Erythropoeitin dose variation in different facilities in different countries and its relationship to drug resistance.
The correction of anemia using erythropoeitin (EPO) is accorded high priority in the management of patients undergoing hemodialysis (HD). Target hemoglobin (Hb) levels have been established in many countries. Following an observation that the mean facility EPO dose in a chain of facilities in the United States varied by more than two-fold, an examination of the practice of anemia correction in other settings was carried out. We reviewed demographic and laboratory parameters in prevalent HD patients in 50 United States facilities and in a single HD facility in Vicenza, Italy. The mean EPO dose profile of the United States facilities was compared with the profiles in 10 facilities in the eastern United Kingdom (UKER) and in 20 facilities reporting to the United Kingdom Renal Registry (UKRR). Analysis of the factors that correlate with EPO resistance was carried out using the United States and Italian data. The average EPO doses, by facility, in the 51 United States, the 10 UKER, and the 19 UKRR facilities were 19,569, 8,416, and 7,992 international units per week (IU/wk), respectively. While examination of the UKRR revealed a similar degree of inter-facility variation (2.6-fold), much larger doses of EPO were being administered in the United States patients, particularly in the low Hb group. Multivariate analysis of the United States data suggested that factors related to inflammation, including low albumin, the use of tunneled catheters for vascular access, and low protein catabolic rate (enPCR) correlated with low Hb and relative EPO resistance. Despite similar guidelines for anemia management, significant differences in practice are observed. While there seems to be a reluctance to administer large EPO doses to individual patients in Europe, this does not seem to apply in the United States, where more EPO is given. EPO resistance seems relative rather than absolute in many patients, allowing some to respond to the higher doses.


T Cell Factor 7 (TCF7)/TCF1 Feedback Controls Osteocalcin Signaling in Brown Adipocytes Independent of the Wnt/β-Catenin Pathway.
Osteocalcin has recently been shown to regulate energy homeostasis through multiple pathways. Adipose tissue is a main organ of energy metabolism, and administration of recombinant osteocalcin in mice promoted energy consumption, thus counteracting obesity and glucose intolerance. The regulation of osteocalcin in islet β cells has been well documented; however, it is unknown whether osteocalcin can also act on adipocytes and, if it does, how it functions. Here, we provide evidence to demonstrate a specific role for osteocalcin in brown adipocyte thermogenesis. Importantly, expression of the Gprc6a gene encoding a G protein-coupled receptor as an osteocalcin receptor was activated by brown fat-like differentiation. Moreover, Gprc6a expression could be further potentiated by osteocalcin. Meanwhile, overexpression and knockdown experiments validated the crucial role of Gprc6a in osteocalcin-mediated activation of thermogenic genes. For the first time, we identified Tcf7 and Wnt3a as putative targets for osteocalcin signaling. T cell factor 7 (TCF7) belongs to the TCF/LEF1 family of DNA binding factors crucial for the canonical WNT/β-catenin pathway; however, TCF7 modulates Gprc6a and Ucp1 promoter activation independent of β-catenin. Further studies revealed that the thermogenesis coactivator PRDM16 and the histone demethylase LSD1 might be required for TCF7 activity. Hence, our study described a TCF7-dependent feedback control of the osteocalcin-GPRC6A axis in brown adipocyte physiologies.


General properties of surface modes in binary metal-dielectric metamaterials.
We present general properties of surface modes in binary metal-dielectric metamaterials. We show mechanism for surface mode formation and analyze their existence conditions for semi-infinite metamaterials in the frame of couple mode theory.


Revisiting polymer surface diffusion in the extreme case of strong adsorption.
Revisiting polymer surface adsorption with a level of quantification not possible at the time of earlier seminal contributions to this field, we employ fluorescence microscopy to quantify the in-plane diffusion of end-labeled polystyrene adsorbed onto quartz and mica from cyclohexane solution, mostly at 25 °C. Care is taken to prohibit a surface-hopping mechanism, and the experimental techniques are adapted to measurements that persist for up to a few days. The main conclusion is that we fail to observe a single Fickian diffusion coefficient: instead, diffusion displays a broad multicomponent spectrum, indicating that the heterogeneity of surface diffusion fails to average out even over these long times and over distances (∼600 nm, the diameter of a diffraction-limited spot) greatly exceeding the size of the polymer molecules. This holds generally when we vary the molecular weight, the surface roughness, and the temperature. It quantifies the long-believed scenario that strongly adsorbed polymer layers (monomer-surface interaction of more than 1k(B)T) intrinsically present diverse surface conformations that present heterogeneous environments to one another as they diffuse. Bearing in mind that in spite of adsorption from dilute solution the interfacial polymer concentration is high, ramifications of these findings are relevant to the interfacial mobility of polymer glasses, melts, and nanocomposites.


Treatment Options for Failing Regenerative Endodontic Procedures: Report of 3 Cases.
Regenerative treatments in necrotic immature teeth are suggested as alternatives to conventional multiple or single-step apexification procedures. Although case reports and case series provide promising results, the treatment protocol is not yet fully established and regenerative procedure might fail. Once failure is encountered, the apexification treatment options still remain. Repetition of the regenerative procedure after initial revitalization failure has not been suggested yet. Here, 3 cases of failing regenerative endodontic procedures are reported. All 3 cases had been initially treated by single-step disinfection/revascularization procedures. In different time intervals, all cases showed signs of recurrent disease. The first case was managed with renegotiation and apical mineral trioxide aggregate plug placement; the second case was managed with renegotiation and conventional root canal treatment; and the third case was managed with renegotiation, long-term calcium hydroxide disinfection, and repetition of the regenerative endodontic procedure. Two years after the second intervention, all cases were considered successful. Repetition of failed regenerative treatment procedures might be a viable alternative to conventional apexification procedures.


Draft Genome Sequence of Lactobacillus plantarum IYO1511, Isolated from Ishizuchi-Kurocha.
Lactobacillus plantarum IYO1511, isolated from a traditional postfermented tea, is a predominant species associated with Ishizuchi-kurocha. Here, we report the whole-genome sequence of this bacterium. The draft genome comprises 3,229,083 nucleotides and 3,044 coding DNA sequences (CDSs), with an average G+C content of 44.5%.


The symbolic/value-expressive function of outgroup attitudes among homosexuals.
The claim that attitudes toward an outgroup symbolically represent beliefs that the outgroup violates important values was examined through the investigation of the intergroup versus intragroup nature of the relations between a sample of feminist lesbians (primarily involved in the women's movement), gay movement lesbians (primarily involved in the gay movement), and gay men. Consistent with the intergroup relations documented between some feminist women and men, feminist lesbians (compared with gay movement lesbians) had less favorable attitudes toward gay men, associated with fewer gay men, perceived less common fate with gay men, wished to cooperate less with gay men, and perceived less value similarity with gay men. These and other findings suggested that feminist lesbians shared an intergroup relationship with gay men, whereas gay movement lesbians and gay men shared an intragroup relationship. Consistent with the notion that intergroup attitudes symbolically represent beliefs that an outgroup violates important values, feminist lesbians' attitudes toward gay men were explained by their perceptions that gay men placed less importance on values they themselves regarded as important. The implications of these findings for understanding the nature of symbolic attitudes and subsequent research are discussed.


The Effect of Moderate- Versus High-Intensity Resistance Training on Systemic Redox State and DNA Damage in Healthy Older Women.
This study investigated effects of a 16-week progressive resistance training program (RTP) with elastic bands at two different intensities on systemic redox state, DNA damage, and physical function in healthy older women. Participants were randomly assigned to the high-intensity group (HIGH; n = 39), moderate-intensity group (MOD; n = 31), or control group (CG; n = 23). The exercise groups performed an RTP twice a week with three to four sets of 6 (HIGH) or 15 (MOD) repetitions of six overall body exercises at a perceived exertion rate of 8-9 on the OMNI-Resistance Exercise Scale for use with elastic bands. Thiol redox state was determined by reduced glutathione (GSH), oxidized glutathione (GSSG), and GSSG/GSH in blood mononuclear cells. Degree of DNA damage was assessed by presence of the oxidized DNA base molecule 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-OHdG) in urine. Physical function monitoring was based on the arm curl, chair stand, up and go, and 6-min walk tests. The HIGH group showed a significant increase in 8-OHdG (+71.07%, effect size [ES] = 1.12) and a significant decrease in GSH (-10.91, ES = -0.69), while the MOD group showed a significant decrease in 8-OHdG levels (-25.66%, ES = -0.69) with no changes in thiol redox state. GSH levels differed significantly between the HIGH and CG groups posttest. The exercise groups showed significant improvements in physical function with no differences between groups. RTP at a moderate rather than high intensity may be a better strategy to reduce DNA damage in healthy older women while also increasing independence.


Hypnotic Effects of Lactobacillus fermentum PS150TM on Pentobarbital-Induced Sleep in Mice.
The bidirectional communication between the gastrointestinal tract and the central nervous system appears to be functionally linked to the intestinal microbiome, namely the microbiome-gut-brain axis (MGBA). Probiotics with health benefits on psychiatric or neurological illnesses are generally called psychobiotics, and some of them may also be able to improve sleep by targeting the MGBA. This study aimed to investigate the effects of a psychobiotic strain, Lactobacillus fermentum PS150TM (PS150TM), on sleep improvement by using a pentobarbital-induced sleep mouse model. Compared with the vehicle control group, the oral administration of PS150TM, but not the other L. fermentum strains, significantly decreased the sleep latency and increased the sleep duration of mice, suggesting strain-specific sleep-improving effects of PS150TM. Moreover, the ingestion of diphenhydramine, an antihistamine used to treat insomnia, as a drug control group, only increased the sleep duration of mice. We also found that the sleep-improving effects of PS150TM are time- and dose-dependent. Furthermore, the oral administration of PS150TM could attenuate a caffeine-induced sleep disturbance in mice, and PS150TM appeared to increase the expression of the gene encoding the adenosine 1 receptor in the hypothalamus of mice, as assessed by quantitative real-time polymerase chain reaction. Taken together, our results present a potential application of PS150TM as a dietary supplement for sleep improvement.


Combination of radiosurgery and immunotherapy in brain metastases: balance between efficacy and toxicities.
The incidence of brain metastasis is high and still increasing. Among local therapies, stereotactic radiosurgery (SRS) is an effective treatment option, optimally sparing normal brain, even for multiple brain metastases. Immune checkpoint inhibitors (ICIs) become the new standard of care in an increasing number of cancers, and the combination SRS and ICI is often proposed to patients, but few data have been published on the efficacy and the toxicity of this association. Explaining this lack of consensus: retrospective studies with different primary cancers, various treatment lines and unknown levels of steroid exposure. Concerning the toxicity, the independent association of radionecrosis with brain-PTV volume was confirmed, and a decreased dose of SRS is now tested in a randomized study. Finally, a 'concurrent' delivery of SRS and ICI (within a 4 weeks' interval) seems the optimal schedule; fractionated radiosurgery for large brain metastasis should be favored. Radio-sensitizing nanoparticles and devices aiming to increase the permeability of the blood brain barrier should be considered in future combinations. The efficacy/toxicity balance of SRS-ICI combination should be regularly re-evaluated, anticipating continued progress in ICI and SRS delivery, with more long-survivors potentially exposed to long-term toxicities. Patients should be included in clinical trials and clearly informed to participate more closely in the final choice.


Painful extremities and neurological disorder in essential thrombocythaemia.
Six of 20 patients with essential thrombocythaemia had neurological features and 8 had peripheral vascular symptoms. Four had cerebrovascular ischaemia or stroke and 3 had gangrene. Pain in the extremities may be a striking symptom in this disorder.


Role of Perirectal Fat in the Carcinogenesis and Development of Early-Onset Rectal Cancer.
The incidence of early-onset rectal cancer (EORC) has been increasing since the past decade, while its underlying cause remained unknown. This study was aimed at clarifying the relationship between perirectal fat area (PFA) and EORC. Patients and Methods. All patients with rectal cancer who received radical excision between January 2016 and December 2017 at our hospital were included. The fat series images of pelvic magnetic resonance imaging scans were obtained and PFA at the ischial spine level was calculated using the ImageJ software. A total of 303 patients were finally included and divided into two groups according to the median PFA: Group 1 (<20.2 cm2, n = 151) and Group 2 (≥20.2 cm2, n = 152). PFA positively correlated with body weight and body mass index. PFA increased with invasion depth, lymph node metastasis, TNM stage, tumor deposits, and vascular invasion. Patients with EORC had higher PFA than those with late-onset rectal cancer (LORC; P = 0.009). Among patients with stage I-III rectal cancers, those in Group 2 had significantly shorter disease-free survival (P = 0.010) and overall survival (P = 0.034) than those in Group 1, and PFA was an independent predictor of disease-free survival (OR: 1.683 [1.126-3.015], P = 0.035) and overall survival (OR: 1.678 [1.022-2.639], P = 0.046). Patients with EORC had significantly higher PFA than those with LORC. PFA is positively correlated with T stage, N stage, TNM stage, tumor deposit, and vascular invasion and is an independent predictor of disease-free survival and overall survival. Therefore, perirectal fat may be involved in the carcinogenesis and development of EORC.


Health-related quality of life in patients with systemic lupus erythematosus and proliferative lupus nephritis.
This study investigated the influence of two different treatments for a kidney inflammation (i.e. proliferative lupus nephritis) on health-related quality of life (HRQoL) in patients with the chronic auto-immune disease systemic lupus erythematosus (SLE). One treatment protocol, the National Institutes of Health (NIH) protocol, was characterized by a high dose of cyclophosphamide (CYC, an immunosuppressive drug), and the second treatment, the Euro-Lupus protocol, involved a low-dose CYC. Thirty-two SLE patients were included based on the received treatment for an episode of proliferative lupus nephritis, according to either the Euro-Lupus or the NIH protocol. The two groups were compared on HRQoL as measured by the SF-36 and the SLE Symptom Checklist (SSC). The Euro-Lupus group (N = 16) tended to show a higher HRQoL than the NIH group (N = 16) on four of seven scales of the SF-36. In addition, the Euro-Lupus group experienced less burden from nausea or vomiting than the NIH group as assessed by the SSC. Fatigue was the most disturbing symptom in both groups. The most burdensome aspects of treatment were related to chemotherapy (55.2%) and use of prednisone (34.5%). Patients with a low HRQoL and high levels of fatigue were more likely to have low levels of serum complement C4 (i.e. elevated immune activity). In conclusion, patients who are treated according to the Euro-Lupus protocol may experience a higher HRQoL than patients who receive the NIH treatment. However, chemotherapy remains burdensome in the low-dose treatment regimen. Potential interventions to further enhance the HRQoL in SLE patients with proliferative lupus nephritis are discussed.


High Fat Diets Sex-Specifically Affect the Renal Transcriptome and Program Obesity, Kidney Injury, and Hypertension in the Offspring.
Obesity and related disorders have increased concurrently with an increased consumption of saturated fatty acids. We examined whether post-weaning high fat (HF) diet would exacerbate offspring vulnerability to maternal HF-induced programmed hypertension and kidney disease sex-specifically, with a focus on the kidney. Next, we aimed to elucidate the gene-diet interactions that contribute to maternal HF-induced renal programming using the next generation RNA sequencing (NGS) technology. Female Sprague-Dawley rats received either a normal diet (ND) or HF diet (D12331, Research Diets) for five weeks before the delivery. The offspring of both sexes were put on either the ND or HF diet from weaning to six months of age, resulting in four groups of each sex (maternal diet/post-weaning diet; n = 5-7/group): ND/ND, ND/HF, HF/ND, and HF/HF. Post-weaning HF diet increased bodyweights of both ND/HF and HF/HF animals from three to six months only in males. Post-weaning HF diet increased systolic blood pressure in male and female offspring, irrespective of whether they were exposed to maternal HF or not. Male HF/HF offspring showed greater degrees of glomerular and tubular injury compared to the ND/ND group. Our NGS data showed that maternal HF diet significantly altered renal transcriptome with female offspring being more HF-sensitive. HF diet induced hypertension and renal injury are associated with oxidative stress, activation of renin-angiotensin system, and dysregulated sodium transporters and circadian clock. Post-weaning HF diet sex-specifically exacerbates the development of obesity, kidney injury, but not hypertension programmed by maternal HF intake. Better understanding of the sex-dependent mechanisms that underlie HF-induced renal programming will help develop a novel personalized dietary intervention to prevent obesity and related disorders.


Antibiotic-loaded Porous Alumina Ceramic for One-stage Surgery for Chronic Osteomyelitis.
The classic treatment of chronic osteomyelitis is usually a two-stage surgery combined with systemic antibiotic therapy for several months. We report the case of a patient presenting a chronic osteomyelitis caused by methicillin-resistant Staphylococcus aureus who was treated with a one-stage surgery using an antibiotic-loaded ceramic. We used a porous alumina ceramic loaded with gentamicin to reconstruct the bone removed during débridement and to avoid its colonization. All bacteriological samples performed before and during the surgery revealed the presence of a methicillin-resistant S aureus. Because of the local release of the antibiotic, very high concentrations (more than 50 times the concentration needed) were administered in the surgical wound, thus helping to cure the infection. Owing to the strength of the ceramic, the patient was allowed to walk 10 days after the surgery. After a follow-up at 14 months, the patient is well-being, without any relapse of the infection. The CT-scan follow-up shows an osseointegration of the ceramic. Even, if it is too early to tell that infection is completely cured, these first results are encouraging for the use, in the future, of this antibiotic-loaded ceramic for complex bone infection.


Bridges between microtubules.
Bridges between microtubules have been studied with the electron microscope in the axostyle of Saccinobaculus and in various tubule systems of chicken testis, including the helix of tubules surrounding the elongating spermatid nucleus and the flagellum of the sperm tail. In addition to the previously described periodic bridges, evidence is presented that nonperiodic bridges exist between certain tubules. An analysis of axial spacing between adjacent nonperiodic bridges suggests that these structures are attached to periodic binding sites on the microtubule wall, but that not all the binding sites are filled. The bridges appear nonperiodic as a result of random occupancy of some fraction of the periodic sites. The distribution of these binding sites is related to the substructure of the microtubule wall as seen with negative staining and optical diffraction.


Breakthrough Exophiala dermatitidis infection during prophylactic administration of micafungin during second umbilical cord blood transplantation after graft failure.
Exophiala dermatitidis infections in patients with hematological malignancies are very rare. Our patient had a blood stream infection caused by E. dermatitidis following the second umbilical cord blood transplantation (UCBT) after graft failure during the first UCBT. To our knowledge, this is the first report describing a breakthrough fungal infection caused by E. dermatitidis during the prophylactic administration of micafungin (MCFG). Therefore, MCFG-treated patients should be monitored for breakthrough E. dermatitidis infection during hematopoietic stem cell transplantation.


Eye movements induced by head rotation in unresponsive patients.
Eye movements induced by head rotation were studied in 6 patients in acute coma, 4 patients in a persistent vegetative state, and 6 healthy, alert control subjects. Results from control subjects suggest that the oculocephalic response in the supine position is principally a vestibulo-ocular reflex. A position-step rotation of the head produced an initial oppositely directed eye movement, followed by a drift of the eyes back toward midline with a negative exponential time course. The time constant of this drift was greater than or equal to 10 seconds in control subjects but less than or equal to 1.5 seconds in unconscious patients and less than or equal to 0.5 seconds in vegetative patients. The rapid drift back of the eyes in unresponsive patients implies dysfunction of reticular and, possibly, cerebellar connections; the rate of this drift may indicate the severity and extent of brain injury. Sinusoidal head rotation produced slow and quick phases of nystagmus in normal subjects. Quick phases were absent in patients in acute coma; although present in vegetative patients, the quick phases did not keep the eyes close to primary position, as was the case in control subjects.


Drug-Induced Reduction in Albuminuria Is Associated with Subsequent Renoprotection: A Meta-Analysis.
Albuminuria has been proposed as a surrogate end point in randomized clinical trials of renal disease progression. Most evidence comes from observational analyses showing that treatment-induced short-term changes in albuminuria correlate with risk change for ESRD. However, such studies are prone to selection bias and residual confounding. To minimize this bias, we performed a meta-analysis of clinical trials to correlate the placebo-corrected drug effect on albuminuria and ESRD to more reliably delineate the association between changes in albuminuria and ESRD. MEDLINE and EMBASE were searched for clinical trials reported between 1950 and April 2014. Included trials had a mean follow-up of ≥1000 patient-years, reported ESRD outcomes, and measured albuminuria at baseline and during follow-up. Twenty-one clinical trials involving 78,342 patients and 4183 ESRD events were included. Median time to first albuminuria measurement was 6 months. Fourteen trials tested the effect of renin-angiotensin-aldosterone-system inhibitors and seven trials tested other interventions. We observed variability across trials in the treatment effect on albuminuria (range, -1.3% to -32.1%) and ESRD (range, -55% to +35% risk change). Meta-regression analysis revealed that the placebo-adjusted treatment effect on albuminuria significantly correlated with the treatment effect on ESRD: for each 30% reduction in albuminuria, the risk of ESRD decreased by 23.7% (95% confidence interval, 11.4% to 34.2%; P=0.001). The association was consistent regardless of drug class (P=0.73) or other patient or trial characteristics. These findings suggest albuminuria may be a valid substitute for ESRD in many circumstances, even taking into account possible other drug-specific effects that may alter renal outcomes.


Thermotolerant cells show an attenuated expression of Hsp70 after heat shock.
Expression of heat shock proteins (hsps) results in the protection of cells from subsequent stresses. However, hsps are also toxic when present within cells for a prolonged time period. Thus, the expression of hsps should be tightly regulated. In the present study, the expression of Hsp70 after heat shock was compared between thermotolerant cells, which contain a large concentration of Hsp70, and nonthermotolerant cells (naive). Accumulation of Hsp70, assessed by Western blotting, was negligible when thermotolerant cells were heat-shocked a second time. Hsp70 transcription was similar between thermotolerant and naive cells during heat shock. However, Hsp70 transcription was attenuated more rapidly in thermotolerant than naive cells immediately upon return to non-heat shock conditions. In addition, Hsp70 mRNA stability was reduced in thermotolerant cells as compared with naive cells following the stress. New synthesis of Hsp70 and the efficiency of Hsp70 mRNA translation were similar between thermotolerant and naive cells during the post-stress period. These results suggest that thermotolerant cells limit Hsp70 expression by transcriptional and pretranslational mechanisms, perhaps to avoid the potential cytotoxic effect of these proteins.


Genetic association between the PRKCH gene encoding protein kinase Ceta isozyme and rheumatoid arthritis in the Japanese population.
Analyses of families with rheumatoid arthritis (RA) have suggested the presence of a putative susceptibility locus on chromosome 14q21-23. This large population-based genetic association study was undertaken to examine this region. A 2-stage case-control association study of 950 unrelated Japanese patients with RA and 950 healthy controls was performed using >400 gene-based common single-nucleotide polymorphisms (SNPs). Multiple SNPs in the PRKCH gene encoding the eta isozyme of protein kinase C (PKCeta) showed significant single-locus disease associations, the most significant being SNP c.427+8134C>T (odds ratio 0.72, 95% confidence interval 0.62-0.83, P = 5.9 x 10(-5)). Each RA-associated SNP was consistently mapped to 3 distinct regions of strong linkage disequilibrium (i.e., linkage disequilibrium or haplotype blocks) in the PRKCH gene locus, suggesting that multiple causal variants influence disease susceptibility. Significant SNPs included a novel common missense polymorphism of the PRKCH gene, V374I (rs2230500), which lies within the ATP-binding site that is highly conserved among PKC superfamily members. In circulating lymphocytes, PRKCH messenger RNA was expressed at higher levels in resting T cells (CD4(+) or CD8(+)) than in B cells (CD19(+)) or monocytes (CD14(+)) and was significantly down-regulated through immune responses. Our results provide evidence of the involvement of PRKCH as a susceptibility gene for RA in the Japanese population. Dysregulation of PKCeta signal transduction pathway(s) may confer increased risk of RA through aberrant T cell-mediated autoimmune responses.


Expression of nuclear receptor and target genes in liver and intestine of neonatal calves fed colostrum and vitamin A.
Nuclear receptors (NR), including retinoic acid and retinoid X receptors (RAR, RXR), pregnane X receptor (PXR), constitutive androstane receptor, and peroxisome proliferator-activated receptor (PPARalpha) modify the expression of other genes, such as cytochrome p450 enzymes (CYP), sulfotransferases (SULT), and UDP glucuronosyl transferases (UGT). Nuclear receptor expression is influenced by exposure to ligands (e.g., vitamin A). We tested the hypothesis that vitamin A feeding influences the expression of hepatic and intestinal NR and their target genes and that colostrum or formula feeding influence these traits differently. Calves (n = 7/ group) were fed colostrum (CO) or a milk-based formula with or without vitamin A (FA, FO, respectively) for 4 d and were euthanized on d 5, followed immediately by tissue collection. Thereafter, RNA was extracted and gene expression quantified by real-time reverse transcription-polymerase chain reaction. Expression relative to housekeeping genes of mRNA was profiled for NR, CYP, SULT, and UGT enzymes. Hepatic mRNA levels of RARbeta and CYP26 were higher in FA than FO cows; expression of CYP2E1, CYP2C8, CYP26, and UGT1A1 was higher in CO than FO cows; and expression of CYP2E1, UGT1A1, and p450 reductase was higher in CO than FA. In colon tissue, abundance of RXRalpha mRNA was lower in FO than CO, and CYP2B6 expression was lower in FO than in CO and FA. In jejunal tissue, there were no significant differences in gene expression among groups. In conclusion, effects of vitamin A feeding were limited, but colostrum feeding had several selective effects on expression of nuclear receptors and target genes.


Rhizosphere Microbial Community Diversity and Function Analysis of Cut Chrysanthemum During Continuous Monocropping.
As an ornamental flower crop, the long-term continuous monocropping of cut chrysanthemum causes frequent occurrence of diseases, seriously affecting the quality of cut chrysanthemum. The rhizosphere microbial community plays an important role in maintaining the healthy growth of plants, whereas the composition and dynamics of rhizosphere microbial community under continuous monocropping of cut chrysanthemum have not been fully revealed. In this study, the Illumina MiSeq high-throughput sequencing platform was used to monitor the dynamic changes of rhizosphere microbial communities in four varieties of cut chrysanthemum during 0-3 years of monocropping, and the soil physicochemical properties were also determined. Results showed that continuous monocropping significantly increased the fungal community richness and altered the profiles of the bacterial and fungal communities, leading to variation of community beta-diversity. With the increase of continuous cropping time, biocontrol bacteria decreased, while some plant pathogenic fungi were enriched in the rhizosphere of cut chrysanthemum. FAPROTAX-based functional prediction showed that the abundance of gene related to nitrogen and sulfur metabolism and chitin lysis was reduced in the rhizosphere of cut chrysanthemum. FUNGuild-based fungal function prediction showed that plant pathogenic fungal taxa were increasing in the rhizosphere of cut chrysanthemum, mainly Acremonium, Plectosphaerellaceae, Fusarium, and Cladosporium. Continuous cropping also reduced the content of ammonium nitrogen and increased soil salinity, resulting in deterioration of soil physical and chemical properties, which, together with the transformation of rhizosphere microbial community, became part of the reasons for the continuous cropping obstacle of cut chrysanthemum.


Endo-beta-mannosidase, a plant enzyme acting on N-glycan: purification, molecular cloning, and characterization.
Endo-beta-mannosidase is a novel endoglycosidase that hydrolyzes the Manbeta1-4GlcNAc linkage in the trimannosyl core structure of N-glycans. This enzyme was partially purified and characterized in a previous report (Sasaki, A., Yamagishi, M., Mega, T., Norioka, S., Natsuka, S., and Hase, S. (1999) J. Biochem. 125, 363-367). Here we report the purification and molecular cloning of endo-beta-mannosidase. The enzyme purified from lily flowers gave a single band on native-PAGE and three bands on SDS-PAGE with molecular masses of 42, 31, and 28 kDa. Amino acid sequence information from these three polypeptides allowed the cloning of a homologous gene, AtEBM, from Arabidopsis thaliana. AtEBM was engineered for expression in Escherichia coli, and the recombinant protein comprised a single polypeptide chain with a molecular mass of 112 kDa corresponding to the sum of molecular masses of three polypeptides of the lily enzyme. The recombinant protein hydrolyzed pyridylamino derivatives (PA) of Manalpha1-6Manbeta1-4Glc-NAcbeta1-4GlcNAc into Manalpha1-6Man and GlcNAcbeta1-4Glc-NAc-PA, showing that AtEBM is an endo-beta-mannosidase. AtEBM hydrolyzed Man(n)Manalpha1-6Manbeta1-4GlcNAcbeta1-4GlcNAc-PA (n = 0-2) but not PA-sugar chains containing Manalpha1-3Manbeta or Xylosebeta1-2Manbeta as for the lily endo-beta-mannosidase. AtEBM belonged to the clan GH-A of glycosyl hydrolases. Site-directed mutagenesis experiments revealed that two glutamic acid residues (Glu-464 and Glu-549) conserved in this clan were critical for enzyme activity. The amino acid sequence of AtEBM has distinct differences from those of the bacterial, fungal, and animal exo-type beta-mannosidases. Indeed, AtEBM-like genes are only found in plants, indicating that endo-beta-mannosidase is a plant-specific enzyme. The role of this enzyme in the processing and/or degradation of N-glycan will be discussed.


Introduction to Focus Issue: Complex network perspectives on flow systems.
During the last few years, complex network approaches have demonstrated their great potentials as versatile tools for exploring the structural as well as dynamical properties of dynamical systems from a variety of different fields. Among others, recent successful examples include (i) functional (correlation) network approaches to infer hidden statistical interrelationships between macroscopic regions of the human brain or the Earth's climate system, (ii) Lagrangian flow networks allowing to trace dynamically relevant fluid-flow structures in atmosphere, ocean or, more general, the phase space of complex systems, and (iii) time series networks unveiling fundamental organization principles of dynamical systems. In this spirit, complex network approaches have proven useful for data-driven learning of dynamical processes (like those acting within and between sub-components of the Earth's climate system) that are hidden to other analysis techniques. This Focus Issue presents a collection of contributions addressing the description of flows and associated transport processes from the network point of view and its relationship to other approaches which deal with fluid transport and mixing and/or use complex network techniques.


The trefoil factor 1 participates in gastrointestinal cell differentiation by delaying G1-S phase transition and reducing apoptosis.
Trefoil factor (TFF)1 is synthesized and secreted by the normal stomach mucosa and by the gastrointestinal cells of injured tissues. The link between mouse TFF1 inactivation and the fully penetrant antropyloric tumor phenotype prompted the classification of TFF1 as a gastric tumor suppressor gene. Accordingly, altered expression, deletion, and/or mutations of the TFF1 gene are frequently observed in human gastric carcinomas. The present study was undertaken to address the nature of the cellular and molecular mechanisms targeted by TFF1 signalling. TFF1 effects were investigated in IEC18, HCT116, and AGS gastrointestinal cells treated with recombinant human TFF1, and in stably transfected HCT116 cells synthesizing constitutive or doxycycline-induced human TFF1. We observed that TFF1 triggers two types of cellular responses. On one hand, TFF1 lowers cell proliferation by delaying G1-S cell phase transition. This results from a TFF1-mediated increase in the levels of cyclin-dependent kinase inhibitors of both the INK4 and CIP subfamilies, leading to lower E2F transcriptional activity. On the other hand, TFF1 protects cells from chemical-, anchorage-free-, or Bad-induced apoptosis. In this process, TFF1 signalling targets the active form of caspase-9. Together, these results provide the first evidence of a dual antiproliferative and antiapoptotic role for TFF1. Similar paradoxical functions have been reported for tumor suppressor genes involved in cell differentiation, a function consistent with TFF1.


Both Neutralizing and Non-Neutralizing Human H7N9 Influenza Vaccine-Induced Monoclonal Antibodies Confer Protection.
Pathogenic H7N9 avian influenza viruses continue to represent a public health concern, and several candidate vaccines are currently being developed. It is vital to assess if protective antibodies are induced following vaccination and to characterize the diversity of epitopes targeted. Here we characterized the binding and functional properties of twelve H7-reactive human antibodies induced by a candidate A/Anhui/1/2013 (H7N9) vaccine. Both neutralizing and non-neutralizing antibodies protected mice in vivo during passive transfer challenge experiments. Mapping the H7 hemagglutinin antigenic sites by generating escape mutant variants against the neutralizing antibodies identified unique epitopes on the head and stalk domains. Further, the broadly cross-reactive non-neutralizing antibodies generated in this study were protective through Fc-mediated effector cell recruitment. These findings reveal important properties of vaccine-induced antibodies and provide a better understanding of the human monoclonal antibody response to influenza in the context of vaccines.


A Critical Review of the Evidence That Metformin Is a Putative Anti-Aging Drug That Enhances Healthspan and Extends Lifespan.
The numerous beneficial health outcomes associated with the use of metformin to treat patients with type 2 diabetes (T2DM), together with data from pre-clinical studies in animals including the nematode, C. elegans, and mice have prompted investigations into whether metformin has therapeutic utility as an anti-aging drug that may also extend lifespan. Indeed, clinical trials, including the MILES (Metformin In Longevity Study) and TAME (Targeting Aging with Metformin), have been designed to assess the potential benefits of metformin as an anti-aging drug. Preliminary analysis of results from MILES indicate that metformin may induce anti-aging transcriptional changes; however it remains controversial as to whether metformin is protective in those subjects free of disease. Furthermore, despite clinical use for over 60 years as an anti-diabetic drug, the cellular mechanisms by which metformin exerts either its actions remain unclear. In this review, we have critically evaluated the literature that has investigated the effects of metformin on aging, healthspan and lifespan in humans as well as other species. In preparing this review, particular attention has been placed on the strength and reproducibility of data and quality of the study protocols with respect to the pharmacokinetic and pharmacodynamic properties of metformin. We conclude that despite data in support of anti-aging benefits, the evidence that metformin increases lifespan remains controversial. However, via its ability to reduce early mortality associated with various diseases, including diabetes, cardiovascular disease, cognitive decline and cancer, metformin can improve healthspan thereby extending the period of life spent in good health. Based on the available evidence we conclude that the beneficial effects of metformin on aging and healthspan are primarily indirect via its effects on cellular metabolism and result from its anti-hyperglycemic action, enhancing insulin sensitivity, reduction of oxidative stress and protective effects on the endothelium and vascular function.


Improving outcomes with online COPD self-care.
If self-management was implemented properly, the NHS could save an estimated £235m over the next 10 years. An online self-management system for people with chronic obstructive pulmonary disease allows patients to access information whenever they need it. A comparison of conventional and online approaches to COPD self-management showed the online system is more effective in terms of health status and inhaler technique.


Structure Guided Design of Protein Biosensors for Phenolic Pollutants.
Phenolic aromatic compounds are a major source of environmental pollution. Currently there are no in situ methods for specifically and selectively detecting these pollutants. Here, we exploit the nature's biosensory machinery by employing Acinetobacter calcoaceticus NCIB8250 protein, MopR, as a model system to develop biosensors for selective detection of a spectrum of these pollutants. The X-ray structure of the sensor domain of MopR was used as a scaffold for logic-based tunable biosensor design. By employing a combination of in silico structure guided approaches, mutagenesis and isothermal calorimetric studies, we were able to generate biosensor templates, that can selectively and specifically sense harmful compounds like chlorophenols, cresols, catechol, and xylenols. Furthermore, the ability of native protein to selectively sense phenol as the primary ligand was also enhanced. Overall, this methodology can be extended as a suitable framework for development of a series of exclusive biosensors for accurate and selective detection of aromatic pollutants from real time environmental samples.


HERF1, a novel hematopoiesis-specific RING finger protein, is required for terminal differentiation of erythroid cells.
The AML1/core binding factor beta (CBFbeta) transcription factor is essential for definitive hematopoiesis; however, the downstream pathways through which it functions remain incompletely defined. Using a differential cloning approach to define components of this pathway, we have identified a novel gene designated HERF1 (for hematopoietic RING finger 1), whose expression during development is dependent on the presence of functional AML1/CBFbeta. HERF1 contains a tripartite RING finger-B box-alpha-helical coiled-coil domain and a C-terminal region homologous to the ret proto-oncogene-encoded finger protein. Expression of HERF1 during embryogenesis coincides with the appearance of definitive erythropoiesis and in adult mice is restricted to erythroid cells, increasing 30-fold during terminal differentiation. Importantly, inhibition of HERF1 expression blocked terminal erythroid differentiation of the murine erythroleukemia cell line MEL, whereas its overexpression induced erythroid maturation. These results suggest an important role for this protein in erythropoiesis.


Environmental risk factors for equine West Nile virus disease cases in Texas.
West Nile Virus (WNV) was first detected in the Texas equine population during June 2002. Infection has since spread rapidly across the state and become endemic in the equine population. Environmental risk factors associated with equine WNV attack rates in Texas counties during the period 2002 to 2004 were investigated. Equine WNV attack rates were smoothed using an empirical Bayesian model, because of the variability among county equine populations (range 46-9,517). Risk factors investigated included hydrological features (lakes, rivers, swamps, canals and river basins), land cover (tree, mosaic, shrub, herbaceous, cultivated and artificial), elevation, climate (rainfall and temperature), and reports of WNV-positive mosquito and wild bird samples. Estimated county equine WNV attack rate was best described by the number of lakes, presence of broadleaf deciduous forest, presence of cultivated areas, location within the Brazos River watershed, WNV-positive mosquito status and average temperature. An understanding of environmental factors that increase equine WNV disease risk can be used to design and target disease control programs.


Coexistence of ferroelectricity and ferromagnetism in tantalum clusters.
The atomic and electronic structures of Ta(N) (N=2-23) clusters have been determined in the framework of pseudopotential density-functional calculations, based upon an unbiased global search with guided simulated annealing to an empirical potential. It is found that the ground-state structures of Ta(N) are very similar to those of Nb(N), showing no preference for the icosahedral growth. Also, a size- and structure-dependent ferroelectricity is found in these tantalum clusters. More importantly, it is found that the ferroelectricity and ferromagnetism can coexist in the homogeneous transition-metal cluster, offering a possibility to obtain a new type of "multiferroic" materials composed of the clusters. Finally, the far-infrared spectroscopy is suggested to be an efficient tool to distinguish the ferroelectric clusters.


Recruitment of MAIT Cells to the Intervillous Space of the Placenta by Placenta-Derived Chemokines.
The intervillous space of the placenta is a part of the fetal-maternal interface, where maternal blood enters to provide nutrients and gas exchange. Little is known about the maternal immune cells at this site, which are in direct contact with fetal tissues. We have characterized the T cell composition and chemokine profile in paired intervillous and peripheral blood samples from healthy mothers giving birth following term pregnancies. Mucosal-associated invariant T (MAIT) cells and effector memory (EM) T cells were enriched in the intervillous blood compared to peripheral blood, suggesting that MAIT cells and other EM T cells home to the placenta during pregnancy. Furthermore, pregnant women had lower proportions of peripheral blood MAIT cells compared to non-pregnant women. The levels of several chemokines were significantly higher in intervillous compared to peripheral blood, including macrophage migration inhibitory factor (MIF), CXCL10, and CCL25, whereas CCL21, CCL27 and CXCL12 were lower. Migration assays showed that MAIT cells and EM T cells migrated toward conditioned medium from placental explants. A multivariate factor analysis indicated that high levels of MIF and CCL25 were associated with high proportions of MAIT cells in intervillous blood. Blocking of MIF or a combination of MIF, CCL25, and CCL20 in migration assays inhibited MAIT cell migration toward placenta conditioned medium. Finally, MAIT cells showed migratory capacities toward recombinant MIF. Together, these findings indicate that term placental tissues attract MAIT cells, and that this effect is at least partly mediated by MIF.


[A novel C27-steroidal glycoside sulfate from Liriope graminifolia].
An unusual novel C27-steroidal glycoside sulfate was isolated from the underground organs of Liriope graminifolia (Linn.) Baker with three known compounds. Their chemical structures were determined by spectral analysis, including HR-MS, 1D and 2D NMR as (25S)-ruscogenin 1-sulfate-3-O-alpha-L-rhamnopyranoside (1), (25S)-ruscogenin 1-O-beta-D-xylopyranosyl-3-O-alpha-L-rhamnopyranoside (2), hesperidin (3), and 4', 7-dihydroxy-5-methoxyflavanone (4). Compound 1 has cytotoxic activities against K562 and HL60 cells with IC50 values of 18.6 microg x mL(-1) and 16.5 microg x mL(-1), respectively.


Methanolic Bark Extract of Abroma augusta (L.) Induces Apoptosis in EAC Cells through Altered Expression of Apoptosis Regulatory Genes.
Abroma augusta (L.), one of the herbal medicinal plants, is widely used for treatment of various maladies. The present study was initiated to determine the antioxidant, hemolytic, cytotoxicity, and anticancer activities of methanolic extract from the bark of the plant. The phytochemical screening was done by analyzing different phytochemicals present in the extract. We observed the presence of alkaloids, steroids, terpenoids, flavonoids, reducing sugars, and glycosides in the bark extract which showed the highest antioxidant capacity. Antioxidant potential of the methanolic extract was evaluated in vitro by DPPH (2,2-diphenyl-1-picrylhydrazyl) scavenging assay method. This extract showed prominent scavenging activity with IC50 value of 38.65 μg/ml. The hemolytic activity of the extract was evaluated at concentrations ranging from 250 to 1000 μg/ml. It was observed that the extract induced hemolysis percentage of 9.41% to 4.1%, which implies that the extract has no potent hemolytic activity. Cytotoxicity and anticancer activities were observed on Ehrlich ascites carcinoma (EAC) cells. In addition, the bark showed promising cytotoxicity with IC50 value of 329.41 μg/ml, and the study indicated that the extract was capable of inhibiting EAC cell growth by 75.5% when administered at 100 mg/kg/day body weight intraperitoneally for five consecutive days to Swiss albino mice. Morphological change of apoptotic cell was determined by fluorescence and optical microscopy. DNA fragmentation is another marker for apoptosis, and the bark extract-treated EAC cells showed smeared and fragmented DNA bands. Apoptosis correlated well with the upregulation of p53 and Bax and also with the downregulation of NF-κB and Bcl-2. Furthermore, activity and interaction of two A. augusta compounds were tested through molecular docking simulation study. In conclusion, our results suggest that A. augusta bark has the potential to be considered as an anticancer agent.


The European Union's Adequacy Approach to Privacy and International Data Sharing in Health Research.
The European Union (EU) approach to data protection consists of assessing the adequacy of the data protection offered by the laws of a particular jurisdiction against a set of principles that includes purpose limitation, transparency, quality, proportionality, security, access, and rectification. The EU's Data Protection Directive sets conditions on the transfer of data to third countries by prohibiting Member States from transferring to such countries as have been deemed inadequate in terms of the data protection regimes. In theory, each jurisdiction is evaluated similarly and must be found fully compliant with the EU's data protection principles to be considered adequate. In practice, the inconsistency with which these evaluations are made presents a hurdle to international data-sharing and makes difficult the integration of different data-sharing approaches; in the 20 years since the Directive was first adopted, the laws of only five countries from outside of the EU, Economic Area, or the European Free Trade Agreement have been deemed adequate to engage in data transfers without the need for further administrative safeguards.


Soluble B7-H3 promotes the invasion and metastasis of pancreatic carcinoma cells through the TLR4/NF-κB pathway.
Many studies have demonstrated a relationship between soluble B7-H3 (sB7-H3) and the poor prognosis of patients with malignant tumors, and increasing evidence has shown a connection between sB7-H3 and NF-κB in tumor progression. In the present study, we demonstrate for the first time that sB7-H3 promotes the invasion and metastasis of pancreatic carcinoma cells through the TLR4/NF-κB pathway. In this study, we observed that sB7-H3 was highly expressed in mB7-H3-positive pancreatic carcinoma (PCa) cells. Exogenous sB7-H3 significantly increased NF-κB activity and promoted the migration and invasion of PCa cells. Further studies proved that sB7-H3 first up-regulated TLR4 expression, then activated NF-κB signaling and finally promoted IL-8 and VEGF expression. In contrast, the silencing of TLR4 using a stable short hairpin RNA significantly decreased the sB7-H3-induced activity of NF-κB and the expression of IL-8 and VEGF in PCa cells. In vivo animal experiments further demonstrated that TLR4-knock-down tumor cells displayed a decreased ability to metastasize compared with the control tumor cells after being induced by sB7-H3. Collectively, these results demonstrate that sB7-H3 promotes invasion and metastasis through the TLR4/NF-κB pathway in pancreatic carcinoma cells.


FGF23-related hypophosphatemia in a patient with small cell lung cancer: a case report and literature review.
Although there are a few case reports of patients with small cell lung cancer developing hypophosphatemia, detailed information on this condition is scarce. A 52-year-old patient with advanced stage small cell lung cancer developed hypophosphatemia (1.1 mg/dL) during chemotherapy. A reduced level of the tubular reabsorption of phosphate concomitant with an inappropriately elevated level of fibroblast growth factor (FGF) 23 (48.4 pg/mL) was noted, leading to the diagnosis of FGF23-related hypophosphatemia. Laboratory data also showed hypercortisolemia with an elevated ACTH level and hyponatremia with an inappropriately unsuppressed level of antidiuretic hormone (ADH). These data suggested the overproduction of FGF23 in addition to ACTH and ADH. Because the octreotide loading test did not present a suppressive effect on ACTH or FGF23 levels, the patient was treated with phosphate supplementation, active vitamin D and metyrapone, which partially improved the serum phosphate and cortisol levels. Even after two subsequent courses of chemotherapy, the small cell lung cancer progressed, and the FGF23 level was further elevated (83.7 pg/mL). Although it is very rare, FGF23-related hypophosphatemia is one of the hormonal disturbances that could be observed in patients with small cell lung cancer. This article reviews similar clinical conditions and revealed that advanced states of malignancy seemed to be associated with the development of renal wasting hypophosphatemia, especially in lung cancer and prostate cancer. Therefore, the parameters related to hypophosphatemia should be monitored in patients with advanced small cell lung cancer to prevent the development of hypophosphatemic osteomalacia.


Recovery of adenovirus type 7 from human brain cell cultures.
A strain of adenovirus type 7 was recovered from cultured brain cells, taken at necropsy from a patient aged 71 years with chronic schizophrenia. This recovery may indicate the reactivation of a latent infection with one of the few adenoviruses that has regularly-if rarely-been associated with clinical encephalitis.


Numeracy and patient safety: the need for regular staff assessment.
The ability to perform calculations competently is a basic requirement for all nurses. Calculations are used in everyday tasks such as working out drug doses, body mass index and fluid balance charts. Healthcare staff may have problems with numeracy and this can lead to drug errors, which can have a devastating effect on patients. The author argues that healthcare professionals' numeracy skills should be assessed on a regular basis using a recognised, validated and reliable assessment tool.


Human mesenchymal stem cell differentiation to NP-like cells in chitosan-glycerophosphate hydrogels.
Intervertebral disc (IVD) degeneration is one of the major causes of low back pain. As current clinical treatments are aimed at restoring biomechanical function and providing symptomatic relief, interest in methods focused on biological repair has increased. Several tissue engineering approaches using different cell types and hydrogels/scaffolds have been proposed. Owing to the unsuitable nature of degenerate cells for tissue engineering attention has focused on the use of mesenchymal stem cells (MSCs). Additionally, while rigid scaffolds have been demonstrated to allow MSC differentiation to the chondrocyte-like cells of the IVD, hydrogels are being increasingly studied as they allow minimally invasive implantation without extensive damage to the IVD. Here, we have studied the temperature-sensitive hydrogel chitosan-glycerophosphate (C/Gp), seeded with human MSCs and cultured for 4 weeks in standard medium. We have analysed the gene and protein expression profile of the MSCs and compared it to that of both nucleus pulposus (NP) cells and articular chondrocytes cultured in C/Gp. Gene expression analysis for chondrocytic-cell marker genes demonstrated differentiation of MSCs to a phenotype which showed similarities to both articular chondrocytes and NP cells. Conventional PCR demonstrated a lack of expression of osteogenic marker genes and the hypertrophic marker gene type X collagen. MSCs also secreted both proteoglycans and collagens in a ratio, which more closely resembled that of NP cells than articular chondrocytes. These results therefore suggest that MSC-seeded C/Gp gels could be used clinically for the regeneration of the degenerate human IVD.


Percutaneous closure of the patent foramen ovale.
A patent foramen ovale (PFO) is a common finding present in 25% of the population. A relationship between PFO and several clinical conditions such as stroke, migraine, platypnea-orthodeoxia syndrome, neurological decompression illness in divers, high altitude pulmonary edema, sleep apnea, and economy class syndrome have been documented. Observational non-randomized studies have shown percutaneous PFO closure more effective than medical treatment for stroke prevention, in particular in patients with complete closure as well as in patients with more than one cerebrovascular event at baseline. In the case of migraine, PFO closure has been shown to result in a marked reduction in migraine burden or migraine days. PFO anatomy, epidemiological data on associated clinical conditions, comparison between percutaneous closure and medical treatment, as well as the technical aspect of the procedure are described in this review.


Evaluation of ratite skinning force in order to fix plant and mechanical solutions.
The skin is the most requested product of ratite slaughter and 'first-rate' ratite's skin has a high economic market. Ostrich hide is tanned in South Africa and sold all over the world. Besides, the ostrich meat is considered a niche production in the marketplace, thus allowing for another pro t for the ostrich breeding. Theorical analysis of skinning process has been carried out, and an automatic measurement system has been designed to record the drawing-force on the animal's body during skinning tests. The aim of this study was to indentify the best animal position and provide values of drawing-force in order to design a speci c machine for ostrich skinning. Experimental results partially con rm the proposed analysis. They point out that the angle of inclination of drawing-force with back-line mostly in uences the value of drawing-force and that this in uence tends to increase as the angle is near to 90 degrees or exceeds this limit. In any case, the applied drawing-force must not exceed 350.0 daN. Therefore, with respect to their anatomy structure and the tensile strenght of the hide, ostrich skinning should be done with vertical-drawing machines and the animal should be suspended by its wings at the rail. In case of low working capacity (8-10 heads per hour), given the di coulties highlighted during the experiments run in this study, the animal should be skinned suspended by the legs.


Impact of mechanical ventilation on quality of life and functional status after ICU discharge: A cross-sectional study.
To evaluate the impact of the need for mechanical ventilation (MV) and its duration throughout ICU stay on the quality of life (QoL) and physical functional status (PFS) after the immediate ICU discharge. This was a cross-sectional study including all subjects consecutively discharged from the ICU during 1-year period. During the first week after ICU discharge, QoL was assessed through WHOQoL-Bref questionnaire and PFS through the Karnofsky Performance Status and modified-Barthel index, and retrospectively compared with the pre-admission status (variation [Δ] of indexes). During the study, 160 subjects met the inclusion criteria. Subjects receiving MV presented PFS impairment (Δ Karnofsky Performance Status [-19.7 ± 20.0 vs. -14.9 ± 18.2; p=0.04] and Δ modified-Barthel index [-17.4 ± 12.8 vs. -13.2 ± 12.9; p=0.05]) compared with those who did not receive MV. Duration of MV was a good predictor of PFS (Δ Karnofsky Performance Status [-14.6-1.12 * total days of MV; p=0.01] and Δ modified-Barthel index [-14.2-0.74 * total days of MV; p=0.01]). QoL, assessed by WHOQoL-Bref, showed no difference between groups (14.0 ± 1.8 vs. 14.5 ± 1.9; p=0.14), and the duration of MV did not influence QoL (WHOQoL-Bref scale [14.2-0.05* total days of MV; p=0.43]). Need for MV and duration of MV decrease patient PFS after ICU discharge.


First detection and genetic characterization of porcine parvovirus 7 from Korean domestic pig farms.
Porcine parvovirus 7 (PPV7) was first detected in Korean pig farms in 2017. The detection rate of PPV7 DNA was 24.0% (30/125) in aborted pig fetuses and 74.9% (262/350) in finishing pigs, suggesting that PPV7 has circulated among Korean domestic pig farms. Phylogenetic analysis based on capsid protein amino acid sequences demonstrated that the nine isolated Korean strains (PPV-KA1-3 and PPV-KF1-6) were closely related to the previously reported USA and Chinese PPV7 strains. In addition, the Korean strains exhibit genetic diversity with both insertion and deletion mutations. This study contributes to the understanding of the molecular epidemiology of PPV7 in Korea.


[Pulse wave velocity - a useful tool in assessing the stiffness of the arteries].
Measurement of pulse wave velocity (PWV) is a simple and noninvasive way to assess stiffness of the arteries. PWV measurement can refer to both the aorta and peripheral arterial vessels. Currently, the most clinically significant is the measurement of PWV between the carotid artery and the femoral artery, which is defined as the speed of the aortic pulse wave. Numerous studies have demonstrated the significance of prognostic PWV aortic measurement as a recognized exponent of subclinical organ damage both among the general population as well as among patients with increased cardiovascular risk, examining patients in detail with hypertension, diabetes, chronic renal failure. The prognostic value of PWV aortic measurement was reflected in the guidelines of the European Society of Cardiology (ESC) and the European Society of Hypertension (ESH). In clinical trials, the repeatability and reproducibility of PWV measurements were also evaluated, both parameters being considered satisfactory. The paper presents reports from studies on the significance of pulse wave velocity results in the prognosis assessment in different disease entities as well as in age groups.


Enzymatic sclerostomy: pilot human study.
To evaluate the feasibility and safety of enzymatic sclerostomy as a new modality to lower intraocular pressure in patients with open-angle glaucoma. This single-center, prospective, noncomparative, interventional case series included 15 blind symptomatic eyes of 15 patients with primary open-angle glaucoma. Enzymatic sclerostomy was performed with the patient under topical or peribulbar anesthesia. A specially designed polymethylmethacrylate enzyme applicator filled with a mean +/- SD of 123 +/- 13 microg of collagenase was introduced through a 5-mm peritomy, and affixed to the limbus by means of cyanoacrylate tissue glue. After 22 to 24 hours, the applicators were removed and the patients were followed up for 1 year. Intraocular pressure changes from baseline and complications related to the procedure were the main outcome measures. Controlled thinning of the treated sclera associated with aqueous percolation and shallow filtration bleb was seen in all eyes in the immediate postoperative period. The mean +/- SD intraocular pressure decreased from 43.5 +/- 9.8 mm Hg (while the patients were receiving a mean +/- SD of 1.75 +/- 0.75 antiglaucoma medications) preoperatively to 24.8 +/- 10.6 mm Hg (a 43.0% decrease from baseline with no antiglaucoma medication) on the first postoperative day and to 34.8 +/- 10.5 mm Hg (a 20.0% decrease from baseline with no antiglaucoma medication) at the end of 1 year. Ophthalmic adverse effects were limited to the treated area and included immediate postoperative transient conjunctival reaction ranging from mild chemosis to conjunctival maceration. Immediate full-thickness perforation developed in 1 eye; the patient was treated and excluded from data analysis. Two eyes developed symptoms related to increase in intraocular pressure after 9 months; the patients were treated and excluded from further data analysis. No systemic complications were noted. Enzymatic sclerostomy demonstrated immediate and sustained intraocular pressure reduction and provided symptomatic relief in blind eyes with primary open-angle glaucoma. The procedure, however, needs further technical refinement.


Physical Activity Estimated by the Wearable Device in Lung Disease Patients: Exploratory Analyses of Prospective Observational Study.
Background. Physical activity is a potential parameter to assess the severity or prognosis of lung disease. However, the differences in physical activity between healthy individuals and patients with lung disease remain unclear. Methods. The analyses in this report are a combined analysis of four cohorts, including a healthy control cohort, in a prospective study designed to evaluate wearable device-estimated physical activity in three cohorts: the lung cancer cohort, the interstitial pneumonia cohort, and the COPD cohort (UMIN000047834). In this report, physical activity in the lung disease cohort was compared with that in the healthy cohort. Subgroup analyses were performed based on age, sex, duration of wearable device use, and lung disease subtype. Results. A total of 238 cases were analyzed, including 216 patients with lung disease and 22 healthy cases. Distance walked and number of steps were significantly lower in the patient group compared to the healthy control group. ROC analysis for the diagnostic value of lung disease by mean distance walked and mean number of steps showed AUC of 0.764 (95%CI, 0.673 to 0.856) and 0.822 (95%CI, 0.740 to 0.905), respectively. There was a significant difference in physical activity by age, but not by gender nor by duration based on the threshold of 7 days of wearing the device. Conclusions. Lung disease decreases physical activity compared to healthy subjects, and aging may bias the estimation of physical activity. The distance walked or number of steps is recommended as a measure of physical activity, with a period of approximately one week and adjusted for age for future investigation.


Effects of N-acetylcysteine on lung glutathione levels in rats after burn injury.
This study was designed to determine the effect of N-acetyl-cysteine (NAC, a natural hydroxyl radical scavenger) treatment on levels of pulmonary malondialdehyde (MDA, the end product of lipid peroxidation) and glutathione (GSH, a natural antioxidant) in thermally injured rats. Severe skin scald injury (30 percent TBSA) caused a significant decrease in GSH levels, and a significant increase in MDA levels in lung tissue both at 1 h and 1 day postburn injury. Treatment of rats with NAC (15 mg/kg intraperitoneally, 15 min and 12 h following the burn) significantly improved GSH levels, and decreased ongoing lipid peroxidation at 1 day. This study showed that thermal injury resulted in increased pulmonary lipid peroxidation, and this remote organ injury was decreased by treatment with NAC. In addition NAC, a scavenger of hydroxyl radicals, improved GSH levels in the lungs. The higher level of GSH in the lungs of the burned rats treated with NAC could be due to either a decrease in the rate of degradation of GSH or to an increase in its synthesis. No data about these possibilities are provided.


Development of a Double Nuclear Gene-Targeting Method by Two-Step Transformation Based on a Newly Established Chloramphenicol-Selection System in the Red Alga Cyanidioschyzon merolae.
The unicellular red alga Cyanidioschyzon merolae possesses a simple cellular architecture that consists of one mitochondrion, one chloroplast, one peroxisome, one Golgi apparatus, and several lysosomes. The nuclear genome content is also simple, with very little genetic redundancy (16.5 Mbp, 4,775 genes). In addition, molecular genetic tools such as gene targeting and inducible gene expression systems have been recently developed. These cytological features and genetic tractability have facilitated various omics analyses. However, only a single transformation selection marker URA has been made available and thus the application of genetic modification has been limited. Here, we report the development of a nuclear targeting method by using chloramphenicol and the chloramphenicol acetyltransferase (CAT) gene. In addition, we found that at least 200-bp homologous arms are required and 500-bp arms are sufficient for a targeted single-copy insertion of the CAT selection marker into the nuclear genome. By means of a combination of the URA and CAT transformation systems, we succeeded in producing a C. merolae strain that expresses HA-cyclin 1 and FLAG-CDKA from the chromosomal CYC1 and CDKA loci, respectively. These methods of multiple nuclear targeting will facilitate genetic manipulation of C. merolae.


Perineural invasion by squamous-cell carcinoma.
Perineural invasion by squamous-cell carcinoma is an ominous sign when discovered by either the pathologist or the chemosurgeon. This report details our experience with seventeen cases of perineural invasion and their successful outcome, using a multidisciplinary approach, including Mohs' surgery.


Growth suppression of human leukemic cells in vitro by L-ascorbic acid.
The suppressive effect of L-ascorbic acid on the growth of bone marrow cells from patients with acute nonlymphocytic leukemia was studied using a modified agar culture method featuring daily feeding to allow the growth of leukemic cell colonies. In seven of 28 patients (25%), the numbers of leukemic cell colonies grown in culture were reduced to 21% of control by the addition of L-ascorbic acid (0.3 mM) to the culture medium. Glutathione did not suppress leukemic cell colonies although it has a similar oxidation-reduction potential to that of L-ascorbic acid. The addition of L-ascorbic acid reduced the pH of the medium. However, a comparable reduction of pH by the addition of HCl did not suppress leukemic cell colonies. In simultaneous cultures for leukemic and normal marrow cells, the suppression of leukemic cell colony was noted with a concentration of L-ascorbic acid as low as 0.1 mM (a concentration achievable in vivo), but normal myeloid colonies were not suppressed until the concentration of L-ascorbic acid reached an extremely high level (1 mM). In conclusion, growth of leukemic cells in culture was suppressed by L-ascorbic acid in a substantial proportion of patients with acute nonlymphocytic leukemia. This suppression was a specific effect of L-ascorbic acid and was not due to its oxidation-reduction potential or pH change. Leukemic cells were selectively affected at an L-ascorbic acid concentration attainable in vivo while normal hemopoietic cells were not suppressed.


An abnormality of the gene that encodes neutrophil Fc receptor III in a patient with systemic lupus erythematosus.
In the course of examining the structure and function of Fc receptors on peripheral blood cells of patients with systemic lupus erythematosus, we identified a patient whose neutrophils did not react with either monoclonal or polyclonal antibodies to Fc receptor III. However, neutrophils from the patient were comparable to neutrophils from healthy controls with respect to their expression of Fc receptor II, complement receptor 1, complement receptor 3, and the phosphatidylinositol-linked, complement regulatory protein, decay-accelerating factor. The abnormality of expression of Fc receptor III was limited to the patient's neutrophils (her natural killer cells reacted normally with anti-Fc receptor III antibodies), and was associated with abnormal recognition and binding of IgG-coated erythrocytes. Analysis of genomic DNA revealed evidence that failure of the patient's neutrophils to express Fc receptor III was most likely due to an abnormality of the gene that encodes this receptor.


Return to work after rehabilitation in chronic low back pain workers. Does the interprofessional collaboration work?
The objective of this study was to assess the workplace information collected and shared between professionals of the centers and occupational health professionals during functional restoration programs intended to chronic low back pain patients. A descriptive study carried out by a questionnaire sent to the French rehabilitation centers offering a functional restoration program. Data collection focused on the kinds of professionals involved in programs, professionals who approach work issues, work analysis, social and occupational information collected, existence of a specific work rehabilitation program, frequency of and methods for sharing information with occupational health professionals. Occupational information was mostly collected at inclusion during an individual interview by the rehabilitation physicians, social workers, and occupational therapists. Workplace environment was the most poorly discussed aspect. A minority of centers adapted their programs regarding these information. Information sharing with occupational physicians was mostly through the patient and was influenced by the presence of an ergonomist or of an occupational physician in the team. The study found poor interest about work environment and that the cooperation between practitioners in disability management remains limited. The various practitioners' cultures and interests may be a brake on cooperation and exchange of information.


Developmental alterations of the C. elegans male anal depressor morphology and function require sex-specific cell autonomous and cell non-autonomous interactions.
We studied the Caenorhabditis elegans anal depressor development in larval males and hermaphrodites to address how a differentiated cell sex-specifically changes its morphology prior to adulthood. In both sexes, the larval anal depressor muscle is used for defecation behavior. However in the adult males, the muscle's sarcomere is reorganized to facilitate copulation. To address when the changes occur in the anal depressor, we used YFP:actin to monitor, and mutant analysis, laser-ablation and transgenic feminization to perturb the cell's morphological dynamics. In L1 and L2 stage larva, the muscle of both sexes has similar sarcomere morphology, but the hermaphrodite sex-determination system promotes more growth. The male anal depressor begins to change in the L3 stage, first by retracting its muscle arm from the neurons of the defecation circuit. Then the muscle's ventral region develops a slit that demarcates an anterior and posterior domain. This demarcation is not dependent on the anal depressor's intrinsic genetic sex, but is influenced by extrinsic interactions with the developing male sex muscles. However, subsequent changes are dependent on the cell's sex. In the L4 stage, the anterior domain first disassembles the dorsal-ventral sarcomere region and develops filopodia that elongates anteriorly towards the spicule muscles. Later, the posterior domain dissembles the remnants of its sarcomere, but still retains a vestigial attachment to the ventral body wall. Finally, the anterior domain attaches to the sex muscles, and then reassembles an anterior-posteriorly oriented sarcomere. Our work identifies key steps in the dimorphic re-sculpting of the anal depressor that are regulated by genetic sex and by cell-cell signaling.


Assessment of body composition by dual energy X-ray absorptiometry, skinfold thickness and creatinine kinetics in chronic kidney disease patients.
Finding a method that can be routinely used to assess body composition with minimum error is still a challenge for those who work with chronic kidney disease (CKD) patients. This study aimed to compare the value of two surrogate techniques, skinfold thickness (SKF) and creatinine kinetics (CK) with dual energy X-ray absorptiometry (DEXA) as the reference method for measuring body fat and fat-free mass in non-dialysed CKD patients. The body fat and fat-free mass of 50 non-dialysed CKD patients (38 male, 12 female) were measured by DEXA and compared with measurements obtained by SKF and CK. The mean values of body fat and fat-free mass obtained by SKF and CK differed significantly from measurements made by DEXA. The intra-class correlation coefficient (r) for body fat between SKF and DEXA (r = 0.74) and between CK and DEXA (r = 0.47) indicated a moderate degree of reproducibility. A Bland and Altman plot analysis showed a better agreement between SKF and DEXA [5.8 +/- 3.9% (-2.0 to 13.6)] than between CK and DEXA [8.8 +/- 8.8% (-8.8 to 26.4)]. Regarding fat-free mass, the intra-class correlation coefficient (r) between SKF and DEXA (r = 0.85) indicated a good degree of reproducibility, while that between SKF and CK (r = 0.57) indicated a moderate degree of reproducibility. The Bland and Altman plot analysis for fat-free mass showed that DEXA agreed better with SKF [-3.1 +/- 3.4 kg (-9.9 to 3.7)] than with CK [-5.5 +/- 6.4 kg (-18.2 to 7.3)]. Skinfold thickness seems to be the method of choice for evaluating body fat. The limitations inherent to DEXA in evaluating fat-free mass makes it difficult to designate an alternate method of choice for assessing this body compartment.


Child and adolescent mental health services and systems in low and middle-income countries: from mapping to strengthening.
Most of the world's children and adolescents live in low and middle-income countries (LMICs) where mental health services are very limited. Here, we reviewed literature over the last 18 months describing the current landscape of child and adolescent mental health services and systems (CAMHSS) in LMICs, and present findings from systems strengthening research. The challenges in CAMHSS are well described with little change over the last two decades. Fortunately, research has started to move from 'mapping' towards systems 'strengthening'. Using the WHO Assessment Instrument for Mental Health Systems (WHO-AIMS) framework, we reviewed recent CAMHSS innovations. Clinical care and human resource innovations focused on primary care with validation of screening tools, training and task-sharing for capacity-building. Intersectoral collaboration emerged as a priority domain for strengthening, alongside a theme around the importance of participatory research to inform policy reforms. The potential role of digital technology to strengthen CAMHSS was identified as an emerging theme. There is an urgent need to increase the priority of CAMHSS in LMICs. This will require innovations at multiple levels aimed at all CAMHSS domains, with active participation of all relevant local stakeholders to ensure the translation of research into policy and practice.


Transgender Minors and the Commencement of Hormone Treatment for Gender Dysphoria: Is Recent English Case Law Likely to Influence the Australian Legal Position?
This article considers recent English case law addressing the issue of whether court approval is required for the commencement of hormone treatment for minors with Gender Dysphoria. In particular, the decision in Bell v The Tavistock and Portman NHS Foundation Trust [2021] EWCA Civ 1363 is considered for the purpose of both distinguishing the legal framework in England from the body of Australian law on this topic, as well as considering whether the case may potentially impact on Australian law moving forward. One important aspect of the Court of Appeal's decision in Bell, which overturned the lower court's decision, is that the case clarifies how the principle of Gillick-competency should be applied in this context. The Court of Appeal held that in line with the House of Lords' reasoning in Gillick, the assessment of a minor's capacity is for the relevant treating health care professional(s) to assess rather than judges. This interpretation may potentially impact on how this principle is applied in the Australian cases relevant to minors and Gender Dysphoria, particularly those that have required an application to court in circumstances where a minor's parent(s) disagree with the conclusion of a treating clinician who has assessed their child as Gillick-competent for the purpose of consenting to hormone treatment.


Hot Deformation Behavior and Microstructure Evolution of Cu-Ni-Co-Si Alloys.
The Cu-1.7Ni-1.4Co-0.65Si (wt%) alloy is hot compressed by a Gleeble-1500D machine under a temperature range of 760 to 970 °C and a strain rate range of 0.01 to 10 s-1. The flow stress increases with the extension of strain rate and decreases with the rising of deformation temperature. The dynamic recrystallization behavior happens during the hot compression deformation process. The hot deformation activation energy of the alloy can be calculated as 468.5 kJ/mol, and the high temperature deformation constitutive equation is confirmed. The hot processing map of the alloy is established on the basis of hot deformation behavior and hot working characteristics. With the optimal thermal deformation conditions of 940 to 970 °C and 0.01 to 10 s-1, the fine equiaxed grain and no holes are found in the matrix, which can provide significant guidance for hot deformation processing technology of Cu-Ni-Co-Si alloy.


[Efficacy of nocodazole et experimental invasion Echinococcus granulosus of white mice].
The therapeutic activity of subcutaneous and intraperitoneal nocodazole injections was studied in albino mice with experimental E. granulosus invasion. The animals were intraperitoneally infected with Echinococcus larval cysts (ELC) from a spontaneously inoculated sheep. Nocodazole aqueous suspension (NAS) was administered at the late stage of invasion in two experiments. In one experiment, the treatment was initiated 7.5 months after inoculation. The animals were given daily subcutaneous injections of gradually increasing daily doses (n = 32) from 5 to 20 mg/kg twice weekly for 4 months (the total active ingredient dose was 400 mg/kg). The mice were dissected 3 months after treatment termination. Their autopsy showed that all ELCs or their vast majority were dead in 17 (70.8%) of 24 NAS-treated mice. Among the completely cured mice, there were animals having dead ELCs amounting to 36.9% of the host's weight. In the other experiment, the mice received intraperitoneal treatment 11.5 months after inoculation. They were given NAS injections (n = 2-8) in the total active ingredient dose of 14-126 mg/kg for 4-32 days. The animals were dissected 12-14 months after inoculation. All the detected ELCs were ascertained to be dead in the mice that had received NAS in an active ingredient dose of 87-126 mg/kg and had been dissected 33-81 days after initiation of treatment. The damaging effect of NAS was accompanied by obvious ELC collapse (the ELC collapse index was 57.5-75.9% for all the cured animals).


Timing of coronary artery bypass surgery in patients with non-ST-segment elevation myocardial infarction and postoperative outcomes.
The aim of the study was to assess whether a cardiac troponin T (cTnT) level 1 ng/ml or below threshold is safe and to evaluate mid-term follow-up results in stable patients with non-ST-segment elevation after acute myocardial infarction. Among cTnT positive patients who presented to the emergency unit with chest pain and received coronary angiography, 100 patients who underwent isolated coronary artery bypass grafting (CABG) constituted the study group (group 1). The same number of patients (n = 100) who were cTnT negative and underwent an isolated CABG operation under elective conditions were selected as the control group (group 2). Among preoperative criteria, group 1 had significantly higher smoking rates (74% vs. 41%, p = 0.0001), and significantly lower ejection fraction values (47.1 ±8.25, 54.69 ±8.73, p = 0.0001). There were no significant differences between the groups with respect to operative parameters. Postoperative follow-up periods were significantly longer in group 1 (23.25 ±14 vs. 17.55 ±7.95 months, p = 0.001). Average waiting time for cTnT to drop below the 1 ng/ml threshold value was 5.73 ±2.95 (1-12) days. Intra-aortic balloon pump use in Groups 1 and 2 was 3% and 1%, respectively. There were no hospital mortalities in either group. Mortality rates at mid term were 6% in both groups. This study compared two groups positive and negative for preoperative cTnT. The findings show that it is safe to wait until cTnT levels decrease to the 1 ng/ml threshold value in cTnT positive patients having a stable course. This waiting period is not very long, which is significant with respect to potential complications.


[CNS changes in HIV-infected patients: magnetic resonance spectroscopy].
Changes that may appear in the central nervous system in the course of AIDS either result directly from HIV infection or--as is the case with opportunistic infections and some neoplasms--develop as a secondary consequence of general immunodeficiency. Neuroimaging techniques may be most useful in the differential diagnosis of these lesions. Basic principles of HIV encephalitis and progressive multifocal leukoencephalopathy differentiation in MRI scans are discussed in the paper, and diagnostic possibilities of MR imaging in some other infections (tuberculosis, toxoplasmosis, and cryptococcosis) are outlined. Special attention is paid, on the one hand, to difficulties in the differentiation between toxoplasmosis and lymphoma, and on the other hand--to the growing diagnostic utility of MR-spectroscopy in this respect.


Dengue-Immune Humans Have Higher Levels of Complement-Independent Enhancing Antibody than Complement-Dependent Neutralizing Antibody.
Dengue is the most important arboviral disease worldwide. We previously reported that most inhabitants of dengue-endemic countries who are naturally immune to the disease have infection-enhancing antibodies whose in vitro activity does not decrease in the presence of complement (complement-independent enhancing antibodies, or CiEAb). Here, we compared levels of CiEAb and complement-dependent neutralizing antibodies (CdNAb) in dengue-immune humans. A typical antibody dose-response pattern obtained in our assay system to measure the balance between neutralizing and enhancing antibodies showed both neutralizing and enhancing activities depending on serum dilution factor. The addition of complement to the assay system increased the activity of neutralizing antibodies at lower dilutions, indicating the presence of CdNAb. In contrast, similar dose-response curves were obtained with and without complement at higher dilutions, indicating higher levels of CiEAb than CdNAb. For experimental support for the higher CiEAb levels, a cocktail of mouse monoclonal antibodies against dengue virus type 1 was prepared. The antibody dose-response curves obtained in this assay, with or without complement, were similar to those obtained with human serum samples when a high proportion of D1-V-3H12 (an antibody exhibiting only enhancing activity and thus a model for CiEAb) was used in the cocktail. This study revealed higher-level induction of CiEAb than CdNAb in humans naturally infected with dengue viruses.


Implementing a routine outcome assessment procedure to evaluate the quality of assistive technology service delivery for children with physical or multiple disabilities: Perceived effectiveness, social cost, and user satisfaction.
There is a lack of evidence on the effects and quality of assistive technology service delivery (ATSD). This study presents a quasi-experimental 3-months follow-up using a pre-test/post-test design aimed at evaluating outcomes of assistive technology (AT) interventions targeting children with physical and multiple disabilities. A secondary aim was to evaluate the feasibility of the follow-up assessment adopted in this study with a view to implement the procedure in routine clinical practice. Forty-five children aged 3-17 years were included. Parents were asked to complete the Individual Prioritised Problem Assessment (IPPA) for AT effectiveness; KWAZO (Kwaliteit van Zorg [Quality of Care]) and Quebec User Evaluation of Satisfaction with Assistive Technology (QUEST) 2.0 for satisfaction with ATSD; Siva Cost Analysis Instrument (SCAI) for estimating the social cost of AT interventions. At follow-up, 25 children used the AT recommended. IPPA effect sizes ranged from 1.4 to 0.7, showing a large effect of AT interventions. Overall, parents were satisfied with ATSD, but Maintenance, Professional Services, and AT Delivery were rated not satisfactory. SCAI showed more resources spent for AT intervention compared to human assistance without technological supports. AT may be an effective intervention for children with disabilities. Issues concerning responsiveness and feasibility of the IPPA and the SCAI instruments are discussed with a view to inform routine clinical practice.


The Value of the Distal Radioulnar Joint Effusion in Diagnosing Triangular Fibrocartilage Complex Tears on Magnetic Resonance Imaging.
A retrospective study was conducted to evaluate the role of distal radioulnar joint (DRUJ) effusion in aiding the diagnostic accuracy of central triangular fibrocartilage complex (TFCC) tears on non-contrast MRI. 89 consecutive patients who had undergone wrist arthroscopy for ulna sided wrist pain in our unit were identified and their preoperative imaging reviewed. Two consultant musculoskeletal Radiologists independently reported the presence or absence of a DRUJ effusion and or a TFCC tear. The inter-observer variability was calculated using weighted Kappa tests. Two by two tables were constructed to calculate the sensitivity and specificity of reported TFCC tear or DRUJ effusion on MRI in correctly diagnosing central TFCC tears identified at arthroscopy. Sensitivity of MRI to report a TFCC tear was 0.56 and specificity was 0.79. Sensitivity increased to 0.89 if either a DRUJ effusion or TFCC tear were seen on MRI. When observed together, the presence of both a DRUJ effusion and a TFCC tear seen on the imaging lead to a sensitivity of 0.74 and PPV of 82% when compared to findings at arthroscopy. In the absence of both DRUJ effusion and TFCC tear, the specificity of MRI increased to 0.92. Agreement by the radiologists on the presence of DRUJ effusion was substantial (k value 0.67) and TFCC tear was moderate (k value 0.58). The presence of DRUJ effusion on MRI can further improve sensitivity of MRI in diagnosing central TFCC tears. The sensitivity of detecting a central TFCC tear on MRI scan when both a DRUJ effusion and a TFCC tear were seen (0.74) is comparable to rates demonstrated on MRA meta-analysis results (0.78). Furthermore, considering the absence of both a DRUJ effusion and TFCC tear seen on MRI is useful in excluding the presence of a TFCC tear at arthroscopy.


A homozygosity-based search for mutations in patients with autosomal recessive retinitis pigmentosa, using microsatellite markers.
To identify possible mutations in known candidate genes in patients with autosomal recessive (ar) and simplex retinitis pigmentosa (RP), by using an established strategy of flexible, multiplexed, microsatellite-based homozygosity mapping. A total of 78 microsatellite markers corresponding to 16 genes known to be responsible for arRP were selected and used in 18 multiplex amplifications, followed by genotyping. Twelve consanguineous probands and 47 nonconsanguineous probands (59 patients with arRP or simplex RP) agreed to the screening. Of the 59 probands examined, 24 had a mean of 1.4 genes showing homozygosity for all markers within the corresponding gene region. Subsequent direct sequencing revealed three homozygous mutations. Two of them were novel mutations in the genes TULP1 (c.1145T-->C, F382S) and CNGB1 (c.3444 + 1G-->A). The other was a mutation in RPE65 (c.1543C-->T, R515W), which is known to cause Leber's congenital amaurosis. The clinical features of each patient, together with the cosegregation analysis, strongly support the pathogenicity of these mutations. This systematic approach facilitated the identification of genes that cause arRP, and the results provide a widened spectrum of the mutation severity associated with a broader range of phenotypic manifestations of arRP.


Naringin and Naringenin Relax Rat Tracheal Smooth by Regulating BKCa Activation.
Naringin and its aglycone, naringenin, occur naturally in our regular diet and traditional Chinese medicines. This study aimed to detect an effective therapeutic approach for cough variant asthma (CVA) through evaluating the relaxant effect of these two bioactive herbal monomers as antitussive and antiasthmatic on rat tracheal smooth muscle. The relaxant effect was determined by measuring muscular tension with a mechanical recording system in rat tracheal rings. Cytosolic Ca2+ concentration was measured using a confocal imaging system in primary cultured tracheal smooth muscle cells. In rat tracheal rings, addition of both naringin and naringenin could concentration dependently relax carbachol (CCh)-evoked tonic contraction. This epithelium-independent relaxation could be suppressed by BaCl2, tetraethylammonium, and iberiotoxin (IbTX), but not by glibenclamide. After stimulating primary cultured tracheal smooth muscle cells by CCh or high KCl, the intracellular Ca2+ increase could be inhibited by both naringin and naringenin, respectively. This reaction was also suppressed by IbTX. These results demonstrate that both naringin and naringenin can relax tracheal smooth muscle through opening big conductance Ca2+-activated K+ channel, which mediates plasma membrane hyperpolarization and reduces Ca2+ influx. Our data indicate a potentially effective therapeutic approach of naringin and naringenin for CVA.


Translating depression biomarkers for improved targeted therapies.
Mood disorders are among the most common medical conditions and cause amongst the greatest disease burden. Currently approved antidepressants target monoamine pathways; these medicines take many weeks to relieve symptoms, and most patients do not have sustained responses. This review will highlight recent advances in translational science identifying dysfunctional biochemical processes and neuronal circuits associated with mood disorders. We will also summarize strategies for targeting these pathways and for enhancing synaptic plasticity to develop most effective and rapidly acting antidepressant therapies.


The digestive system and nutritional considerations for individuals with Rett syndrome.
Rett syndrome (RS) is a neurodevelopmental syndrome of genetic origin that mainly affects females. Individuals diagnosed with RS exhibit a variety of functional difficulties that impair their quality of life. One of the affected systems is the digestive system, where 74% of persons with RS have abnormal functioning. The affected digestive system causes this population to present an array of problems, such as gastroesophageal reflux (GER), constipation, and malnutrition, leading to failure to thrive (FTT), which resolves in reduced functional ability. Due to the severe effects of the dysfunctional digestive system of individuals with RS, this article will describe the problems common to this population, as well as propose some clinical suggestions for intervention.


Whole-exome sequencing of ovarian cancer families uncovers putative predisposition genes.
Despite the identification of several ovarian cancer (OC) predisposition genes, a large proportion of familial OC risk remains unexplained. We adopted a two-stage design to identify new OC predisposition genes. We first carried out a large germline whole-exome sequencing study on 158 patients from 140 families with significant OC history, but without evidence of genetic predisposition due to BRCA1/2. We then evaluated the potential candidate genes in a large case-control association study involving 381 OC cases in the Cancer Genome Atlas project and 27,173 population controls from the Exome Aggregation Consortium. Two new putative OC risk genes were identified, namely, ANKRD11, a putative tumor suppressor, and POLE, an enzyme involved in DNA repair and replication. These two genes likely confer moderate OC risk. We performed in vitro experiments and showed an ANKRD11 mutation identified in our patients markedly lowered the protein expression by compromising protein stability. Upon future validation and functional characterization, these genes may shed light on cancer etiology along with improving ascertainment power and preventive care of individuals at high risk of OC.


Effect of substrate on hypoxic response of pulmonary artery.
Main pulmonary arteries (MPA) were isolated from young guinea pigs and incubated in a modified Krebs-Henseleit solution containing either glucose and sucrose, or sucrose alone. Experimental hypoxia (PO2=30 mmHg) was induced by aerating the muscle chamber with a gas mixture of 95% nitrogen and 5% carbon dioxide. In must experiments the MPA was electrically stimulated, whereas in some no electrical stimulation was used. The isometric tension of electrically stimulated MPA was analyzed by means of resting tension (RT), active tension (ATmax), and maximum rate of tension development (dT/dt). It was demonstrated that when MPA was exposed to acute hypoxia in a glucose-free medium a significant increase in resting tension was observed in both electrically stimulated and nonstimulated preparations. However, the significantly hypoxic response was inhibited by the presence of glucose in the experimental medium. This tonic response of MPA is suggestive of the in vivo hypoxic pressor response of pulmonary circulation. A lower oxygen tension (PO2=95 mmHg) exposure prior to hypoxia significantly potentiated this hypoxic response of the MPA. In a separate series of experiments, isolated aortas demonstrated a similar response when exposed to acute hypoxia in vitro. Similarly, as in experiments with MPA, the presence of glucose inhibited the hypoxic tonic response of isolated aorta.