocysteinemia which is only partially corrected by folic acid and pyridoxine supplementation. We and others have reported that various forms of parenteral cobalamin reduce plasma total homocysteine (tHcy) concentrations of patients with ESRD substantially below the lowest levels attainable with folic acid. We here report a 16-week randomized controlled crossover trial which directly compared the Hcy-lowering effect of intravenous hydroxocobalamin (HC) with that of cyanocobalamin (CC). Folic acid- and vitamin B12-replete maintenance hemodialysis patients were randomly assigned to receive either 1 mg intravenous HC weekly for 8 weeks followed by CC for a further 8 weeks, or CC for 8 weeks followed by HC for 8 weeks. Hydroxocobalamin increased serum cobalamin concentrations 40-fold, whereas CC increased them only 10-fold, but both treatments reduced plasma tHcy concentrations similarly by 33% (P < .001). Crossover to the alternate form of the vitamin greatly affected the serum cobalamin concentration but was without further effect on the plasma tHcy concentration. These results confirm that weekly cobalamin injections lower plasma tHcy concentrations of hemodialysis patients well below the level attainable with folic acid. Hydroxocobalamin and CC are equipotent despite producing very different serum cobalamin concentrations.


[Identification of recurrent inferior laryngeal nerve during a thyroid lobectomy].
Based an their findings during thyroid operations and pathological examination of 100 specimens, the authors report the principal steps for identification and dissection of recurrent nerve during a thyroid lobectomy.


Bioinformatics analysis of prognostic value and immunological role of MeCP2 in pan-cancer.
Methyl-CpG-binding protein 2(MeCP2) is an important epigenetic regulatory factor that promotes many tumor developments, such as liver cancer, breast cancer, and colorectal cancer. So far, no pan-cancer analysis has been reported. Therefore, this study aims to explore pan-cancer's prognostic value, immune infiltration pattern, and biological function. We used bioinformatics methods to analyze the expression and prognostic significance of MeCP2, and the relationship between MeCP2 and clinicopathological parameters, genetic variation, methylation, phosphorylation, immune cell infiltration, and biological function in pan-cancer from using a public database. The results showed that expression of MeCP2 was up-regulated in 8 cancers and down-regulated in 2 cancers, which was remarkably correlated with the prognosis, pathological stage, grade and subtype of cancers. The promoter methylation level of MeCP2 DNA was decreased in bladder urothelial carcinoma (BLCA), breast invasive carcinoma (BRCA), liver hepatocellular carcinoma (LIHC), prostate adenocarcinoma (PRAD), uterine corpus endometrial carcinoma (UCEC), testicular germ cell tumors (TGCT), and stomach adenocarcinoma (STAD);decreased phosphorylation of S25, S90, S92, S241, S286, S325 and S435 was found in MeCP2, such as UCEC, lung adenocarcinoma (LUAD), ovarian serous cystadenocarcinoma (OV), colon adenocarcinoma (COAD), and kidney renal clear cell carcinoma (KIRC). Furthermore, MeCP2 expression was significantly associated with multiple immunomodulators and immune cell infiltration levels across most tumors. Therefore, our pan-cancer explored the prognostic markers and immunotherapeutic value of MeCP2 in different cancers.


Facile Affinity Maturation of Single-Domain Antibodies Using Next-Generation DNA Sequencing.
Binding affinity is one of the primary determinants of antibody function. Here, we provide a protocol for simple and rapid affinity maturation of single-domain antibodies (sdAbs) using tandem phage display selection and next-generation DNA sequencing. The sequence of a model camelid sdAb directed against Clostridioides difficile toxin A (A26.8) was diversified using either random or site-saturation mutagenesis and cloned into a phagemid vector upstream of gene 3. The resulting phage-displayed sdAb libraries were panned against C. difficile toxin A and the panning outputs interrogated using Illumina MiSeq sequencing. Through bioinformatic analyses, we were able to identify individual affinity-enhancing amino acid substitutions in the sdAb complementarity-determining regions that, when combined, resulted in affinity improvements of approximately 10-fold. The advantages of this method are that it does not require extensive screening and characterization of individual clones, nor structural information on the mechanism of the sdAb:antigen interaction.


Production and characterization of hirudin variant-1 by SUMO fusion technology in E. coli.
Hirudin is the most potent non-covalent inhibitor of thrombin. Several expression systems have been used to produce recombinant hirudin for pharmaceutical purposes. However, high expression of active hirudin in Escherichia coli cytoplasm has not been successful owing to the fact that heterogenetic small peptide is easily degraded in the cell. To solve this problem, we constructed a recombinant form of the hirudin variant-1 (HV1) as a fusion protein with the small ubiquitin-related modifier gene (SUMO) by use of over-lap PCR. The fusion gene His(6)-SUMO-HV1 was highly expressed in E. coli BL21 (DE3) in which the SUMO-HV1 accounts for over 30% of the soluble fraction. The fusion protein was purified by Ni-NTA affinity chromatography and cleaved by a SUMO-specific protease Ulp1 to release the HV1 with natural N-terminal. The recombinant HV1 (rHV1) was further purified by Ni-NTA affinity chromatography and then by Q anion-exchange chromatography. N-terminal sequencing result demonstrated the purified rHV1 had the same N-terminal sequence as the native hirudin. MALDI-TOF/MS analysis indicated that the molecular weight of the purified rHV1 protein was 6939.161 Da, which was similar to the theoretical molecular weight of rHV1 6,944 Da. The Chromozym TH assay result showed that the anti-thrombin activity of purified rHV1 was 8,800 ATU/mg and comparable to the specific activity of native hirudin.


Characteristics of Ca2+/calmodulin- and Ca2+/phosphatidylserine-stimulated phosphoproteins in rat striatum.
The characteristics of endogenous Ca2+/calmodulin (CaM)- and Ca2+/phosphatidylserine (PS)-stimulated phosphorylated proteins in the striatum of rat were partially determined and compared in this study. The Ca2+/CaM-dependent phosphoproteins were associated with serine and threonine residues. The sensitivity of these proteins for phosphorylation by Ca2+/CaM was not affected by pretreatment of tissue with Ca2+ chelating agent, EGTA or with non-ionic detergent, Triton X-114. Triton X-114 phase separation experiments revealed that these Ca2+/CaM-dependent phosphoproteins were partitioned in the detergent rich phase suggesting that they are integral proteins of the striatal membrane. On the other hand, the Ca2+/PS-dependent phosphorylated proteins were primarily associated with the serine residue. Phosphorylation of these proteins by Ca2+/PS were abolished after the treatment with EGTA or Triton X-114. These results suggest that Ca2+/PS-dependent striatal phosphoproteins are biochemically unstable in maintaining their state of phosphorylation.


Characterization of a transferrin-independent uptake system for iron in HeLa cells.
HeLa cells incubated in serum-free medium accumulated 59Fe ("non-transferrin iron") when incubated with either 59Fe-citrate, 59Fe-nitrilotriacetate, or 59Fe dissolved in Tricine ascorbate. Accumulation of iron was time-, concentration-, and Ca2+-dependent and was saturable. Uptake of non-transferrin (non-Tf) iron was transferrin-independent because of the fact that uptake occurred at pH 5.5, a pH at which transferrin binds iron poorly and at which transferrin is not internalized by cells. Uptake of non-Tf iron was less affected than uptake of transferrin iron by 1) exposure of cells to trypsin, a maneuver that cleaves Tf receptors, or 2) incubation of cells with phenylarsine oxide, an agent that inhibits both fluid- and receptor-mediated internalization. After exposure of cells to non-Tf iron at 37 degrees C, most of the cell-associated radioactivity was recovered in heme and ferritin, demonstrating that iron gained access to intracellular compartments and was not simply adsorbed to the cell surface. Uptake of non-Tf iron could be partially blocked by Cu2+ in a dose-dependent manner, while the accumulation of transferrin-bound iron was unaffected by Cu2+. Other transition metals, such as Zn2+, Cd2+, and Mn2+ were able to inhibit the uptake of non-Tf iron to different degrees. The accumulation of 109Cd was inhibited by incubation of cells with non-Tf iron, Cu2+, or Mn2+. The extent of inhibition was concentration- and metal-dependent. A number of cultured cell lines including HeLa, human skin fibroblasts, and Chinese hamster ovary cells demonstrated uptake of non-Tf iron and 109Cd. Additionally, an endosome acidification mutant of Chinese hamster ovary cells, which exhibited an increase in non-Tf iron uptake, also exhibited an increase in the uptake of Cd2+. These observations suggest that the characteristics of the non-Tf iron transport system in HeLa cells are similar if not identical to those reported for perfused rat liver (Wright, T. L., Brissot, P., Ma, W.-L., and Weisiger, P. A. (1986) J. Biol. Chem. 261, 10909-10914) and suggest the existence of a family of transition metal transport systems, each with a different metal specificity.


A randomized, double-blind, placebo-controlled, dose-response study of the analgesic effect of lornoxicam after surgical removal of mandibular third molars.
The aim of the present study was to investigate the dose-effect relationship of single doses of 4 to 32 mg of lornoxicam (LNX), a new nonsteroidal antiinflammatory drug belonging to the oxicam group, compared with placebo and 10 mg ketorolac (KET) in the treatment of pain after oral surgery. Also, it was the aim of the study to evaluate the relationship between adverse events and different doses of LNX. After the surgical removal of a mandibular third molar, test medication was taken when the patients experienced at least moderate pain. After medication, pain relief, pain intensity, and any discomfort from the medication were noted in a questionnaire. Paracetamol was used as rescue medication. A total of 278 patients completed the study according to the protocol. The primary efficacy parameter was total pain relief after 6 hours, and all active treatments showed significantly better effect than placebo, with LNX 16 and 32 mg being significantly superior to LNX 4 mg. All other efficacy parameters showed the same dose-effect relationship. A total of 37 adverse events were reported evenly distributed in the 6 treatment groups; only 3 of these were considered severe, and all disappeared without treatment. In conclusion, the study showed a dose-effect relationship of LNX without a rise in adverse events. The effect of 10 mg KET seemed to be at the level of 8 to 16 mg LNX.


Intrathecal injection of KN93 attenuates paradoxical remifentanil-induced postoperative hyperalgesia by inhibiting spinal CaMKII phosphorylation in rats.
Remifentanil is a short-acting and highly selective mu opiate agonist that is used in many clinical surgical situations for intraoperative pain relief. Under certain conditions, remifentanil can produce "paradoxical" hyperalgesia. This study aims to investigate mechanisms of actions mediating this "paradoxical" effect. Sprague-Dawley rats were divided into 6 groups including control and treatment groups. The paw withdrawal mechanical threshold and the paw withdrawal thermal latency of the rats were tested. The changes of rat behaviors were measured at 24h before intrathecal injection and at 2h, 6h, 24h, and 48h after operation. According to the changes in behavioral indicators of pain, the specimens of all groups were collected at 2h, 6h, 24h, and 48h after the operation. The level of calcium/calmodulin-dependent protein kinase II (CaMKII) phosphorylation in the spinal dorsal horn was analyzed by Western blotting. Intraoperative infusion of remifentanil induced postoperative hyperalgesia in the rats. Intrathecal KN93 injection increased nociceptive thresholds of paw withdrawal mechanical threshold and paw withdrawal thermal latency in a dose-dependent manner. Western blotting results showed that CaMKII phosphorylation in the spinal dorsal horn was increased significantly by remifentanil. Inhibition of CaMKII phosphorylation relieved the hyperalgesia pain state. Intrathecal injection of KN93 attenuates postoperative hyperalgesia induced by intraoperative infusion of remifentanil in rats through inhibiting spinal CaMKII phosphorylation.


Simultaneous fNIRS and thermal infrared imaging during cognitive task reveal autonomic correlates of prefrontal cortex activity.
Functional Near Infrared-Spectroscopy (fNIRS) represents a powerful tool to non-invasively study task-evoked brain activity. fNIRS assessment of cortical activity may suffer for contamination by physiological noises of different origin (e.g. heart beat, respiration, blood pressure, skin blood flow), both task-evoked and spontaneous. Spontaneous changes occur at different time scales and, even if they are not directly elicited by tasks, their amplitude may result task-modulated. In this study, concentration changes of hemoglobin were recorded over the prefrontal cortex while simultaneously recording the facial temperature variations of the participants through functional infrared thermal (fIR) imaging. fIR imaging provides touch-less estimation of the thermal expression of peripheral autonomic. Wavelet analysis revealed task-modulation of the very low frequency (VLF) components of both fNIRS and fIR signals and strong coherence between them. Our results indicate that subjective cognitive and autonomic activities are intimately linked and that the VLF component of the fNIRS signal is affected by the autonomic activity elicited by the cognitive task. Moreover, we showed that task-modulated changes in vascular tone occur both at a superficial and at larger depth in the brain. Combined use of fNIRS and fIR imaging can effectively quantify the impact of VLF autonomic activity on the fNIRS signals.


Is high-dose cholecalciferol justified in children with chronic kidney disease who failed low-dose maintenance therapy?
We aimed to investigate the effect of single, high-dose intramuscular cholecalciferol on vitamin D3 and intact parathyroid hormone (iPTH) levels in children with chronic kidney disease (CKD). Between January 2012 and June 2012, we conducted a prospective, uncontrolled study at the Pediatric Nephrology Unit of King Abdulaziz University Hospital, Jeddah, to investigate the effect of single, high-dose intramuscular vitamin D3 on 25(OH)D3 and iPTH levels in vitamin D insufficient/deficient children with CKD. Serum vitamin D3, iPTH, calcium, phosphate, alkaline phosphatase (ALP), and creatinine levels were measured before intramuscular vitamin D3 (300,000 IU) administration, and these were subsequently repeated at 1 and 3 months after treatment. Statistical analysis was performed with the Statistical Package for the Social Sciences (SPSS Inc., Chicago, IL, USA). Nineteen children fulfilled the criteria. At 3 months after treatment, vitamin D3 levels were significantly higher than at baseline (p < 0.001) but lower than the levels at 1 month. iPTH levels decreased significantly at 3 months (p = 0.01); however, the drop in iPTH levels was not significant at 1 month (p = 0.447). There were no changes in calcium, phosphate, ALP, or creatinine levels after treatment. Single-dose intramuscular vitamin D3 (300,000 IU) resulted in significant improvement of vitamin D3 and iPTH levels in children with CKD.


Complementary therapies: the appeal to general practitioners.
Pragmatism--among consumers seeking a cure and among general practitioners seeking clinical results and more patients--is not a complete explanation for the burgeoning of complementary and alternative medicine (CAM) in Western societies. Instead, this growth is substantially a result of pervasive and rapid social change, alternatively termed 'globalisation' and 'postmodernisation'. Globalisation and postmodernisation are creating a new social reality, of which a prominent characteristic is the proliferation of consumer choice. GPs are enmeshed in this social change and subject to the trend to greater choice--both their patients' and their own. On the one hand, GPs are reacting to social change as "economic pragmatists", responding to consumers' increasing demand for CAM. On the other hand, GPs themselves are acting as agents of social change by acknowledging the limitations of orthodox biomedical treatments and promoting CAM as part of their service delivery. Lack of scientific validation of CAM has not prevented GPs' use of such therapies. The phrase "clinical legitimacy" can be seen as a trump card that overrides "scientific legitimacy". It is the shibboleth of a postmodern movement among GPs towards healing and the "art" of medicine, as opposed to the "science" of medicine per se.


Analysis of the induction and deinduction of tyrosine aminotransferase in enucleated HTC cells.
Anucleate HTC cells have been used to determine the importance of the nucleus in the regulation of the intracellular levels of tyrosine aminotransferase (TAT) in hepatoma tissue culture (HTC) cells. In the absence of the nucleus, neither the induction of the enzyme by dexamethasone nor its deinduction upon removal of the hormone occurs. Degradation of the enzyme takes place when protein synthesis is inhibited in anucleates by cycloheximide. Therefore, the maintenance of induced levels of enzyme activity after dexamethasone withdrawal from pre-induced anucleates suggest that the nucleus is required for the inactivation of the TAT mRNA.


Advanced-stage hepatocellular carcinoma with portal vein thrombosis: conventional versus drug-eluting beads transcatheter arterial chemoembolization.
Our study sought to compare the overall survival in patients with hepatocellular carcinoma (HCC) and portal venous thrombosis (PVT), treated with either conventional trans-arterial chemoembolization (cTACE) or drug-eluting beads (DEB) TACE. This retrospective analysis included a total of 133 patients, treated without cross-over and compared head-to-head by means or propensity score weighting. Mortality was compared using survival analysis upon propensity score weighting. Adverse events and liver toxicity grade ≥3 were recorded and reported for each TACE. In order to compare with historical sorafenib studies, a sub-group analysis was performed and included patients who fulfilled the SHARP inclusion criteria. The median overall survival (MOS) of the entire cohort was 4.53 months (95 % CI, 3.63-6.03). MOS was similar across treatment arms, no significant difference between cTACE (N = 95) and DEB-TACE (N = 38) was observed (MOS of 5.0 vs. 3.33 months, respectively; p = 0.157). The most common adverse events after cTACE and DEB- TACE, respectively, were as follows: post-embolization syndrome [N = 57 (30.0 %) and N = 38 (61.3 %)], diarrhea [N = 3 (1.6 %) and N = 3 (4.8 %)], and encephalopathy [N = 11 (5.8 %) and N = 2 (3.2 %)]. Our retrospective study could not reveal a difference in toxicity and efficiency between cTACE and DEB-TACE for treatment of advanced stage HCC with PVT. • Conventional TACE (cTACE) and drug-eluting-beads TACE (DEB-TACE) demonstrated equal safety profiles. • Survival rates after TACE are similar to patients treated with sorafenib. • Child-Pugh class and tumor burden are reliable predictors of survival.


A local reaction at or near injection site: case definition and guidelines for collection, analysis, and presentation of immunization safety data.
The need for developing a case definition and guidelines for a local reaction at or near the injection site, methods for the development of the case definition and guidelines as an adverse event following immunization as well as the rationale for selected decisions about the case definition for a local reaction at or near the injection site are explained in the Preamble section. The case definition is structured in 2 levels of diagnostic certainty: level 1 includes any description of morphological or physiological change at or near the injection site that is described or identified by a healthcare provider. Level 2 is any description of morphological or physiological change at or near injection site that is described by any other person. In Guidelines section, the working group recommends to enable meaningful and standardized data collection, analysis, and presentation of information about a local reaction at or near the injection site. However, implementation of all guidelines might not be possible in all settings. The availability of information may vary depending upon resources, geographic region, and whether the source of information is a prospectively designed clinical trial, a post-marketing surveillance or epidemiologic study, or an individual report of a local reaction at injection site.


Study of the uncertainty in the determination of the absorbed dose to water during external beam radiotherapy calibration.
To achieve a good clinical outcome in radiotherapy treatment, a certain accuracy in the dose delivered to the patient is required. Therefore, it is necessary to keep the uncertainty in each of the steps of the process inside some acceptable values, which implies a global uncertainty as low as possible. This work is focused on the uncertainty evaluation of absorbed dose to water in the routine calibration for clinical beams, in the range of energies used in external radiotherapy. With this aim, different uncertainty components (corrected electrometer reading, calibration factor, beam quality correction factor and reference conditions) associated to beam calibration have been considered. Results show a typical uncertainty in the determination of absorbed dose to water during beam calibration around 1.3% for photon beams and 1.5% for electron beams (k=1 in both cases) when the N(D,w) formalism is used and is theoretically calculated. These values may be different depending on the uncertainty provided by the standards laboratory for calibration factor, which is shown in the work. If the total application of the N(D,w) formalism, that is to say, specific calibrations of each chamber in the user's beam qualities, is taken into account the uncertainty in this step of the process could be placed close to 1.0%. Furthermore, the possibility of an uncertainty reduction with the absorbed dose to water formalism adoption against the air kerma one is discussed.


The effect of clomiphene citrate on human preovulatory oocyte maturation in vivo.
Sixty-four infertile women underwent diagnostic laparoscopy in the periovulatory period at time-bracketed intervals following their endogenous luteinizing hormone (LH) surge. Forty-eight of these women were studied during natural cycles and 16 had mild oligoovulation and were administered clomiphene citrate (CC) to regulate their cycles. No patient received human chorionic gonadotropin. No patient was undergoing either in vitro fertilization (IVF) or gamete intrafallopian transfer (GIFT). Follicle puncture was performed and the oocytes were observed immediately for stage of maturation. Oocytes obtained from follicles exposed to CC were found to require an increased interval of time to reach metaphase I compared to oocytes obtained from natural cycles (27.75 +/- 2.2 vs 22.5 hr; mean +/- SE). Furthermore, the interval of time required for metaphase I oocytes to achieve metaphase II was statistically significantly shortened for CC cycles (2.4 hr for CC vs 10 hr for natural cycles. Nevertheless, there was no difference between natural and CC cycles in the time interval between LH surge onset and ovulation. These in vivo findings suggest a direct effect of CC on human oocyte maturation and may help explain the well-established discrepancy between the relatively high ovulation rate and the relatively low conception rate in clomiphene-induced cycles.


Reconstruction with β-tricalcium phosphate for giant cell tumor of the talus.
Giant cell tumor of bone (GCTB) is a locally aggressive tumor, commonly occurs in the long bones, and is rare in the talus and the foot. The talus is a weight-bearing bone and strut reconstruction is preferred. Reconstruction with low porosity β-tricalcium phosphate (β-TCP) blocks is reported for GCTB in the knee. In the current report, a 25-year-old female suffered from GCTB in the talus extending to the subchondral bone. The tumor was treated by curettage and the bone was reconstructed with low porosity β-TCP blocks, which have strong compressive strength. The implanted β-TCP blocks were incorporated successfully. The current reconstruction method can be applied for GCTB in the talus.


Chylothorax complicating thoracic surgery: conservative or early surgical management?
Postoperative chylothorax is a rare complication in thoracic surgery. There is considerable controversy concerning the management of chylothorax with some physicians favoring conservative treatment while others favor a surgical one. Considering the current surgical experience with VATS and by reviewing the problems and outcome of conservative management, the guidelines regarding timing of surgery in patients with chylous leak need to be revised.


Simple probe for localized cryogenic blockade in the brain.
The construction of a simple probe utilizing an air-space thermal insulation and circulating coolant for localized cooling of brain tissue is described. Results of isotherm studies in the cerebellum and electrophysiological observations in the motor cortex are presented indicating the effectiveness of localized cooling by the probe.


Interactive effect of long-term mental stress and cardiac stress reactivity on carotid intima-media thickness: the Cardiovascular Risk in Young Finns study.
The present study examined the interaction between vital exhaustion and cardiac reactivity and recovery on preclinical atherosclerosis assessed by carotid intima-media thickness (IMT) in young men and women. We measured heart rate (HR), respiratory sinus arrhythmia (RSA), and pre-ejection period (PEP) in response to mental arithmetic and speech tasks. Vital exhaustion and carotid IMT were also measured. Significant associations were observed for men aged 28-37 years, but not for men aged 22-25 years, nor for women in these age groups. It was shown that, among highly exhausted men in the older age group, lower HR reactivity was related to greater IMT. Our results also imply that, among non-exhausted men in this age group, slow HR and RSA recovery after acute stress predicted higher IMT. These results suggest that long-term stress as assessed by vital exhaustion is a risk only if it has resulted in ineffective cardiac stress reactivity. Autonomic imbalance resulting from chronic stress may be the common mechanism linking vital exhaustion and cardiac responsiveness to an increased risk of atherosclerosis.


Enhanced lethality and tissue levels of chloroquine in rats pretreated with pyrogen.
The lethality, and concentrations of chloroquine in plasma, brain liver and heart, in control and pyrogen-treated rats were investigated. Pyrogen treatment increased the lethality, the convulsive activity, plasma and myocardial concentrations of chloroquine significantly. The results suggest that the initiation of therapy with chloroquine in acute febrile conditions may require smaller than usual dosage.


Aggregation of the metallocycles {Cu8} and {Cu20} using [Cu(bp)] units (H2bp = bis(2-hydroxybenzyl)amine): structures and magnetic properties.
Two metallocycles, {Cu8(bp)4(OH)4(H2O)4(ClO4)4} (1) and {Cu20(bp)20} (2), were afforded by the reactions of the semi-flexible tridentate ligand bis(2-hydroxybenzyl)amine (H2bp) with Cu(ClO4)2·6H2O and Cu(OAc)2·H2O. Complex 1 has a saddle-shaped cyclic structure and complex 2 has a nanosized wheel-shaped structure. The two compounds consist of [Cu(bp)] units.


Forecasting carbon emissions from energy consumption in Guangdong Province, China with a novel grey multivariate model.
Carbon dioxide has a significant impact on global climate change due to its natural greenhouse effect. The objective and credible forecast of carbon emissions is very important for the government to formulate and implement the corresponding emission reduction targets. For controlling the growth of carbon emissions, Chinese government has put forward the low-carbon pilot policy and carbon trading policy. However, the existing grey models cannot measure the impact of policies and their interactions. In order to remedy the defect, a novel grey multivariable model based on dummy variables and their interactions is established. Two kinds of grey multivariable models and back propagation neural network model are chosen as comparison models to highlight that the introduction of dummy variables and their interactions plays an important part in improving the model performance. To verify the effectiveness, these four models are selected to simulate and predict the carbon emissions generated from primary energy consumption in Guangdong Province of China. The empirical results indicate that the mean absolute percentage errors of the novel model are 2.87% and 0.86%, respectively, which is significantly better than these three competing models. Finally, based on the outstanding performance of the novel model, it is chosen to forecast the fluctuating tendency of carbon emissions in the next 5 years.


Deletion mutations in Duchenne muscular dystrophy (DMD) in Western Saudi children.
Duchenne and Becker muscular dystrophy (DMD and BMD) are caused, in the majority of cases, by deletions in the dystrophin gene (DMD). The disease is an X-linked neuromuscular diseases typically caused by disrupting (DMD) or non-disrupting (BMD) the reading frame in the dystrophin (DMD) gene. In the present study, amplifications of the genomic DNAs of unrelated 15 Saudi DMD males were carried out using multiplex polymerase chain reaction (PCR) for nine-hotspot regions of exons 4, 8, 12, 17, 19, 44, 45, 48 and 51. We detected six Saudi patients having deletions in a frequency of 40%. The frequency of deletions in exon 51 (20%) was the most common deletion frequently associated with our Saudi sample males. Exons 19, 45, and 48 were present in a frequency of 6.7% each. All deletions were recognized as an individual exonic deletions, while no gross deletion where detected. Finally, the molecular deletions in the Saudi males was expected to be characterized by a moderate frequency among different populations due to the geographical KSA region, which it is in the crossroad of intense migrations and admixture of people coming from continental Asia, Africa, and even Europe. In conclusion, attempts to include an extra DNA samples might reflect a valid vision of the deletions within the high frequency deletion regions (HFDR's) in the DMD gene mutations in KSA.


Continuous-flow hydration-condensation reaction: Synthesis of α,β-unsaturated ketones from alkynes and aldehydes by using a heterogeneous solid acid catalyst.
A simple, practical and efficient continuous-flow hydration-condensation protocol was developed for the synthesis of α,β-unsaturated ketones starting from alkynes and aldehydes by employing a heterogeneous catalyst in a flow microwave. The procedure presents a straightforward and convenient access to valuable differently substituted chalcones and can be applied on multigram scale.


Unsuccessful treatment attempt: cord blood stem cell transplantation in a patient with Niemann-Pick disease type A.
Niemann-Pick disease type A (NP-A; OMIM 257200) is an autosomal recessive lysosomal storage disorder caused by deficiency of acid sphingomyelinase and resulting in accumulation of sphingomyelin, unesterified cholesterol, and other complex lipids in many tissues. It is characterized by failure to thrive, hepatosplenomegaly, and a rapidly progressive neurodegenerative course culminating in death by 3 years of age. There is no known effective treatment. We report the case of a prenatally diagnosed girl who underwent cord blood stem cell transplantation (CBSCT) at 3 months of age. She was neurologically intact at the time of CBSCT. Hepatosplenomegaly, was detected at 6 weeks of age; the splenomegaly resolved following CBSCT. Recovery was complicated by graft-versus-host disease. She subsequently developed and continues to show marked global developmental delay, generalized hypotonia, and signs of neurological regression, despite continued engraftment. Bilateral cherry red spots were detected at 10 months of age, 7 months post-CBSCT. Although she is doing better than her affected brother, she shows little overall benefit from CBSCT.


Bedtime Routines Intervention for Children (BRIC) project: results from a non-randomised feasibility, proof-of concept study.
Bedtime routines are highly recurrent family activities with implications for children's wellbeing, development and health. The objective of this study is to co-develop and test in a feasibility, proof-of-concept study a bedtime routines intervention using text messages aimed at first-time parents with young children. Fifty first-time parents with children aged 1-3 years were recruited for this study. Parents received a text message-based intervention for 7-consecutive nights which provided support and information on achieving optimal bedtime routines. Parents completed pre- and post-intervention questionnaires focusing on children's sleep, bedtime routines and parental mood disturbance. Feedback was provided at the end of the study. Recruitment target and high retention with 98%, or 49 out of 50 participants completing the study were achieved. Pre- and post-intervention, there were improvements in total children's sleep with children sleeping longer and having less disrupted sleep overall (MD = - 7.77 (SD = 17.91), t(48) = - 3.03, p = .004, CI (- 12.91, - 2.63) and in overall quality of bedtime routines (MD = - 5.00, SD = 7.01, t(48) = - 4.98, p < .001, CI (- 7.01, - 2.98). Parental mood disturbance decreased pre- to post-intervention (MD = 5.87, SD = 15.43, t(48) = 2.66), p = .010, CI (1.44, 10.30). Parents provided positive feedback about the intervention and valued the support that was provided to them. Bedtime routines were successfully altered with short-term benefits for children's sleep and parental mood. Future research will need to utilize a more robust, longitudinal approach for a definite exploration of sustained changes in bedtime routines and their long-term implications for children and parents.


Genome-wide epigenetic and proteomic analysis reveals altered Notch signaling in EPC dysfunction.
Endothelial progenitor cells (EPCs) are bone-marrow-derived mononuclear cells that participate in tube formation in vitro and vessel formation in vivo. EPC transplantation, as a therapeutic approach in cardiovascular diseases, has produced mixed results likely due to underlying disease states and environmental factors affecting EPC function. In this study, we investigated the mechanisms by which a high-salt diet impairs EPC function. The number of endothelial progenitor cells (CD34(+), VEGFR2(+), CD133(+), and c-Kit(+)) was decreased in the bone marrow of Sprague-Dawley (SD) rats fed a high-salt diet (HSD; 4% NaCl) as compared to SD rats on a normal-salt diet (NSD; 0.4% NaCl). NSD EPCs augmented endothelial cell tube formation in vitro, whereas HSD EPCs did not. NSD EPCs were a potent therapeutic restoring electrical stimulation-induced angiogenesis in vivo. HSD EPCs were not able to restore angiogenesis in vivo. EPC DNA methylation was analyzed by reduced representative bisulfite sequencing and membrane proteins were analyzed using high accuracy liquid chromatography mass spectrometry. Differentially methylated genes and differentially abundant membrane proteins measured between the NSD and HSD EPCs, revealed a total of 886 gene-protein sets where reciprocal methylation and expression occurred. Based on stringent criteria, Notch4 was found to be hypermethylated in HSD EPCs and had corresponding decrease in protein expression. Suppression of Notch4 protein expression in EPCs using siRNA confirmed a role for Notch4 in EPC-mediated angiogenesis, suggesting Notch4 suppression as a mechanism by which high-salt diet inhibits EPC-mediated angiogenesis.


The treatment with sGC stimulator improves survival of hypertensive rats in response to volume-overload induced by aorto-caval fistula.
Heart failure (HF) has been declared as global pandemic and current therapies are still ineffective, especially in patients that develop concurrent cardio-renal syndrome. Considerable attention has been focused on the nitric oxide (NO)/soluble guanylyl cyclase (sGC)/cyclic guanosine monophosphate (cGMP) pathway. In the current study, we aimed to investigate the effectiveness of sGC stimulator (BAY41-8543) with the same mode of action as vericiguat, for the treatment of heart failure (HF) with cardio-renal syndrome. As a model, we chose heterozygous Ren-2 transgenic rats (TGR), with high-output heart failure, induced by aorto-caval fistula (ACF). The rats were subjected into three experimental protocols to evaluate short-term effects of the treatment, impact on blood pressure, and finally the long-term survival lasting 210 days. As control groups, we used hypertensive sham TGR and normotensive sham HanSD rats. We have shown that the sGC stimulator effectively increased the survival of rats with HF in comparison to untreated animals. After 60 days of sGC stimulator treatment, the survival was still 50% compared to 8% in the untreated rats. One-week treatment with sGC stimulator increased the excretion of cGMP in ACF TGR (109 ± 28 nnmol/12 h), but the ACE inhibitor decreased it (-63 ± 21 nnmol/12 h). Moreover, sGC stimulator caused a decrease in SBP, but this effect was only temporary (day 0: 117 ± 3; day 2: 108 ± 1; day 14: 124 ± 2 mmHg). These results support the concept that sGC stimulators might represent a valuable class of drugs to battle heart failure especially with cardio-renal syndrome, but further studies are necessary.


Research Progress on the Pathogenesis of Aortic Dissection.
Aortic dissection is a critical cardiovascular disease due to the separation of media and adventitia caused by the rupture of vascular wall intima. The disease has a high mortality rate of about 1%-3% for each additional hour, since the adventitia of the aorta can rupture and bleed to death at any time. Although great progress has been made in clinical treatment of aortic dissection, and the mortality rate has been significantly reduced, the pathogenesis is still not very clear. At present, related studies have confirmed that inflammation of aortic wall promotes the occurrence and development of Aortic dissection. Although the mechanism of aortic dissection is more complicated, some studies have shown that the infiltration of monocytes/macrophages into the aortic wall is the main pathogenic mechanism of the disease. This review introduces the latest research results on the mechanism of macrophage infiltration and plasticity in aortic dissection.


Ballistic contractions in fast or slow human muscles: discharge patterns of single motor units.
1. Single motor units were recorded from the masseter, soleus and first dorsal interosseous muscles of normal adult man. An analysis of discharge patterns was carried out either during slow ramp voluntary contractions, or during self-initiated isolated ballistic voluntary contractions. The isometric myogram was simultaneously recorded.2. Each motor unit was only recruited when the peak force of a brisk contraction exceeded a certain value and a ;ballistic force threshold' (in kg) was estimated for the unit from a large series of brisk contractions of different strengths. For each muscle, the ranking order for recruitment of different motor units recorded from one electrode position was virtually identical in slow ramp versus brisk ballistic contractions of different force (Kendall rank correlation coefficient = 0.91-1.0). There was no evidence for any consistent selective activation of fast twitch motor units in ballistic contractions.3. The ballistic force threshold is considerably reduced with respect to the slow ramp force threshold for the motor units of the soleus muscle. This drop is also marked for the units of the first interosseous and tibialis anterior muscles, whereas it is only small for the units of the masseter muscle. These data have been validated after consideration of the complicating factor related to the possible differential involvement of synergic muscles in ramp or ballistic contractions.4. In the masseter and first interosseous muscles, the time to peak is about 80 msec in small ballistic voluntary contractions and it increases to about 150 msec in strong contractions. This effect appears related to repetitive discharges of single motor units when their force threshold is exceeded. By contrast, in the soleus muscle, the time to peak remains at about 150 msec both in small and in strong ballistic contractions and most soleus motor units fire only one spike in the ballistic burst.5. Brisk ballistic contractions are graded in force by the recruitment of additional motor units according to their usual rank order. The importance of rate gradation through the repetitive firing of motor units varies in the different human muscles investigated, being quite significant in isometric brisk contractions of the masseter and first interosseous muscles but much less so in the soleus muscle in which little repetitive firing of single motor units was observed over the range of ballistic forces studied.


Benign biliary strictures refractory to standard bilioplasty treated using polydoxanone biodegradable biliary stents: retrospective multicentric data analysis on 107 patients.
To assess mid-term outcome of biodegradable biliary stents (BBSs) to treat benign biliary strictures refractory to standard bilioplasty. Institutional review board approval was obtained and patient consent was waived. 107 patients (61 males, 46 females, mean age 59 ± 16 years), were treated. Technical success and complications were recorded. Ninety-seven patients (55 males, 42 females, aged 57 ± 17 years) were considered for follow-up analysis (mean follow-up 23 ± 12 months). Fisher's exact test and Mann-Whitney U tests were used and a Kaplan-Meier curve was calculated. The procedure was always feasible. In 2/107 cases (2 %), stent migration occurred (technical success 98 %). 4/107 patients (4 %) experienced mild haemobilia. No major complications occurred. In 19/97 patients (18 %), stricture recurrence occurred. In this group, higher rate of subsequent cholangitis (84.2 % vs. 12.8 %, p = 0.001) and biliary stones (26.3 % vs. 2.5 %, p = 0.003) was noted. Estimated mean time to stricture recurrence was 38 months (95 % C.I 34-42 months). Estimated stricture recurrence rate at 1, 2, and 3 years was respectively 7.2 %, 26.4 %, and 29.4 %. Percutaneous placement of a BBS is a feasible and safe strategy to treat benign biliary strictures refractory to standard bilioplasty, with promising results in the mid-term period. • Percutaneous placement of a BBS is 100 % feasible. • The procedure appears free from major complications, with few minor complications. • BBSs offer promising results in the mid-term period. • With a BBS, external catheter/drainage can be removed early. • BBSs represent a new option in treating benign biliary stenosis.


Synthesis of docosahexaenoic acid derivatives designed as novel PPARgamma agonists and antidiabetic agents.
To discover novel peroxisome proliferator-activated receptor gamma (PPARgamma) agonists that could be used as antidiabetic agents, we designed docosahexaenoic acid (DHA) derivatives (2 and 3), which have a hydrophilic substituent at the C4-position, based on the crystal structure of the ligand-binding pocket of PPARgamma. These compounds were synthesized via iodolactone as a key intermediate. We found that both DHA derivatives (2 and 3) showed PPARgamma transactivation higher than, or comparable to, that of pioglitazone, which is a TZD derivative used as an antidiabetic agent. DHA derivatives related to these potent compounds 2 and 3 were also synthesized to study structure-activity relationships. Furthermore, 4-OH DHA 2, which shows strong PPARgamma transcriptional activity, was separated as an optically pure form.


Three-dimensional free breathing whole heart cardiovascular magnetic resonance T1 mapping at 3 T.
This study demonstrates a three-dimensional (3D) free-breathing native myocardial T1 mapping sequence at 3 T. The proposed sequence acquires three differently T1-weighted volumes. The first two volumes receive a saturation pre-pulse with different recovery time. The third volume is acquired without magnetization preparation and after a significant recovery time. Respiratory navigator gating and volume-interleaved acquisition are adopted to mitigate misregistration. The proposed sequence was validated through simulation, phantom experiments and in vivo experiments in 12 healthy adult subjects. In phantoms, good agreement on T1 measurement was achieved between the proposed sequence and the reference inversion recovery spin echo sequence (R2 = 0.99). Homogeneous 3D T1 maps were obtained from healthy adult subjects, with a T1 value of 1476 ± 53 ms and a coefficient of variation (CV) of 6.1 ± 1.4% over the whole left-ventricular myocardium. The averaged septal T1 was 1512 ± 60 ms with a CV of 2.1 ± 0.5%. Free-breathing 3D native T1 mapping at 3 T is feasible and may be applicable in myocardial assessment. The proposed 3D T1 mapping sequence is suitable for applications in which larger coverage is desired beyond that available with single-shot parametric mapping, or breath-holding is unfeasible.


Public perceptions of non-adherence to pandemic protection measures by self and others: A study of COVID-19 in the United Kingdom.
Novel viral pandemics present significant challenges to global public health. Non-pharmaceutical interventions (e.g. social distancing) are an important means through which to control the transmission of such viruses. One of the key factors determining the effectiveness of such measures is the level of public adherence to them. Research to date has focused on quantitative exploration of adherence and non-adherence, with a relative lack of qualitative exploration of the reasons for non-adherence. To explore participants' perceptions of non-adherence to COVID-19 policy measures by self and others in the UK, focusing on perceived reasons for non-adherence. Qualitative study comprising 12 focus groups conducted via video-conferencing between 25th September and 13th November 2020. Participants were 51 UK residents aged 18 and above, reflecting a range of ages, genders and race/ethnicities. Data were analysed using a thematic approach. Participants reported seeing an increase in non-adherence in others over the course of the pandemic. Reports of non-adherence in self were lower than reports of non-adherence in others. Analysis revealed six main themes related to participants' reported reasons for non-adherence in self and others: (1) 'Alert fatigue' (where people find it difficult to follow, or switch off from, information about frequently changing rules or advice) (2) Inconsistent rules (3) Lack of trust in government (4) Learned Helplessness (5) Resistance and rebelliousness (6)The impact of vaccines on risk perception. Participants perceived a number of systemic failures (e.g. unclear policy, untrustworthy policymakers) to strongly contribute to two forms non-adherence-violations and errors. Findings suggest that latent and systemic failures-in the form of policy decisions that are commonly experienced as too changeable, inconsistent and confusing, and policy makers that are commonly perceived as untrustworthy-may play a significant role in creating the conditions that enable or encourage non-adherence.


Does early-life exposure to organophosphate insecticides lead to prediabetes and obesity?
Human exposures to organophosphate insecticides are ubiquitous. Although regarded as neurotoxicants, increasing evidence points toward lasting metabolic disruption from early-life organophosphate exposures. We gave neonatal rats chlorpyrifos, diazinon or parathion in doses devoid of any acute signs of toxicity, straddling the threshold for barely-detectable cholinesterase inhibition. Organophosphate exposure during a critical developmental window altered the trajectory of hepatic adenylyl cyclase/cyclic AMP signaling, culminating in hyperresponsiveness to gluconeogenic stimuli. Consequently, the animals developed metabolic dysfunction resembling prediabetes. When the organophosphate-exposed animals consumed a high fat diet in adulthood, metabolic defects were exacerbated and animals gained excess weight compared to unexposed rats on the same diet. At the same time, the high fat diet ameliorated many of the central synaptic defects caused by organophosphate exposure, pointing to nonpharmacologic therapeutic interventions to offset neurodevelopmental abnormalities, as well as toward fostering dietary choices favoring high fat intake. These studies show how common insecticides may contribute to the increased worldwide incidence of obesity and diabetes.


The interaction of direct and indirect risk selection.
This paper analyzes the interaction of direct and indirect risk selection in health insurance markets. It is shown that direct risk selection - using measures unrelated to the benefit package like selective advertising or 'losing' applications of high risk individuals - nevertheless has an influence on the distortions of the benefit package caused by indirect risk selection. Direct risk selection (DRS) may either increase or decrease these distortions, depending on the type of equilibrium (pooling or separating), the type of DRS (positive or negative) and the type of cost for DRS (individual-specific or not). Regulators who succeed in reducing DRS by, e.g., banning excessive advertising or implementing fines for 'losing' applications, may therefore (unintendedly) mitigate or exacerbate the distortions of the benefit package caused by indirect risk selection. It is shown that the interaction of direct and indirect risk selection also alters the formula for optimal risk adjustment.


The semen quality of the mobile phone users.
The increased use of mobile phones, the media's attention for general health, and the increase of idiopathic male infertility suggest to investigate the possible consequences of an excessive use of mobile phones on semen quality. To evaluate the conventional and some of the main biofunctional sperm parameters in healthy men according to the different use of the mobile phone. All the enrolled subjects in this study were divided into four groups according to their active cell phone use: group A= no use (no.=10 subjects); group B= <2 h/day (no.=16); group C= 2-4 h/day (no.=17); and group D= >4 h/day (no.=20). Among the subjects of the group D (>4 h/day), a further evaluation was made between the "trousers users"(no.=12) and "shirt users"(no.=8), and they underwent semen collection to evaluate conventional and biofunctional sperm parameters (density, total count, morphology, progressive motility, apoptosis, mithocondrial membrane potential, chromatin compaction, DNA fragmentation). None of the conventional sperm parameters examined were significantly altered. However, the group D and the trousers users showed a higher percentage of sperm DNA fragmentation compared to other groups. These results suggest that the sperm DNA fragmentation could represent the only parameter significantly altered in the subjects who use the mobile phone for more than 4 h/day and in particular for those who use the device in the pocket of the trousers.


Transcriptome analysis of stem wood of Nothapodytes nimmoniana (Graham) Mabb. identifies genes associated with biosynthesis of camptothecin, an anti-carcinogenic molecule.
Camptothecin (CPT), a monoterpene indole alkaloid, is a potent inhibitor of DNA topoisomerase I and has applications in treating ovarian, small lung and refractory ovarian cancers. Stem wood tissue of Nothapodytes nimmoniana (Graham) Mabb. (family Icacinaceae) is one of the richest sources of CPT. Since there is no genomic or transcriptome data available for the species, the present work sequenced and analysed transcriptome of stem wood tissue on an Illumina platform. From a total of 77,55,978 reads, 9,187 transcripts were assembled with an average length of 255 bp. Functional annotation and categorization of these assembled transcripts unraveled the transcriptome architecture and also a total of 13 genes associated with CPT biosynthetic pathway were identified in the stem wood tissue. Four genes of the pathway were cloned to full length by RACE to validate the transcriptome data. Expression analysis of 13 genes associated with CPT biosynthetic pathway in 11 different tissues vis-a-vis CPT content analysis suggested an important role of NnPG10H, NnPSLS and NnPSTR genes in the biosynthesis of CPT. These results indicated that CPT might be synthesized in the leaves and then perhaps exported to stem wood tissue for storage.


The relationship between the undergraduate clinical learning environment and work readiness in new graduate nurses: A pre-post survey study.
Due to projected nurse shortages, it is necessary that undergraduate programs optimise work readiness outcomes in new graduate nurses. Research that quantitatively evaluates characteristics of clinical nursing programs that predict increased work readiness is required. To explore the relationship between the undergraduate clinical learning environment and nurse perceptions of work readiness prior to and following, commencement as a new graduate nurse. A pre-post follow-up study. Undergraduates were surveyed at the end of their Bachelor's degree (baseline) and at 8-10 weeks after commencement as a graduate nurse (Time 1). A multi-site, metropolitan private hospital in Victoria, Australia. Nursing graduates who completed a university fellowship program (n = 26), or were undertaking their graduate year and had completed placement blocks within (n = 18) or outside (n = 31) the healthcare organisation. Participants self-completed the Clinical Learning Environment Inventory (CLEI) and Work Readiness Scale for Graduate Nurses (WRS-GN) at baseline and Time 1. Multiple regression analyses were performed. CLEI scores significantly predicted work readiness outcomes (all p-values<.05), accounting for 16-36% and 17-28% of the variance of WRS-GN scores at baseline and Time 1, respectively. After adjusting for clustering due to clinical placement groups, CLEI Individualisation (p = .023) and Valuing Nurses Work (p = .01) predicted improved Time 1 WRS-GN Organisational Acumen. CLEI Innovative and Adaptive Culture scores predicted poorer Time 1 Organisational Acumen (p = .001). Learning environments that offered high levels of individualised attention and valued nurses' work appeared to facilitate post-graduation engagement and identification with nursing practice. However, highly innovative and adaptive education may detract from optimal work readiness. Findings revealed that while important, the clinical learning environment only accounted for a small-to-moderate degree of nursing graduates' work readiness. To facilitate robust evidence-based improvement of clinical nursing education, future research should attempt to empirically establish the value of additional facilitators of work readiness.


Enzymatic activity of the Staphylococcus aureus SplB serine protease is induced by substrates containing the sequence Trp-Glu-Leu-Gln.
Proteases are of significant importance for the virulence of Staphylococcus aureus. Nevertheless, their subset, the serine protease-like proteins, remains poorly characterized. Here presented is an investigation of SplB protease catalytic activity revealing that the enzyme possesses exquisite specificity and only cleaves efficiently after the sequence Trp-Glu-Leu-Gln. To understand the molecular basis for such selectivity, we solved the three-dimensional structure of SplB to 1.8 A. Modeling of substrate binding to the protease demonstrated that selectivity relies in part on a canonical specificity pockets-based mechanism. Significantly, the conformation of residues that ordinarily form the oxyanion hole, an essential structural element of the catalytic machinery of serine proteases, is not canonical in the SplB structure. We postulate that within SplB, the oxyanion hole is only formed upon docking of a substrate containing the consensus sequence motif. It is suggested that this unusual activation mechanism is used in parallel with classical determinants to further limit enzyme specificity. Finally, to guide future development, we attempt to point at likely physiological substrates and thus the role of SplB in staphylococcal physiology.


The clinical value of detecting microcalcifications on a mammogram.
Many breast lesions are associated with microcalcifications that are detectable by mammography. In most cases, radiologists are able to distinguish calcifications usually associated with benign diseases from those associated with malignancy. In addition to their value in the early detection of breast carcinoma and accurate radiological diagnosis, the presence of microcalcifications often affects the extent of surgical intervention. Certain types of microcalcifications are associated with negative genetic and molecular characteristics of the tumor and unfavorable prognosis. Microcalcifications localized in the larger ducts (duct-centric, casting-type microcalcifications) represent an independent negative prognostic marker compared to lesions containing other types of microcalcifications and to non-calcified lesions. In this review, we summarize the theoretical and methodological background for understanding the clinical impact and discuss the diagnostic and prognostic value of microcalcifications detected in the breast by mammography.


Preparation and electrical properties of inorganic electride [Y2Ti2O6]2+(2e-).
Oxygen-depleted samples [Y2Ti2O7-x ]2x+(2xe-) (0 ≤ x ≤ 1.0) were prepared by reducing Y2TiO7 powders at 500 °C to 650 °C using CaH2 as a reductive agent, where x represents the content of , which was determined by thermogravimetric analysis. Powder X-ray diffraction patterns illustrate that the pure pyrochlore phase is kept for the samples with x ≤ 1.0, whereas the apparent x values surpass 1.0, and the impurity phase Y2O3 appears. The electride [Y2Ti2O7-x ]2x+(2xe-) (x ≈ 1.0) can be obtained under a reductive condition, in which the concentration of VO is 7.75 × 1021 cm-3. The electron paramagnetic resonance measurements gave the concentration of unpaired electrons in the electride as 1.30 × 1021 cm-3, indicating that the degree of the ionization of is less than 10%. Conductivity measurements for a sintered pellet sample (relative density ∼ 70%) indicate that the electride has quite high conductivity (∼1.09 S cm-1 at 300 K). The conduction was interpreted by using the variable range hopping mechanisms.


Effect of ionophorous anticoccidials on invasion and development of Eimeria: comparison of sensitive and resistant isolates and correlation with drug uptake.
Prophylactic levels of three ionophorous antibiotics, monensin, salinomycin, and lasalocid, were administered to groups of chickens and turkeys. All three ionophores markedly inhibited invasion of cecal tissues by sporozoites of ionophore-sensitive (IS) Eimeria tenella. Monensin and salinomycin also reduced invasion in turkeys by sporozoites of E. adenoeides, but lasalocid only minimally inhibited invasion. Invasion of ceca of monensin-medicated chickens was significantly greater by sporozoites of ionophore-resistant (IR) E. tenella than of the IS isolate. Concomitant experiments showed significant differences in [14C]monensin accumulation among IS and IR isolates of E. tenella. The decreased uptake of monensin by the IR isolates appeared to be accompanied by a decrease in responsiveness to the activity of monensin as well as to two other ionophores, salinomycin and narasin in cell culture. The amount of monensin, salinomycin or narasin required to inhibit development of E. tenella by 50% was 20 to 40 times higher for the IR isolates than for the IS ones. Collectively, the data suggest that differences in ionophore accumulation by IS and IR isolates of E. tenella might reflect differences in membrane chemistry and that these differences are responsible for the expressions of resistance that were observed in these studies. This expression of resistance appears to be common to all ionophores tested.


Fatty acid composition of tissue phospholipids and prostaglandin excretion in hyperlipidemia induced in rats by implantation of the mammotropic pituitary tumor MtT-F4.
A mammotropic pituitary tumor, MtT-F4, was implanted into male Fisher 344 rats for a period of 4 weeks. This tumor induced growth retardation, hyperlipidemia, hepatic hypertrophy and adrenal hyperplasia. Lipids were extracted from various tissues. In tumor-bearing rats, phospholipid concentration was found to be increased in plasma, spleen and testis. Distribution among the various phospholipid classes was similar to that of controls except in liver and heart, where phosphatidylcholine was increased at the expense of phosphatidylinositol and phosphatidylserine. The main difference was in the fatty acid composition of major phospholipids. The proportion of omega 6 fatty acids was lower and that of docosahexaenoic acid of the omega 3 series (22:6 omega 3) was higher in most tissues, especially in plasma, liver, heart and kidney. Concurrently, the urinary excretion of two endogenous metabolites of PGI2 (2,3-dinor-6-keto-PGF1 alpha and 6,15-diketo-13,14-dihydro-2,3-dinor-PGF1 alpha) was found to be increased significantly in tumor-bearing rats. The results raise the hypothesis that hormonal changes induced by the MtT-F4 tumor accelerate the conversion of arachidonic acid (20:4 omega 6) to prostaglandins. This effect, perhaps coupled with a diversion of linoleic acid (18:2 omega 6) towards other metabolic processes, would account for a partial depletion of membrane phospholipids in 18:2 omega 6 and for the reduced production of longer chain omega 6 unsaturated acids from 20:4 omega 6, creating a state of "relative essential fatty acid deficiency." As a result, the metabolism of omega 3 fatty acids is altered towards an enhanced production of 22:6 omega 3 which accumulates in the lipids of cell membranes to compensate for the depletion of unsaturated acids of the omega 6 series.


Pivotal role of high-mobility group box 1 (HMGB1) signaling pathways in glioma development and progression.
Human gliomas represent the most common type of intracranial tumors, with highest morbidity and mortality. They are characterized by excessive invasiveness and cell proliferation while their unclear boundaries predispose to tumor recurrence soon after conventional treatment. Elucidation of the molecular mechanisms implicated in their development and/or treatment resistance is highly demanded. The high-mobility group box 1 (HMGB1) protein, a highly conserved nuclear protein that functions as a chromatin-binding factor, facilitating nucleosome stabilization and regulating gene transcription, has been implicated in glioma formation and progression. Extracellular released HMGB1 binds to high-affinity receptors, including the receptor for advanced glycation end-products (RAGE) and toll-like receptor (TLR)-2, TLR-4, and TLR-9. Upon receptor binding, HMGB1 triggers the activation of key signaling pathways and immune responses, involved in the regulation of cell growth, differentiation, motility, and apoptosis. Based on the type of receptor and/or cell, HMGB1 is capable to promote oncogenesis or suppress tumor growth, thus affecting treatment efficacy. Herein, we discuss recent evidence implicating HMGB1 in glioma cell differentiation, proliferation, and metastasis with both clinical and prognostic significance. In addition, potential therapeutic approaches to target this protein in order to reduce chemoresistance of glioma cells are also addressed.


Thermodynamic study of the influence of NADPH on the binding of methotrexate and its metabolites to a mammalian dihydrofolate reductase.
Interaction of methotrexate and some of its metabolites with a mammalian dihydrofolate reductase was studied using two complementary methods, potentiometry and microcalorimetry. The major plasma metabolite of this anticancer agent, 7-hydroxymethotrexate, was found to have a different binding behavior from that of polyglutamyl derivatives and of methotrexate itself. Indeed, 7-hydroxymethotrexate binds without a pK shift to dihydrofolate reductase, whereas polyglutamyl derivatives bind to the enzyme with a proton uptake, as the parent drug does. NADPH increases the association constant of the 7-hydroxy metabolite by a factor of 10-20, while for methotrexate and for polyglutamates this increase is about 100-fold. It was demonstrated that the enhancement of the binding by NADPH had an enthalpic origin. Finally, the binding behavior of dihydrofolate reductase seemed to be independent of its enzymatic activity.


Chronic social instability stress down-regulates IL-10 and up-regulates CX3CR1 in tumor-bearing and non-tumor-bearing female mice.
Extensive literature has reported a link between stress and tumor progression, and between both of these factors and mental health. Despite the higher incidence of affective disorders in females and the neurochemical differences according to sex, female populations have been understudied. The aim of this study was therefore to analyze the effect of stress on tumor development in female OF1 mice. For this purpose, subjects were inoculated with B16F10 melanoma cells and exposed to the Chronic Social Instability Stress (CSIS) model. Behavioral, neurochemical and neuroendocrine parameters were analyzed. Female mice exposed to CSIS exhibited reduced body weight and increased arousal, but there was no evidence of depressive behavior or anxiety. Exposure to CSIS did not affect either corticosterone levels or tumor development, although it did provoke an imbalance in cerebral inflammatory cytokines, decreasing IL-10 expression (IL-6/IL-10 and TNF-α/IL-10); chemokines, increasing CX3CR1 expression (CX3CL1/CX3CR1); and glucocorticoid receptors, decreasing GR expression (MR/GR). In contrast, tumor development did not alter body weight and, although it did alter behavior, it did so to a much lesser extent. Tumor inoculation did not affect corticosterone levels, but increased the MR/GR ratio in the hippocampus and provoked an imbalance in cerebral inflammatory cytokines and chemokines, although differently from stress. These results underscore the need for experimental approaches that allow us to take sex differences into account when exploring this issue, since these results appear to indicate that the female response to stress is mediated by mechanisms different from those often proposed in relation to male mice.


The role of amygdala glutamate receptors in fear learning, fear-potentiated startle, and extinction.
Using a paradigm known as fear-potentiated startle, we have examined the neurobiological substrates of Pavlovian fear conditioning. In these experiments, rats are trained to fear an initially neutral stimulus by pairing that stimulus with shock. The amount of fear elicited by the stimulus [i.e., now a conditioned stimulus (CS)] is later assessed by presenting startle-eliciting noise bursts both in the presence and also the absence of the CS. After training, startle responses are typically greater in the presence of the CS. Findings reviewed here suggest that amygdala N-methyl-D-aspartate (NMDA) receptors play a key role in triggering the neural changes that support fear learning and also the loss of fear that accompanies extinction training. Amygdala (+/-)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors also participate in fear learning. However, unlike NMDA receptor antagonists, AMPA receptor antagonists also block fear-potentiated startle when infused prior to testing. Very recent data indicate that glutamate metabotropic Group II receptor agonists also block fear learning when infused into the amygdala prior to training, and block fear-potentiated startle when infused prior to testing. A fuller understanding of the role of amygdala glutamate systems in fear and fear learning may suggest novel pharmacological approaches to the treatment of clinical anxiety disorders.


Long Head of the Biceps Autograft Performs Biomechanically Similar to Human Dermal Allograft for Superior Capsule Reconstruction After Rotator Cuff Tear.
To provide a biomechanical comparison between human dermal (HD) allograft and long head of biceps tendon (LHBT) autograft with and without posterior side-to-side suturing for superior capsule reconstruction. Eight fresh-frozen cadaveric shoulder specimens were tested in 5 conditions: (1) intact, (2) complete supraspinatus tear, (3) LHBT, (4) LHBT with side-to-side suturing, and (5) HD allograft with side-to-side suturing. Functional abduction force, superior translation of humeral head, translational range of motion, and rotational range of motion were tested at 0°, 30°, 60°, and 90° of abduction within each condition. Data were analyzed using analysis of variance with post-hoc Tukey testing for pairwise comparison, with a significance value set at .05. Functional abduction force in the LHBT, LHBT + suture, and HD + suture conditions was significantly increased compared with the supraspinatus tear condition at abduction angles of 30° (P = .011, .001, and .017, respectively), 60° (P = .004, .001, and .002, respectively), and 90° (P = .013, .001, and .038, respectively). In addition, superior translation of the humeral head in the LHBT, LHBT + suture, and HD + suture conditions was significantly decreased compared with the tear condition at abduction angles of 30° (P = .03, .049, .03, respectively) and 60° (P = .02, .04, .03, respectively). All 3 reconstructive techniques were statistically identical to the intact rotator cuff condition in regard to translational and rotational range of motion. Superior capsule reconstruction with LHBT autograft without side-to-side suturing, LHBT with posterior side-to-side suturing, and HD allograft with posterior side-to-side suturing all equivalently restore functional abduction force and decrease superior translation of the humeral head after a complete supraspinatus tear. Superior capsule reconstruction with long head of the biceps tendon autograft and human dermal allograft both restore functional abduction force and decrease superior translation of the humeral head, while displaying no losses in the range of motion in a cadaveric model.


Differential transforming abilities of non-secreted and secreted forms of human fibroblast growth factor-1.
Fibroblast growth factor (FGF)-1(1-154), the precursor for acidic FGF-1(21-154), is a potent angiogenic polypeptide, the structure of which lacks a signal peptide sequence for secretion. To investigate the biological significance of this structural feature, we have attempted forced secretion of FGF-1 through fusion of the entire FGF-1 coding frame with the signal peptide (sp) from the hst/KS3 gene, a secretory member of the heparin-binding growth factor family. We also studied the transforming ability of the signal-less forms of FGF-1 comprising FGF(1-154) and FGF-1(21-154). The presence of a soluble and biologically active form of FGF-1 was readily detected in the conditioned medium of NIH 3T3 cells transfected with sp-hst/KS3:FGF-1(1-154) as demonstrated by Western blot analysis and DNA synthesis assays, whereas sp-hst/KS3:FGF-1(21-154) was not detectable in conditioned medium even though the protein was detected in cellular extracts. The secreted form of sp-hst/KS3:FGF-1(1-154) stimulated the proliferation of human umbilical vein endothelial cells in vitro and was able to induce receptor-mediated tyrosine phosphorylation. Furthermore, the forced secretion of biologically active FGF-1 resulted in NIH 3T3 cell transformation as demonstrated by altered morphology in vitro, the formation of discrete colonies in soft agarose, growth under serum-free conditions, and ability to rapidly form highly vascular tumors in vivo. Interestingly, sp-hst/KS3:FGF-1(21-154) also mediated the transition to a transformed phenotype despite the inability to detect extracellular FGF-1 in the media conditioned by these NIH 3T3 cell transfectants. Although the transfection of FGF-1(21-154) yielded similar NIH 3T3 cell morphologic changes, these transfectants did not grow under serum-free conditions or yield colonies in soft agarose, and formed tumors in vivo with delayed kinetics. Furthermore, the FGF-1(1-154) NIH 3T3 cell transfectants did not exhibit morphologic changes, and this may be due to the inability of mRNA to express protein. These data suggest that although non-sp forms of FGF-1 may alter the monolayer phenotype of NIH 3T3 cells in vitro, the ability of FGF-1 to transform NIH 3T3 cells requires the function of a sp-directed secretory pathway and suggests that this pathway increases tumorigenicity in vivo.


Lung Cancer in Non-smokers in Czech Republic: Data from LUCAS Lung Cancer Clinical Registry.
LUCAS is a clinical lung cancer registry (ClinicalTrials.gov identifier is NCT04228237), prospectively collecting data from newly diagnosed lung cancer patients in seven pneumooncology centers in the Czech Republic, since June 1, 2018. The aim of the study was to assess the stage of the disease at the time of diagnosis, percentage of morphological types, survival, percentage of driving mutations, eligibility for radical surgery, and percentage of patients who undergo radical surgery, in the non-smoking population in comparison with smokers and former smokers. The total number of patients in the registry at the time of the analysis was 2,743. Only 2,439 patients with complete records (smoking status, stage, and type of tumor) were included in this study. The analysis indicated that non-smokers are diagnosed at a later stage of the disease but they have a better survival rate than smokers. Fewer smokers with stage III disease who are eligible for radical surgery will undergo surgery compared to non-smokers with the same clinical stage. Driving mutations are more common in non-smokers, even after adjustment for the more frequent occurrence of adenocarcinoma in the group of non-smokers. The data from LUCAS registry are consistent with already known facts, suggesting that the LUCAS registry is a useful clinical tool.


Inferior epigastric artery pseudoaneurysm following trocar injury.
Herein is described the development of an inferior epigastric pseudoaneurysm caused by a trocar injury during laparoscopic surgery. After the accessory trocar was placed in the left lower quadrant, the patient's condition became clinically unstable, requiring blood transfusions postoperatively and transfer to our tertiary care center. On arrival, she continued to have pain, with a palpable tender mass in the left lower quadrant. A computed tomography scan revealed a 5 × 6-cm mass in the anterior rectus sheath, with central hyperattenuation. This was better characterized at ultrasonography. The findings were consistent with an unstable pseudoaneurysm from the left inferior epigastric artery, with surrounding hematoma. Urgent embolization was performed by Interventional Radiology using coils inserted distal, into, and proximal to the pseudoaneurysm. The patient's condition was stable after the procedure, and she returned to the referring hospital for convalescence. Pseudoaneurysm of the inferior epigastric artery from a trocar injury is a rare occurrence. This case is the first report of a pseudoaneurysm forming in the inferior epigastric artery resulting from a trocar injury during gynecologic surgery.


Systems biology-defined NF-kappaB regulons, interacting signal pathways and networks are implicated in the malignant phenotype of head and neck cancer cell lines differing in p53 status.
Aberrant activation of the nuclear factor kappaB (NF-kappaB) pathway has been previously implicated as a crucial signal promoting tumorigenesis. However, how NF-kappaB acts as a key regulatory node to modulate global gene expression, and contributes to the malignant heterogeneity of head and neck cancer, is not well understood. To address this question, we used a newly developed computational strategy, COGRIM (Clustering Of Gene Regulons using Integrated Modeling), to identify NF-kappaB regulons (a set of genes under regulation of the same transcription factor) for 1,265 genes differentially expressed by head and neck cancer cell lines differing in p53 status. There were 748 NF-kappaB targets predicted and individually annotated for RELA, NFkappaB1 or cREL regulation, and a prevalence of RELA related genes was observed in over-expressed clusters in a tumor subset. Using Ingenuity Pathway Analysis, the NF-kappaB targets were reverse-engineered into annotated signature networks and pathways, revealing relationships broadly altered in cancer lines (activated proinflammatory and down-regulated Wnt/beta-catenin and transforming growth factor-beta pathways), or specifically defective in cancer subsets (growth factors, cytokines, integrins, receptors and intermediate kinases). Representatives of predicted NF-kappaB target genes were experimentally validated through modulation by tumor necrosis factor-alpha or small interfering RNA for RELA or NFkappaB1. NF-kappaB globally regulates diverse gene programs that are organized in signal networks and pathways differing in cancer subsets with distinct p53 status. The concerted alterations in gene expression patterns reflect cross-talk among NF-kappaB and other pathways, which may provide a basis for molecular classifications and targeted therapeutics for heterogeneous subsets of head and neck or other cancers.


Diagnostic value of scratch-chamber test, skin prick test, histamine release and specific IgE in birch-allergic patients with oral allergy syndrome to apple.
The aim of the study was to examine the diagnostic value of skin prick test (SPT), scratch-chamber test (SCT), histamine release (HR) and specific immunoglobulin E (IgE) in birch-allergic patients with oral allergy syndrome to apple. Ten birch-allergic patients with oral allergy syndrome to apple and 10 control subjects were included. All were tested with SPT, SCT, HR and specific IgE [CAP, Pharmacia, Sweden and Magic Lite (ML), ALK-ABELLO, Denmark]. The SPT with apple, acetone extract of apple (A72) and commercial apple extract showed sensitivities of 0.80, 0.90 and 0.10, respectively. The SCT with the same extracts showed sensitivities of 0.30, 0.50 and 0.20, respectively. The sensitivity of specific IgE to apple were 0.90 (CAP) and 0.10 (ML). The sensitivity of the HR test was 90% (A72), and 25% using the commercial extract. The SPT and HR test with apple and A72 showed a good diagnostic value with a sensitivity of more than 70% and a specificity of 100%. The SCT showed a poor sensitivity to apple, A72 and commercial apple extract. The ML test was not suitable in detecting specific IgE to apple compared with the CAP test. In daily practice a detailed case history about symptoms of oral allergy syndrome combined with a SPT with fresh apple peel or A72 will be useful.


Low-level laser (light) therapy (LLLT) for treatment of hair loss.
Alopecia is a common disorder affecting more than half of the population worldwide. Androgenetic alopecia, the most common type, affects 50% of males over the age of 40 and 75% of females over 65. Only two drugs have been approved so far (minoxidil and finasteride) and hair transplant is the other treatment alternative. This review surveys the evidence for low-level laser therapy (LLLT) applied to the scalp as a treatment for hair loss and discusses possible mechanisms of actions. Searches of PubMed and Google Scholar were carried out using keywords alopecia, hair loss, LLLT, photobiomodulation. Studies have shown that LLLT stimulated hair growth in mice subjected to chemotherapy-induced alopecia and also in alopecia areata. Controlled clinical trials demonstrated that LLLT stimulated hair growth in both men and women. Among various mechanisms, the main mechanism is hypothesized to be stimulation of epidermal stem cells in the hair follicle bulge and shifting the follicles into anagen phase. LLLT for hair growth in both men and women appears to be both safe and effective. The optimum wavelength, coherence and dosimetric parameters remain to be determined.


An easy and rapid method to screen large numbers of antibodies against internal cellular determinants.
A rapid and easy method is described to screen great numbers of antisera or antibodies against internal cellular antigens including viral antigens or to screen various target cells for proper expression of antigens; the method can also be applied to determine fluorescent foci to enumerate non-cytopathic viruses. Cells, infected with a particular virus or uninfected, adhering to flat-bottomed 96-well microtiter plates were fixed with conventional phosphate-buffered saline containing 4% formaldehyde for 10 min, alternatively, cells were first fixed with 3% paraformaldehyde for 10 min and were then treated with Trition X-100 for another 10 min. After two washes, either fluorescein-labelled antiviral antibodies or first antiviral antibodies followed by labelled anti-species antibodies were applied, incubated and washed off as usual. A few drops of a balanced salt solution were kept in the well and were drained off gently just before the plates were examined. The plates were viewed directly in an inverted UV microscope or were inspected and photographed bottoms up with a conventional UV microscope mounted with an old-fashioned uncorrected objective (20 X) which, because of its shorter length, permitted proper focussing. For most cases studied, sensitivity was comparable to the fluorescence analysis method of cells on slides. The plates could be stored for several months in a dark refrigerator if kept moist. The method is rapid because it avoids individual handling of samples for the washing procedures and does not need growing and mounting of cells on slides; up to 1000 samples can be tested by one person in a day.


Does probiotic Kefir reduce dyslipidemia, hematological disorders and oxidative stress induced by zearalenone toxicity in wistar rats?
Zearalenone (ZEA) is a toxic metabolite of the genus Fusarium, which causes hepatotoxicity and induces oxidative stress. Kefir is an important probiotic dairy-product showing important in vitro antioxidant potential. In this study, the effect of Kefir supplementation to mitigate ZEA toxicity in rats was investigated. Animals were divided into four groups of five rats each, which received sterile milk (200 μL/day) during the first week. Then, they were switched to Kefir (200 μL/day), ZEA (40 mg/kg b. w./day) and Kefir + ZEA for the second week. Hematological and biochemical parameters, as well as liver histological analysis were determined. Kefir administration prevented the changes occurred in the count of all blood cells, and improved the antioxidant enzymes in the liver, such as catalase, glutathione peroxidase and superoxide dismutase activities that increased by 6, 4.5 and 1.3 folds, respectively, compared to ZEA group. Interestingly, the concurrent regimen Kefir + ZEA removed ZEA residues in the serum and liver. Furthermore, the Kefir + ZEA group showed a reduction in the levels of bilirubin, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase and hepatic malonaldehyde by ∼82, 54, 66, 50 and 36%, respectively, compared to the ZEA group. The histopathological analysis showed a normal liver histological architecture in Kefir + ZEA group, while degenerative changes were observed in ZEA group. These results suggest that Kefir as probiotic consortium may have a hepatoprotective effect against ZEA poisoning.


The MoSeS dynamic omnigami paradigm for smart shape and composition programmable 2D materials.
The properties of 2D materials can be broadly tuned through alloying and phase and strain engineering. Shape programmable materials offer tremendous functionality, but sub-micron objects are typically unachievable with conventional thin films. Here we propose a new approach, combining phase/strain engineering with shape programming, to form 3D objects by patterned alloying of 2D transition metal dichalcogenide (TMD) monolayers. Conjugately, monolayers can be compositionally patterned using non-flat substrates. For concreteness, we focus on the TMD alloy MoSe[Formula: see text]S[Formula: see text]; i.e., MoSeS. These 2D materials down-scale shape/composition programming to nanoscale objects/patterns, provide control of both bending and stretching deformations, are reversibly actuatable with electric fields, and possess the extraordinary and diverse properties of TMDs. Utilizing a first principles-informed continuum model, we demonstrate how a variety of shapes/composition patterns can be programmed and reversibly modulated across length scales. The vast space of possible designs and scales enables novel material properties and thus new applications spanning flexible electronics/optics, catalysis, responsive coatings, and soft robotics.