Quality of life in glaucoma and its relationship with visual function.
The aims of this study were (a) to explore patients self-reported visual disability resulting from glaucoma by means of a questionnaire developed for this purpose; (b) identify activities strongly associated with a measure of visual field loss, (c) to quantify different psychophysical aspects of visual function; (d) to assess the relationship between objective measures of visual function and patients' perception of their vision-related quality of life. Three groups of glaucoma patients (n = 47) with mild (n = 18), moderate (n = 19), and severe visual field loss (n = 10) and a group of normal controls (n = 19) underwent a comprehensive clinical examination, completed a questionnaire and, on a separate visit, performed a number of psychophysical tests of visual function. Questionnaire responses (vision-related quality of life, general health and psychosocial variables), visual acuity, visual fields, Esterman binocular disability scores, contrast sensitivity, critical flicker frequency, color vision, dark adaptation, glare disability (brightness acuity), and stereoacuity scores were measured. Fifteen of the 50 questions were noted to have a strong significant relationship with a measure of visual field loss and were included in a new questionnaire scale, the Glaucoma Quality of Life - 15 (GQL-15). The scale validity showed a significant correlation with perimetric mean deviation (MD) values (r = -0.6; P < 0.0001), the reliability of the scale was high (Cronbach alpha = 0.95), and test-retest reliability of the questionnaire was strong (r = 0.87). An overall statistically significant decrease in performance-related quality of life was noted between normal subjects and all groups of glaucoma patients. A significant relationship was found between the scale questionnaire summary performance measure and a number of psychophysical tests: Pelli-Robson contrast sensitivity (r = -0.45, P < 0.001), glare disability (r = -0.41, P < 0.001), Esterman binocular visual field test (r = -0.39, P < 0.001), dark adaptation (r = 0.34, P = 0.007), and stereopsis (r = 0.26, P = 0.04). Perceived visual disability relating to certain tasks (particularly involving dark adaptation and disability glare, activities demanding functional peripheral vision such us tripping over and bumping into objects and outdoor mobility tasks) was significantly associated with the severity of binocular visual field loss. As a result, a new glaucoma-specific questionnaire scale with good performance characteristics is presented in this study. The difficulties encountered by patients in everyday life (as measured with the questionnaire) were also mirrored in their performance on a number of psychophysical tests, especially contrast sensitivity, glare disability, Esterman binocular visual field test, and dark adaptation.


Estimated net acid excretion inversely correlates with urine pH in vegans, lacto-ovo vegetarians, and omnivores.
Diet affects urine pH and acid-base balance. Both excess acid/alkaline ash (EAA) and estimated net acid excretion (NAE) calculations have been used to estimate the effects of diet on urine pH. This study's goal was to determine if free-living vegans, lacto-ovo vegetarians, and omnivores have increasingly acidic urine, and to assess the ability of EAA and estimated NAE calculations to predict urine pH. This study used a cross-sectional design. This study assessed urine samples of 10 vegan, 16 lacto-ovo vegetarian, and 16 healthy omnivorous women in the Boston metropolitan area. Six 3-day food records from each dietary group were analyzed for EAA content and estimated NAE, and correlations with measured urine pH were calculated. The mean (+/- SD) urine pH was 6.15 +/- 0.40 for vegans, 5.90 +/- 0.36 for lacto-ovo vegetarians, and 5.74 +/- 0.21 for omnivores (analysis of variance, P = .013). Calculated EAA values were not significantly different among the three groups, whereas mean estimated NAE values were significantly different: 17.3 +/- 14.5 mEq/day for vegans, 31.3 +/- 8.5 mEq/day for lacto-ovo vegetarians, and 42.6 +/- 13.2 mEq/day for omnivores (analysis of variance, P = .01). The average deattenuated correlation between urine pH and EAA was 0.333; this value was -0.768 for estimated NAE and urine pH, with a regression equation of pH = 6.33 - 0.014 NAE (P = .02, r = -0.54). Habitual diet and estimated NAE calculations indicate the probable ranking of urine pH by dietary groups, and may be used to determine the likely acid-base status of an individual; EAA calculations were not predictive of urine pH.


A scrapie epidemic in Cyprus.
Scrapie is endemic in the sheep flocks of many countries, but good epidemiological information on this disease is scarce. Data on the initial stages of an epidemic are even more rare. We describe the ongoing epidemic of scrapie in Cyprus that has been tracked since it began in the mid-1980s. The early stages of the spread of scrapie from farm to farm, between 1985 and 2000, is analysed with a simple mathematical model. The flock-to-flock basic reproductive number (R0) for the spread of scrapie was estimated at between 1.4 and 1.8. The impact of interventions on the control of the epidemic are discussed from an epidemiological and economic point of view. Early identification of scrapie cases on farms can have a large impact on the number of farms affected. The long period before detection of disease in a flock means that policies based on whole-flock slaughter can be inefficient in preventing spread. Under a range of scenarios, a concentration of resources on early detection and quarantine may be more effective in terms of both the costs and control of the epidemic.


The impact of client-counselor similarity on acceptance of counseling services for women living with HIV.
This study investigates the effect of similarity of health status between counselors and clients on the acceptance of counseling services among women living with HIV (WLWH). We hypothesized that WLWH should be more willing to seek counseling from an HIV-positive counselor as opposed to one living free of HIV or with another stigmatized disease like Hepatitis C, because a counselor with HIV should be perceived as more empathetic and credible. Moreover, the positive effect of similarity on acceptance should be particularly pronounced among WLWH who perceive high levels of HIV-related stigmatization and low levels of social support. Participants were 89 WLWH in Germany. In an online scenario experiment, we varied the similarity of health status between participants and a fictitious female counselor by presenting participants with one of three counselor profiles: The profile either stated that she was living with HIV but not Hepatitis C, with Hepatitis C but not HIV, or with neither HIV nor Hepatitis C. We then measured participants' perceptions of the counselor's similarity, empathy, and credibility, and their willingness to accept counseling with her. Results from an ANOVA with planned contrasts supported our assumption that participants presented with an HIV-positive counselor perceived her to be more similar to themselves and were more willing to accept the counseling than participants exposed to a HIV-negative counselor (either with or without Hepatitis C), for all relevant contrasts, η2s ≥ .08. Regression analyses corroborated that this effect was mediated by the counselor's perceived empathy and credibility, total indirect effect = .36, 95%CI [0.22, 0.53]. Moreover, moderated regression analyses revealed that the similarity effect on acceptance was particularly strong when participants experienced high levels of stigmatization and low levels of social support, for both interaction terms, ΔR2s ≥ .04, F(1, 85)s ≥ 5.03, ps ≤ .028.


Eaf1 and Eaf2 negatively regulate canonical Wnt/β-catenin signaling.
Eaf factors play a crucial role in tumor suppression and embryogenesis. To investigate the potential mechanism of Eaf activity, we performed loss- and gain-of-function assays in zebrafish using morpholino and mRNA injections, respectively. We found that eaf1 and eaf2 inhibit Wnt/β-catenin signaling, thereby modulating mesodermal and neural patterning in the embryo. Moreover, ectopic expression of eaf1 and eaf2 in embryos and cultured cells blocked β-catenin reporter activity. By immunoprecipitation, we also observed that Eaf1 and Eaf2 bound to the Armadillo repeat region and C-terminus of β-catenin, as well as to other β-catenin transcription complex proteins, such as c-Jun, Tcf and Axin, suggesting the formation of a novel complex. In addition, the N-terminus of Eaf1 and Eaf2 bound to β-catenin and exhibited dominant-negative activity, whereas the C-terminus appeared to either harbor a suppression domain or to recruit a repressor. Both the N- and C-terminus must be intact for Eaf1 and Eaf2 suppressive activity. Lastly, we demonstrate a conservation of biological activities for Eaf family proteins across species. In summary, our evidence points to a novel role for Eaf1 and Eaf2 in inhibiting canonical Wnt/β-catenin signaling, which might form the mechanistic basis for Eaf1 and Eaf2 tumor suppressor activity.


Copper-mediated synthesis of phthalocyanino-fused Dehydro
Cyclooligomeric phthalocyanines with the special feature of having a dehydroannulene core are described. Compounds 4a,b and 5a,b were prepared by an oxidative coupling mediated by copper from the corresponding diethynyl unsymmetrically substituted phthalocyanines 8a,b, which are easily accessible from the corresponding diiodo compounds 6a,b by a palladium-copper-catalyzed coupling. Appropriate conditions to selectively form cyclodimers and cyclotrimers using Glaser and Eglinton methodologies have been attempted. In this way, two compounds, 4a and 5b, each representative of a kind of oligomers, could be appropriately isolated and characterized by MALDI-MS. The UV-vis spectra of compounds 4a and 5b show a split Q-band shifted to the red with respect to the corresponding precursor 8a,b. This can be interpreted, in light of previous results, as a consequence of intramolecular electronic coupling between the Pc subunits. Extensive formation of aggregates in chloroform can be also inferred from the spectra. No significant differences could be observed in the spectra by comparison with that of the open-chain analogue 11, most probably due to a saturation phenomenon of the optical properties already pointed out in the literature for other alkynyl-linked open-chain dimers.


Genetic diversity of noroviruses and sapoviruses in children with acute sporadic gastroenteritis in New Delhi, India.
Human caliciviruses (HuCVs) cause gastroenteritis throughout the world. Limited information is available on molecular epidemiology of caliciviruses from developing countries including India. Standardization and evaluation of a two-step multiplex RT-PCR assay for HuCVs and characterization of strains. Two hundred and twenty-six stool samples were collected from children with acute gastroenteritis (AGE) over a one and half year to study the prevalence and diversity of HuCVs in children with AGE in New Delhi, India. A multiplex two-step RT-PCR using 3 sets of external and 4 sets of internal primers from the RdRp gene was standardized for detection of NoVs and SaVs. Molecular characterization of some HuCV strains was done by sequencing followed by phylogenetic analysis. Fifty-nine HuCVs strains were detected in 54 (24%) of the samples; 5 samples had mixed infections. Of these 59 HuCVs, 36 (61%) were norovirus (34 were GGII; 2 were GGI) and 23 (39%) were sapovirus (22 were GGI; 1 was GGII). Phylogenetic analysis of partial RdRp gene of 12 HuCV strains identified three genotypes (GGI/4, GGII/3 and a newly identified GIIb/Hilversum cluster) in NoVs and one genotype (GGI/1) in SaVs. This is one of the few reports from India on detection and characterization of HuCVs by multiplex RT-PCR assay. This assay can be a useful tool for epidemiological studies of HuCV infections.


Workplace in fluency management: factoring the workplace into fluency management.
This article addresses competency-based standards and guidelines for the involvement of speech-language pathologists in the workplace of clients who stutter. It advocates broadening customary practices in stuttering treatment and suggests that speech-language pathologists should extend their scope of service delivery to the workplace. It presents a sequence for the collaborative involvement of the employer and other workplace members and proposes strategies for evaluating workplace based fluency programs. Issues of fluency management, transfer, maintenance, and efficacy are discussed in the workplace context. Also addressed is workplace communication as well as such factors as stereotypes, discrimination, and resistance to change which may impinge on workplace intervention. It is argued that structured intervention, transfer, and generalization within a collaborative workplace framework facilitates best practice for the fluency clinician and more appropriate outcomes for the diversity of clients who stutter.


Folinic acid + 5-fluorouracil (5-FU) versus equidose 5-FU in advanced colorectal cancer. Phase III study of 'GISCAD' (Italian Group for the Study of Digestive Tract Cancer).
In a multicentre Phase III trial, 182 patients were randomized to either folinic acid (FA) (200 mg/sqm i.v. x 5 days) + 5-fluorouracil (5-FU) (400 mg/sqm i.v. in 15' x 5 days) every 4 weeks (Arm A), or to 5-FU alone at the same dosage (Arm B). Response rates were 20.6% (Arm A) and 10% (Arm B) with a significant (p = 0.046) advantage for FA + 5-FU. Median time to progression (6 and 6 months) and overall survival (11.5 and 11 months) were similar in the 2 groups of patients, while neither treatment was effective in reducing pain or improving performance status. Univariate analysis showed that no prognostic factors other than treatment influenced response, although survival was affected by the number and site of metastases, performance status, and the presence and degree of pain. Toxicity was acceptable and lower in comparison with other Phase II-III trials, with no significant difference between the 2 arms. However, in individual patients, grade 3-4 side effects (mainly stomatitis and diarrhoea) were observed, particularly in patients receiving FA: this led to interruption of the treatment in 7 cases. The superiority, in terms of objective response, of FA + 5-FU over 5-FU alone would seem to justify a large-scale evaluation of this combination in the adjuvant setting. Further improvements in relation to advanced disease (i.e., modifications to the schedule and/or introduction of other modulators) are warranted.


Modelling the cost-effectiveness of brief aftercare interventions following hospital-treated self-harm.
Prior self-harm represents the most significant risk factor for future self-harm or suicide. To evaluate the cost-effectiveness of a theoretical brief aftercare intervention (involving brief follow-up contact, care coordination and safety planning), following a hospital-treated self-harm episode, for reducing repeated self-harm within the Australian context. We employed economic modelling techniques to undertake: (a) a return-on-investment analysis, which compared the cost-savings generated by the intervention with the overall cost of implementing the intervention; and (b) a cost-utility analysis, which compared the net costs of the intervention with health outcomes measured in quality-adjusted life years (QALYs). We considered cost offsets associated with hospital admission for self-harm and the cost of suicide over a period of 10 years in the base case analysis. Uncertainty and one-way sensitivity analyses were also conducted. The brief aftercare intervention resulted in net cost-savings of AUD$7.5 M (95% uncertainty interval: -56.2 M to 15.1 M) and was associated with a gain of 222 (95% uncertainty interval: 45 to 563) QALYs over a 10-year period. The estimated return-on-investment ratio for the intervention's modelled cost in relation to cost-savings was 1.58 (95% uncertainty interval: -0.17 to 5.33). Eighty-seven per cent of uncertainty iterations showed that the intervention could be considered cost-effective, either through cost-savings or with an acceptable cost-effectiveness ratio of 50 000 per QALY gained. The results remained robust across sensitivity analyses. A theoretical brief aftercare intervention is highly likely to be cost-effective for preventing suicide and self-harm among individuals with a history of self-harm.


A case of multiple dental anomalies: a variant of Ekman-Westborg-Julin trait.
Simultaneous occurrence of multiple dental anomalies is relatively common and has been reported particularly in cases with systemic alterations or syndromes. However, in 1974, Ekman-Westborg and Julin described a unique case of multiple macrodontia and multituberculism of posterior teeth accompanied by multiple dental malformations without other systemic anomalies. Here we report the case of a 20-year-old female patient who presented with macrodontia affecting her maxillary lateral teeth, mandibular incisors, and impacted multituberculated wisdom teeth accompanied by other dental anomalies that manifested itself as a variant of the Ekman-Westborg-Julin trait.


Kupffer cell activation after no-flow ischemia versus hemorrhagic shock.
Kupffer cell-derived oxidant stress is critical for reperfusion injury after no-flow ischemia. However, the importance of Kupffer cells as source of reactive oxygen formation is unclear in a hemorrhagic shock model. Therefore, we evaluated Kupffer cell activation after 60 or 120 min of hemorrhage and 90 min of resuscitation (HS/RS) in pentobarbital-anesthetized male Fischer rats. Plasma glutathione disulfide (GSSG) as indicator for a vascular oxidant stress showed no significant changes after HS/RS. Plasma ALT activities were only moderately increased (100-200 U/L). Kupffer cells isolated from postischemic livers did not generate more superoxide than cells from sham controls. In contrast, the 10-fold increase of plasma GSSG and the 9-fold higher spontaneous superoxide formation of Kupffer cells after 60 min of hepatic no-flow ischemia followed by 90 min of reperfusion demonstrated the activation of Kupffer cells in this experimental model. Plasma ALT activities (1930 +/- 240 U/L) indicated severe liver injury. These results demonstrate a fundamental difference in the degree of Kupffer cell activation between the two models of warm hepatic ischemia. Our findings suggest that different therapeutic strategies are necessary to ameliorate the initial injury after low flow ischemia (hemorrhage) compared to cold (transplantation) or warm (Pringle maneuver) no-flow ischemia.


Ab initio gene finding in Drosophila genomic DNA.
Ab initio gene identification in the genomic sequence of Drosophila melanogaster was obtained using (human gene predictor) and Fgenesh programs that have organism-specific parameters for human, Drosophila, plants, yeast, and nematode. We did not use information about cDNA/EST in most predictions to model a real situation for finding new genes because information about complete cDNA is often absent or based on very small partial fragments. We investigated the accuracy of gene prediction on different levels and designed several schemes to predict an unambiguous set of genes (annotation CGG1), a set of reliable exons (annotation CGG2), and the most complete set of exons (annotation CGG3). For 49 genes, protein products of which have clear homologs in protein databases, predictions were recomputed by Fgenesh+ program. The first annotation serves as the optimal computational description of new sequence to be presented in a database. Reliable exons from the second annotation serve as good candidates for selecting the PCR primers for experimental work for gene structure verification. Our results shows that we can identify approximately 90% of coding nucleotides with 20% false positives. At the exon level we accurately predicted 65% of exons and 89% including overlapping exons with 49% false positives. Optimizing accuracy of prediction, we designed a gene identification scheme using Fgenesh, which provided sensitivity (Sn) = 98% and specificity (Sp) = 86% at the base level, Sn = 81% (97% including overlapping exons) and Sp = 58% at the exon level and Sn = 72% and Sp = 39% at the gene level (estimating sensitivity on std1 set and specificity on std3 set). In general, these results showed that computational gene prediction can be a reliable tool for annotating new genomic sequences, giving accurate information on 90% of coding sequences with 14% false positives. However, exact gene prediction (especially at the gene level) needs additional improvement using gene prediction algorithms. The program was also tested for predicting genes of human Chromosome 22 (the last variant of Fgenesh can analyze the whole chromosome sequence). This analysis has demonstrated that the 88% of manually annotated exons in Chromosome 22 were among the ab initio predicted exons. The suite of gene identification programs is available through the WWW server of Computational Genomics Group at http://genomic.sanger.ac.uk/gf. html.


Hes1 but not Hes5 regulates an astrocyte versus oligodendrocyte fate choice in glial restricted precursors.
To determine the role of Hes genes in the differentiation process of neuroepithelial (NEP) cells to glial restricted precursor cells (GRPs) and subsequently GRPs to oligodendrocytes and astrocytes, we have examined the effects of Hes1 and Hes5 on glial differentiation. We find that both Hes1 and Hes5 are expressed by GRPs and that Hes1 can drive GRPs to an astrocyte cell fate at the expense of oligodendrocyte differentiation. Overexpression of Hes1 in GRPs results in the up-regulation of the astrocyte markers glial fibrillary acidic protein and CD44 and the down-regulation of oligodendrocyte markers myelin proteolipid protein/DM20, GalC, and CNPase. Transcription factors involved in oligodendrocyte differentiation, such as Nkx2.2, Olig1, and Mash1, are also down-regulated in Hes1-overexpressing cells. The effect of Hes1 on gliogenesis is stage-specific as Hes1 does not direct NEP cells to an astrocytic fate. In contrast to Hes1, Hes5 does not promote astrocyte differentiation. Instead, it inhibits both astrocyte and oligodendrocyte differentiation. Overexpression of Notch1 has an effect on gliogenesis similar to that of Hes1 and the mRNA levels of Hes1 are up-regulated in cells overexpressing Notch1, suggesting that Notch1 could be an upstream activator of Hes1.


Emulsion-templated macroporous carbons synthesized by hydrothermal carbonization and their application for the enzymatic oxidation of glucose.
Carbon-based monoliths have been designed using a simple synthetic pathway based on using high internal phase emulsion (HIPE) as a soft template to confine the polymerization and hydrothermal carbonization of saccharide derivatives (furfural) and phenolic compounds (phloroglucinol). Monosaccharides can be isolated from the cellulosic fraction of lignocellulosic biomass and phloroglucinol can be extracted from the bark of fruit trees; however, this approach constitutes an interesting sustainable synthetic route. The macroscopic characteristics can be easily modulated; a high macroporosity and total pore volume of up to 98 % and 18 cm(3)g(-1) have been obtained, respectively. After further thermal treatment under inert atmosphere, the as-synthesized macroporous carbonized HIPEs (carbo-HIPEs) have shaping capabilities relating to interesting mechanical properties as well as a high electrical conductivity of up to 300 Sm(-1) . These conductive foams exhibit a hierarchical structure associated with the presence of both meso- and micropores that exhibit specific Brunauer-Emmett-Teller (BET) surface areas and DFT total pore volumes up to 730 m(2)g(-1) and 0.313 cm(3)g(-1) , respectively. Because of their attractive structural characteristics and intrinsic properties, these macroporous monoliths have been incorporated as a proof of principle within electrochemical devices as modified thin carbon disc electrodes. A promising two-fold improvement in the catalytic current is observed for the electrooxidation of glucose after the immobilization of a glucose oxidase-based biocatalytic mixture onto the carbo-HIPE electrodes compared to that observed if using commercial glassy carbon electrodes.


Celastrol inhibits microglial pyroptosis and attenuates inflammatory reaction in acute spinal cord injury rats.
Pyroptosis pathway is closely related to inflammation. However, Celastrol effect on pyroptosis pathway after spinal cord injury (SCI) are poorly understood. We studied the anti-inflammatory and neuroprotective effects of Celastrol on acute spinal cord injury in rats, and its anti-inflammatory effects on lipopolysaccharide (LPS)/ATP-induced microgliosis. Our results show that Celastrol can improve the recovery of hindlimb motor function after SCI in Sprague-Dawley (SD) rats, and reduce the cavity area of spinal cord injury along with the neuronal loss. Celastrol simultaneously reduced the activation of microglia (especially M1 microglia) in the spinal cord, inhibited the pyroptosis-related proteins (NLRP3 ASC Caspase-1 GSDMD), reduced the release of TNF-α IL-1β and IL-18 inflammatory factors, and increased the release of IL10 cytokines. In vitro studies showed that Celastrol reduced the toxicity resulting from the administration of LPS with ATP to BV-2 cells, inhibited the pyroptosis-related proteins (NLRP3 Caspase-1 GSDMD), and inhibited the release of corresponding inflammatory factors. Finally, Celastrol can inhibit the expression of NFκB/p-p65 in vitro and in vivo. Our results show that Celastrol can attenuate the inflammatory response of the spinal cord after SCI, which is associated with inhibition of microglial activation and pyroptosis pathway. Further study to explore the use of Celastrol to treat SCI is warranted.


Finite element modeling and experimental characterization of crosstalk in 1-D CMUT arrays.
Crosstalk is the coupling of energy between the elements of an ultrasonic transducer array. This coupling degrades the performance of transducers in applications such as medical imaging and therapeutics. In this paper, we present an experimental demonstration of guided interface waves in capacitive micromachined ultrasonic transducers (CMUTs). We compare the experimental results to finite element calculations using a commercial package (LS-DYNA) for a 1-D CMUT array operating in the conventional and collapsed modes. An element in the middle of the array was excited with a unipolar voltage pulse, and the displacements were measured using a laser interferometer along the center line of the array elements immersed in soybean oil. We repeated the measurements for an identical CMUT array covered with a 4.5-microm polydimethylsiloxane (PDMS) layer. The main crosstalk mechanism is the dispersive guided modes propagating in the fluid-solid interface. Although the transmitter element had a center frequency of 5.8 MHz with a 130% fractional bandwidth in the conventional operation, the dispersive guided mode was observed with the maximum amplitude at a frequency of 2.1 MHz, and had a cut-off frequency of 4 MHz. In the collapsed operation, the dispersive guided mode was observed with the maximum amplitude at a frequency of 4.0 MHz, and had a cut-off frequency of 10 MHz. Crosstalk level was lower in the collapsed operation (-39 dB) than in the conventional operation (-24.4 dB). The coverage of the PDMS did not significantly affect the crosstalk level, but reduced the phase velocity for both operation modes. Lamb wave modes, A0 and S0, were also observed with crosstalk levels of -40 dB and -65 dB, respectively. We observed excellent agreement between the finite element and the experimental results.


The effects and challenges of alcohol use disorder peer support service in South Korea: A focus group study.
Although alcohol use disorder (AUD) is associated with a high disease burden due to medical consequences, people with AUD often do not receive appropriate treatment or community health service support. Peer-support services, intended to bridge the gap between patients with AUD and mental health providers have produced successful results. However, the number of studies on peer supporters in South Korea, especially those with AUD, is limited. Therefore, research on the effectiveness or challenges faced by AUD peer supporters in Korea is required to meet the challenges posed by increases in the numbers and capabilities of peer supporters in the mental health field. This qualitative study (N = 13), included focus group interviews of AUD peer supporters (n = 7), and supervisors of peer supporters (n = 6). Focus group data were analysed using thematic analysis methods. These analyses identified themes including 'Life before AUD peer supporters: The moment of change', 'Effects of peer support services: Working as peer supporters changed our lives', 'Challenges of peer supporter services: Things experienced as a team' and 'Future directions: How we can improve peer support services'? Findings indicate that healthcare professionals, educated to maintain clear boundaries, are discouraged from disclosing personal information or developing personal relationships with patients. On the other hand, peer supporters discuss personal histories and prioritize personal connections. By acting as comrades, peer supporters have positive effects. By sharing their experiences, peer supporters formed appropriate relationships with AUD patients and families resulting in more active engagement in treatment programmes and increased numbers of patients receiving outpatient treatment.


[Repair of mandibular defects using dosed distraction. Part II. Bound osteoplasty of the mandible by distraction osteogenesis].
Five variants of bound osteoplasty based on the distraction osteogenesis phenomenon were developed by the author for the treatment of patients with gunshot mandibular defects during the war in Afghanistan. Three of these variants are described in this paper; indications for their use and the technique of operation are presented. In fact, bound osteoplasty for gunshot wounds is primary early osteoplasty of the mandible -- the target of several generations of maxillofacial surgeons.


Enhanced respiratory muscular function in normal adults after lessons in proprioceptive musculoskeletal education without exercises.
A subjective sense of enhanced ease of breathing has been described after instruction in the Alexander technique of proprioceptive musculoskeletal education (awareness and voluntary inhibition of personal habitual patterns of rigid musculoskeletal constriction). We investigated the effects of AT instruction on respiratory function in healthy adult volunteers (group 1, ten subjects), who received 20 private AT lessons at weekly intervals. Spirometric tests, including maximum static mouth pressures, were assessed before and after each course of lessons. Healthy control subjects, matched for age, gender, height, and weight (group 2, ten subjects), without instruction, were tested over a similar interval. Group 1 showed significant increases in PEF (9 percent, p less than .05), MVV (6 percent, p less than .05), MIP (12 percent, p less than .02), and MEP (9 percent, p less than .005) (paired Student's t testing). Group 2 showed no significant changes. Possible mechanisms for the changes in group 1 include increased length and decreased resting tension of muscles of the torso, which in turn may increase their strength, increase thoracic compliance, and/or enhance coordination. We conclude that AT musculoskeletal education may enhance respiratory muscular function in normal adult subjects.


A quantitative tool for measuring the quality of medical training in emergency medicine.
The most common method of assessing the quality of medical education is through a selection of qualitative assessments, usually as part of a programme evaluation. Common qualitative assessments include measurements of students' and teachers' participation, outcome measures such as assessment results, and qualitative assessments such as interviews and questionnaires of students and teachers. Programme evaluation can therefore be a process that is both laborious and subject to accusations of a lack of objectivity. As a result, the development of a quantitative tool that could be used alongside a programme evaluation may be both useful and desirable. A pragmatic scoring system, utilizing routinely collected quantitative data, termed as the Quality Assessment Tool, was developed during the 2013 academic year within the setting of an Emergency Medicine training programme in the UK. This tool was tested against the standard assessment currently used for this programme to establish whether the quantitative tool correlated with the programme evaluation. Second, the individual items within the tool were investigated to identify any correlations with the current assessment of quality established by the programme evaluation. The Quality Assessment Tool appears to be correlated to the quality of training delivered at individual training sites in a single specialty. It certainly identifies those centres delivering the highest quality of training and also identifies those centres whose training is consistently of a lower standard. The assessment tool is less accurate at ranking those training centres whose training is merely 'satisfactory'; whether this is a result of the imprecision of the tool itself or a reflection of the subjective nature of the current assessment (i.e. whether the current evaluation system lacks validity) cannot be stated. In summary, it appears to be possible to use a single quantitative tool to reliably, and with validity, measure the quality of training delivered at a postgraduate medical training centre. Although it is not envisaged that this would, or should, replace ongoing quality assurance systems such as programme evaluations, a validated tool can be derived for a given setting to usefully inform and augment current quality management systems in postgraduate medical education.


Smoking and quality of life among female survivors of breast, colorectal and endometrial cancers in a prospective cohort study.
To examine the association of smoking and quality of life (QOL) among survivors of breast, colorectal, or endometrial cancers. The study included women who joined the Iowa Women's Health Study in 1986 and were subsequently diagnosed with breast, colorectal, or endometrial cancers through 2004 (n = 1920). Smoking status was reported at baseline and in 2004; QOL was assessed in 2004 using the Medical Outcomes Study Short Form-36. Multivariate-adjusted odds ratios were calculated to examine the associations of smoking status and poor QOL (score lower than one-half a standard deviation below the mean of the non-smokers). Compared with non-smokers, persistent smokers had higher likelihood of reporting poor Physical Functioning (odds ratio [OR] = 2.40, 95% confidence interval [CI] = 1.32-4.37), Mental Health (OR = 1.92, CI = 1.09-3.40), and Role Emotional (OR = 2.01, CI = 1.10-3.66), whereas former smokers had higher likelihood of reporting poor Physical Functioning (OR = 1.65, CI = 1.10-2.45), Mental Health (OR = 1.62, CI = 1.11-2.37), and General Health (OR = 1.51, CI = 1.03-2.21). A statistically significant trend toward higher likelihood of poor QOL was observed across smoking groups in Vitality, Physical Functioning, Mental Health, and Role Emotional. Further adjustment for physical activity resulted in attenuation of the odds ratios and p-values for trend. Among women with breast, colorectal, or endometrial cancers, smokers were more likely than former or non-smokers to have poor QOL. Physical activity explained, in part, the association between smoking status and QOL in our study.


Determining the affinities of high-affinity antibodies using KinExA and surface plasmon resonance.
Accurate and efficient affinity measurement techniques are essential for the biophysical characterization of therapeutic monoclonal antibodies, one of the fastest growing drug classes. Surface plasmon resonance (SPR) is widely used for determining antibody affinity, but does not perform well with extremely high affinity (low picomolar to femtomolar range) molecules. In this study, we compare the SPR-based Carterra LSA and the kinetic exclusion assay (KinExA) for measuring the affinities of 48 antibodies generated against the SARS-CoV-2 receptor-binding domain. These data reveal that high-affinity antibodies can be generated straight from selections using high-quality in vitro library platforms with 54% correspondence between affinities measured using LSA and KinExA. Generally, where there was a 2-fold or greater difference between LSA and KinExA, KinExA reported that affinities were tighter. We highlight the differences between LSA and KinExA, identifying the benefits and pitfalls of each in terms of dynamic range and throughput. Furthermore, we demonstrate for the first time that single-point screening with KinExA can significantly improve throughput while maintaining a strong correlation with full binding curve equilibrium measurements, enabling the accurate rank-ordering of clones with exceptionally tight binding properties.


Crystal structure of RNA helicase from genotype 1b hepatitis C virus. A feasible mechanism of unwinding duplex RNA.
Crystal structure of RNA helicase domain from genotype 1b hepatitis C virus has been determined at 2.3 A resolution by the multiple isomorphous replacement method. The structure consists of three domains that form a Y-shaped molecule. One is a NTPase domain containing two highly conserved NTP binding motifs. Another is an RNA binding domain containing a conserved RNA binding motif. The third is a helical domain that contains no beta-strand. The RNA binding domain of the molecule is distinctively separated from the other two domains forming an interdomain cleft into which single stranded RNA can be modeled. A channel is found between a pair of symmetry-related molecules which exhibit the most extensive crystal packing interactions. A stretch of single stranded RNA can be modeled with electrostatic complementarity into the interdomain cleft and continuously through the channel. These observations suggest that some form of this dimer is likely to be the functional form that unwinds double stranded RNA processively by passing one strand of RNA through the channel and passing the other strand outside of the dimer. A "descending molecular see-saw" model is proposed that is consistent with directionality of unwinding and other physicochemical properties of RNA helicases.


FGO: a novel ontology for identification of ligand functional group.
Small molecules play crucial role in the modulation of biological functions by interacting with specific macromolecules. Hence small molecule interactions are captured by a variety of experimental methods to estimate and propose correlations between molecular structures to their biological activities. The tremendous expanse in publicly available small molecules is also driving new efforts to better understand interactions involving small molecules particularly in area of drug docking and pharmacogenomics. We have studied and designed a functional group identification system with the associated ontology for it. The functional group identification system can detect the functional group components from given ligand structure with specific coordinate information. Functional group ontology (FGO) proposed by us is a structured classification of chemical functional group which acts as an important source of prior knowledge that may be automatically integrated to support identification, categorization and predictive data analysis tasks. We have used a new annotation method which can be used to construct the original structure from given ontological expression using exact coordinate information. Here, we also discuss about ontology-driven similarity measure of functional groups and uses of such novel ontology for pharmacophore searching and de-novo ligand designing.


The water quality of the River Thames at a rural site downstream of Oxford
Water quality information is presented for the River Thames 34 km downstream of the market town of Oxford in Oxfordshire to provide an overview of the hydrochemical functioning of a major agriculturally impacted river entering the North Sea. The data, which cover the period from the spring of 1997 to the spring of 1999, relate to three types of data. These types are: (1) weekly spot sampling for determination of major, minor and trace elements, pH, alkalinity and herbicides; (2) tri-weekly spot sampling for pH, alkalinity and dissolved silicon; and (3) continuous measurements of pH and dissolved oxygen. Calcium and bicarbonate provide, respectively, the dominant cation and anion in solution and their compositions remain relatively constant through time, irrespective of flow levels. In contrast, many determinands show seasonally related fluctuations. Concentrations for most of the major anions, sodium, potassium as well as soluble reactive phosphorus and several soluble trace elements such as boron, antimony, arsenic and molybdenum decrease as flow increases. A reverse pattern is observed for nitrate, some herbicides and trace elements associated with particulate phases: concentrations increase with increasing flow. These patterns reflect the influence of: (1) a calcium carbonate rich groundwater system which provides the main stream flow component; (2) dilution of point source pollutant inputs associated with sewage and possibly light industry at high flows for several major, nutrient and trace elements; (3) enhanced nitrate and herbicide runoff from agricultural land at high flows; (4) enhanced microparticulate trace metal levels associated with increased suspended sediment loads at high flows; and (5) biological processes which affect pH, dissolved silicon, dissolved carbon dioxide and dissolved oxygen levels. An examination of soluble reactive phosphorus (SRP) and boron relationships reveals a reduction in concentrations for SRP associated possibly with phosphorus removal from a major sewage treatment works on an upstream tributary of the Thames, the Thame.


Decreased cardiac glutathione peroxidase levels and enhanced mandibular apoptosis in malformed embryos of diabetic rats.
To characterize normal and malformed embryos within the same litters from control and diabetic rats for expression of genes related to metabolism of reactive oxygen species (ROS) or glucose as well as developmental genes. Embryos from nondiabetic and streptozotocin-induced diabetic rats were collected on gestational day 11 and evaluated for gene expression (PCR) and distribution of activated caspase-3 and glutathione peroxidase (Gpx)-1 by immunohistochemistry. Maternal diabetes (MD group) caused growth retardation and an increased malformation rate in the embryos of MD group rats compared with those of controls (N group). We found decreased gene expression of Gpx-1 and increased expression of vascular endothelial growth factor-A (Vegf-A) in malformed embryos of diabetic rats (MDm group) compared with nonmalformed littermates (MDn group). Alterations of messenger RNA levels of other genes were similar in MDm and MDn embryos. Thus, expression of copper zinc superoxide dismutase (CuZnSOD), manganese superoxide dismutase (MnSOD), and sonic hedgehog homolog (Shh) were decreased, and bone morphogenetic protein-4 (Bmp-4) was increased, in the MD embryos compared with the N embryos. In MDm embryos, we detected increased activated caspase-3 immunostaining in the first visceral arch and cardiac area and decreased Gpx-1 immunostaining in the cardiac tissue; both findings differed from the caspase/Gpx-1 immunostaining of the MDn and N embryos. Maternal diabetes causes growth retardation, congenital malformations, and decreased general antioxidative gene expression in the embryo. In particular, enhanced apoptosis of the first visceral arch and heart, together with decreased cardiac Gpx-1 levels, may compromise the mandible and heart and thus cause an increased risk of developing congenital malformation.


Coping with copper: legacy effect of copper on potential activity of soil bacteria following a century of exposure.
Copper has been intensively used in industry and agriculture since mid-18(th) century and is currently accumulating in soils. We investigated the diversity of potential active bacteria by 16S rRNA gene transcript amplicon sequencing in a temperate grassland soil subjected to century-long exposure to normal (∼15 mg kg(-1)), high (∼450 mg kg(-1)) or extremely high (∼4500 mg kg(-1)) copper levels. Results showed that bioavailable copper had pronounced impacts on the structure of the transcriptionally active bacterial community, overruling other environmental factors (e.g. season and pH). As copper concentration increased, bacterial richness and evenness were negatively impacted, while distinct communities with an enhanced relative abundance of Nitrospira and Acidobacteria members and a lower representation of Verrucomicrobia, Proteobacteria and Actinobacteria were selected. Our analysis showed the presence of six functional response groups (FRGs), each consisting of bacterial taxa with similar tolerance response to copper. Furthermore, the use of FRGs revealed that specific taxa like the genus Nitrospira and several Acidobacteria groups could accurately predict the copper legacy burden in our system, suggesting a potential promising role as bioindicators of copper contamination in soils.


Developmental regulation of angiotensin type 1 and 2 receptor gene expression and heart growth.
Little is known regarding the developmental regulation of the cardiac angiotensin type 1 (AT1) and type 2 (AT2) receptor genes or their role in normal cardiac growth. Regulation of AT1 and AT2 receptor genes were examined using total and poly A + RNA isolated from whole Sprague-Dawley rat hearts. AT1 mRNA levels were 3.5-fold higher in the 19-day-old fetal heart compared to the 90-day-old adult as detected with 2 or 5 microg of poly A + RNA. AT2 mRNA was only detectable with 20 microg of poly A + RNA. AT2 mRNA levels were highest in the 19-day-old fetal heart with no detectable message in the 90-day-old adult heart. Qualitative PCR for AT2 mRNA also could not detect AT2 mRNA in the adult heart. Treatment with the AT1 receptor antagonist losartan for 3 weeks in the 21-day-old rat or for 4 days in the 38-day-old rat resulted in a significant decrease in heart/body weight in both groups and body weight in the 3-week treatment group. AT2 blockade for 4 days with PD123319 or beta-receptor blockade with propranolol for 3 weeks did not alter heart/body weights. Losartan treatment also resulted in a three-fold increase in cardiac AT1 mRNA levels in both the 4-day and 3-week treatment groups compared to controls. We conclude that Ang II, acting primarily, if not exclusively via the AT1 receptor plays a significant role in the regulation of normal cardiac growth in the young rat.


Caenorhabditis elegans UNC-103 ERG-like potassium channel regulates contractile behaviors of sex muscles in males before and during mating.
During mating behavior the Caenorhabditis elegans male must regulate periodic and prolonged protractor muscle contractions to insert his copulatory spicules into his mate. The protractors undergo periodic contractions to allow the spicules to reattempt insertion if a previous thrust failed to breach the vulva. When the spicule tips penetrate the vulva, the protractors undergo prolonged contraction to keep the spicules inside the hermaphrodite until sperm transfer is complete. To understand how these contractions are regulated, we isolated EMS-induced mutations that cause males to execute prolonged contraction inappropriately. Loss-of-function mutations in the unc-103 ERG-like K(+) channel gene cause the protractor muscles to contract in the absence of mating stimulation. unc-103-induced spicule protraction can be suppressed by killing the SPC motor neurons and the anal depressor muscle: cells that directly contact the protractors. Also, reduction in acetylcholine suppresses unc-103-induced protraction, suggesting that UNC-103 keeps cholinergic neurons from stimulating the protractors before mating behavior. UNC-103 also regulates the timing of spicule protraction during mating behavior. unc-103 males that do not display mating-independent spicule protraction show abnormal spicule insertion behavior during sex. In contrast to wild-type males, unc-103 mutants execute prolonged contractions spontaneously within sequences of periodic protractor contractions. The premature prolonged contractions cause the spicules to extend from the male tail before the spicule tips penetrate the vulva. These observations demonstrate that unc-103 controls various aspects of spicule function.


Anti-endothelial cell antibodies in patients with systemic lupus erythematosus.
Using unfixed cultured endothelial cells isolated from human umbilical veins, we performed cellular enzyme-linked immunosorbent assay (ELISA) for the detection of anti-endothelial cell antibodies (AECA) in the sera of 74 patients with systemic lupus erythematosus (SLE) and 82 normal individuals. Significantly higher levels of AECA were demonstrated in the patient group, as compared with the control group (0.12 +/- 0.07 vs 0.07 +/- 0.05, p less than 0.001). Fourteen of the 74 patients (19%) had endothelial cell binding activities 2 standard deviations above the mean for healthy controls. Patients with cutaneous vasculitis, Raynaud's phenomenon, or lupus nephropathy had higher mean values of AECA than those patients without such manifestations, although the differences were not statistically significant. Patients with central nervous system involvement did not have increased levels of AECA. There was a close relationship between raised levels of AECA and hypocomplementemia (p less than 0.05). No difference was observed between patients positive and negative for anti-native DNA antibodies. We conclude that frequent occurrence of AECA is confirmed in Chinese patients with SLE and that the appearance of AECA is probably related to lupus activity. However, the role of AECA in vascular damage in SLE needs further clarification.


Influence of different caregiving styles on fundamental movement skills among children.
This study investigated the influence of parenting and grandparenting caregiving styles on fundamental motor skills (FMS) of preschool children. A total of 1,326 preschool children (698 boys, 628 girls) aged 4-6 years were recruited from the kindergartens of Jinhua City, China. Locomotor skills (LM), ball skills (BS), and total fundamental movement skills (TS) of children were assessed by the Test of Gross Motor Development-3rd edition (TGMD-3). There were 978 children in parenting and 348 children in grandparenting caregiving styles. The LM, BS and TS scores of children were considerably (p < 0.001) increased with age (irrespective of sex or caregiving style). For the sex comparisons, BS scores of boys were significantly higher than girls (p < 0.001), while LM and TS scores were not different between boys and girls. For the caregiving style comparison, parenting is superior to grandparenting in developing of children's FMS. Parenting boys of 4-, 5-, and 6-years old showed better BS compared to age-matched parenting girls, whereas boys of 5-years old in grandparenting only showed better BS compared to same-age grandparenting girls (p < 0.05). Furthermore, parenting boys of 6-years reported higher LM (p < 0.01), BS (p < 0.001), and TS (p < 0.001) scores compared to grandparenting boys, but girls' FMS at all ages were not significantly different between the caregiving styles. Parenting caregiving style is positively associated with proper development of FMS among children. Girl children with poor FMS in grandparenting may need a special care or intervention programs to promote their FMS.


Mpox Genital Lesions: A Large Single-center Experience With Intermediate Follow-up.
Since the Mpox (formerly known as Monkeypox virus) global outbreak, there have been limited reports on the clinical course and management of genital lesions related to Mpox infections. Genital lesions have been reported to manifest in almost 50% of patients infected with Mpox. We set out to describe the clinical manifestations, management, and outcomes of a large cohort of subjects undergoing treatment with tecovirimat with intermediate follow-up. This was a retrospective case series of patients with genital Mpox lesions undergoing treatment with tecovirimat under the Centers for Disease Control and Prevention Emergency Authorization-Investigational protocol at a single, quaternary referral center. Fisher's exact tests were used to assess the association between Mpox-related genital skin changes and selected categorical variables. A total of 68 subjects were included. The mean age was 34.9 years, and all participants were assigned male sex at birth. The mean follow-up period was 20.3 days. Management consisted of supportive care, antibiotic treatment for bacterial superinfection, medical debridement with collagenase for severe lesions. Urological consultation was obtained in 5 (7.4%) cases. Sixteen (23.5%) patients had significant penile skin changes at final follow-up, which was significantly associated with lesion size (P = .001). No subjects in this cohort required surgical interventions. We report this large series of Mpox-related genital lesions in men undergoing treatment with tecovirimat. Urologists are not required for the routine diagnosis and treatment of these lesions, but are important in determining appropriate treatment for severe lesions.


Effects of interaction with calcineurin on the reactivities of calmodulin lysines.
Calmodulin was trace labeled by acetylation with [3H]acetic anhydride in the presence and absence of a 30% molar excess of the phosphatase calcineurin; phenylalanine was included in the reaction mixtures as an internal standard. The level of 3H acetylation of each of the 7 lysines was determined and corrected for differences arising from reaction conditions using the labeling of the internal standard, following procedures that are closely similar to those used in a previous study of the interaction of calmodulin with myosin light chain kinase (Jackson, A. E., Carraway, K. L., III, Puett, D., and Brew, K. (1986) J. Biol. Chem. 261, 12226-12232). The interaction with calcineurin was found to produce a 10-fold reduction in the acetylation of lysine 75, with lesser but significant effects on lysines 21 and 148. A small but reproducible perturbation of lysine 77 was also observed. The results are similar to those that are produced by the interaction with myosin light chain kinase. However, when they are compared with two recent reports between which there are major discrepancies (Manalan, A. S., and Klee, C. B. (1987) Biochemistry 26, 1382-1390; Winkler, M. A., Fried, V. A., Merat, D. L., and Cheung, W. Y. (1987) J. Biol. Chem. 262, 15466-15471), our results are in good agreement with those obtained in the former study. From the location of the perturbed groups in the three-dimensional structure of calmodulin, it appears that the interaction site on calmodulin for calcineurin, as well as for myosin light chain kinase, is very extended and may include hydrophobic pockets at homologous sites near the carboxyl-terminal ends of the two halves of the molecule.


[Synthesis of heat shock proteins following amino acid or oxygen limitation in Bacillus subtilis relA+ and relA strains].
Some of the presumable heat shock proteins will be produced in Bacillus subtilis in response to different environmental conditions, e.g. heat shock, amino acid limitation or oxygen limitation. During amino acid limitation or during oxygen limitation the relA+ strain is able of synthesizing this set of proteins but the relA strain is not. We suggest that the accelerated rate of the synthesis of some heat shock proteins depends on the induction of the stringent response because the (p)ppGpp production does not occur in the relA strain during amino acid or oxygen limitation. On the other hand the relA strain can produce heat shock proteins under heat stress. Therefore different mechanisms must be responsible for the expression of this set of genes during heat and other stress stimuli. It can be supposed that in B. subtilis the (p)ppGpp-dependent stringent control is a central defense reaction against different adverse environmental conditions and furthermore, that the synthesis of "stress" proteins as an essential component of the stringent response is part of a general adaptation mechanism under non-growing conditions.


The stability of hepatitis C virus RNA after storage at +4 degrees C.
One of the major issues in nucleic acid testing is how to store blood samples to obtain reliable results. We therefore studied hepatitis C virus (HCV) RNA concentration in samples after storage at +4 degrees C or freezing and thawing. Six HCV RNA-positive, untreated subjects were studied. Blood samples were collected from these subjects in plasma preparation tubes. The HCV RNA concentration was analysed after storage at +4 degrees C for 168 h or after five freeze-thaw cycles. For HCV RNA quantification we used a qualitative and a quantitative commercial test. After 168 h of storage at +4 degrees C, the HCV RNA concentration was similar to that observed at time-point 0 (5.025 log vs 5.492 log). In one sample we observed a significant fall in HCV RNA concentration. After five freeze-thaw cycles, the HCV RNA concentration was lower than that observed at time-point 0 (4.454 log vs 5.492 log) and in four samples we observed a significant fall in HCV RNA concentration. Our data suggest that HCV RNA is stable in whole blood samples stored at +4 degrees C for 168 h. Based on our results, we conclude that the standard procedures for transport of blood samples (at room temperature for a maximum of 5 h) and storage schedules (+4 degrees C for a maximum of 48 h) can be maintained without compromising the quality of results.


Studies on antimicrobial activity of pyramidal black pine (Pinus nigra ssp. pallasiana var. pyramidata): an endemic plant close to become extinct.
Turkey is one of the richest areas at middle latitudes in terms of plant diversity. One of Turkey's (Anatolia) endemic plants is pyramidal black pine (Pinus nigra ssp. pallasiana var. pyramidata). But, it was observed that the pyramidal black pine, which is part of Turkey's important biological richness, came close to become extinct. This study was carried out to investigate the drying of the pyramidal black pine in the specific Vakifkoy area having semi arid to humid climatic conditions on the one hand, and the effects of different thermal power plants on drying of the pyramidal black pine on the other hand. In addition, the study was designed to examine the effects of mistletoe on drying this plant and even the antimicrobial activities of this plant. As a result, we can conclude that the negative effects of semi arid climatic conditions, climatic variables, drought, mistletoe, silver factory and thermal power plants are still not clear on the pyramidal black pine trees. However, when the results of this study were compared with ampicillin (10 mcg) and nystatin (30 mcg) standards, it was found that extracts of pyramidal black pine were particularly found to possess stronger antimicrobial activity.


Renal anaemia and EPO hyporesponsiveness associated with vitamin D deficiency: the potential role of inflammation.
Resistance to erythropoiesis-stimulating agents (ESAs) has been observed in a considerable proportion of patients with chronic kidney disease (CKD) and it is reportedly associated with adverse outcomes, such as increased cardiovascular morbidity, faster progression to end-stage renal disease (ESRD) and all-cause mortality. The major causes of ESA resistance include chronic inflammation producing suppressive cytokines of early erythroid progenitor proliferation. In addition, pro-inflammatory cytokines stimulate hepcidin synthesis thus reducing iron availability for late erythropoiesis. Recent studies showing an association in deficiencies of the vitamin D axis with low haemoglobin (Hb) levels and ESA resistance suggest a new pathophysiological co-factor of renal anaemia. The administration of either native or active vitamin D has been associated with an improvement of anaemia and reduction in ESA requirements. Notably, these effects are not related to parathyroid hormone (PTH) values and seem to be independent on PTH suppression. Another possible explanation may be that calcitriol directly stimulates erythroid progenitors; however, this proliferative effect by extra-renal activation of 1α-hydroxylase enzyme is only a hypothesis. The majority of studies concerning vitamin D deficiency or supplementation, and degree of renal anaemia, point out the prevalent role of inflammation in the mechanism underlying these associations. Immune cells express the vitamin D receptor (VDR) which in turn is involved in the modulation of innate and adaptive immunity. VDR activation inhibits the expression of inflammatory cytokines in stromal and accessory cells and up-regulates the lymphocytic release of interleukin-10 (IL-10) exerting both anti-inflammatory activity and proliferative effects on erythroid progenitors. In CKD patients, vitamin D deficiency may stimulate immune cells within the bone marrow micro-environment to produce cytokines, inducing impaired erythropoiesis. Immune activation involves the reticuloendothelial system, increasing hepcidin synthesis and functional iron deficiency. Consequences of this inflammatory cascade are erythropoietin (EPO) resistance and anaemia. Given the key role of inflammation in the response to EPO, the therapeutic use of agents with anti-cytokines properties, such as vitamin D and paricalcitol, may provide benefit in the prevention/treatment of ESA hyporesponsiveness.


Aligning with Patients and Families: Exploring Youth and Caregiver Openness to Pediatric Headache Interventions.
Primary headache disorders are common yet underestimated in youth, resulting in functional disability, decreased quality of life, and caregiver burden. Despite the ubiquity of options, adherence remains challenging for families. One potential factor impacting willingness to engage in recommended treatments is openness. This study explored openness to multidisciplinary headache interventions and the relationships with demographic, pain-related, and psychological variables, among youth and their caregivers. Participants (n = 1087) were youth/caregiver dyads presenting for initial headache evaluation. They completed assessments of openness to headache treatments, medical information, functional disability, and pain-related distress. Overall openness was moderately high for youth and caregivers, and highly correlated between them (r = 0.70). Relationships between youth/caregiver openness to specific interventions were moderate-high (r = 0.42-0.73). These were stronger for interventional techniques but weaker for lifestyle changes. In hierarchical regression models predicting youth and caregiver openness, we found that counterpart openness accounted for the largest portion of variance in their own openness (31-32%), beyond demographic (3%), pain-related (10%), and psychological variables (2-3%). Our findings highlight the importance of involving caregivers in pediatric headache management, given their influence on youth openness and potential involvement in adherence. Awareness of youth/caregiver openness may guide clinicians providing recommendations.


Depth Quality Improvement with a 607 MHz Time-Compressive Computational Pseudo-dToF CMOS Image Sensor.
In this paper, we present a prototype pseudo-direct time-of-flight (ToF) CMOS image sensor, achieving high distance accuracy, precision, and robustness to multipath interference. An indirect ToF (iToF)-based image sensor, which enables high spatial resolution, is used to acquire temporal compressed signals in the charge domain. Whole received light waveforms, like those acquired with conventional direct ToF (dToF) image sensors, can be obtained after image reconstruction based on compressive sensing. Therefore, this method has the advantages of both dToF and iToF depth image sensors, such as high resolution, high accuracy, immunity to multipath interference, and the absence of motion artifacts. Additionally, two approaches to refine the depth resolution are explained: (1) the introduction of a sub-time window; and (2) oversampling in image reconstruction and quadratic fitting in the depth calculation. Experimental results show the separation of two reflections 40 cm apart under multipath interference conditions and a significant improvement in distance precision down to around 1 cm. Point cloud map videos demonstrate the improvements in depth resolution and accuracy. These results suggest that the proposed method could be a promising approach for virtually implementing dToF imaging suitable for challenging environments with multipath interference.


Dynamic CT in patients with superficial temporal-middle cerebral artery anastomosis.
Using dynamic computed tomographic (CT) scanning and an iodinated contrast material, changes in cerebral hemodynamics in cerebrovascular occlusive disease were studied before and after anastomosis of the superficial temporal artery and the middle cerebral artery. Because the iodinated contrast material is a nondiffusable indicator, it does not pass through the bloodbrain barrier. Thus, this method is capable of measuring the relative tissue blood flow (intravascular blood flow) but incapable of measuring the absolute cerebral blood flow. However, it does allow the three-dimensional measurement of cerebral hemodynamics by a simple procedure, and when the primarily clear brain structure seen with CT is considered, it is a very useful diagnostic method.


Using Comparative Genomics to Leverage Animal Models in the Identification of Cancer Genes. Examples in Prostate Cancer.
The identification of cancer biomarkers that will predict susceptibility to disease and subsequent clinical outcome are key components of future genomics-based tailored medical care. Animal models of disease provide a rich resource for the identification of potential cancer biomarkers. Animal models of prostate cancer in particular offer the potential to identify cancer genes associated with dietary and environmental factors. The key issue is the timely and efficient identification of candidate genes that are likely to impact on human prostate cancer. Here, we demonstrate comparative genomics-based methods for the identification of candidate genes in animal models that are associated with human chromosomal regions implicated in prostate cancer. Using publicly available bioinformatics tools, comparisons can be made between cancer-specific datasets, genomic sequencing data and cross-species comparative maps to identify potential cancer biomarkers. This process is demonstrated by using rat models of prostate cancer to identify candidate human prostate cancer genes. Genes identified through these techniques can be screened as biomarkers for response to chemopreventive agents, as well as being used in transgenic or knockout mice to engineer better animal models of human prostate cancer. The bioinformatics techniques outlined here can be used to leverage genomic data from any animal cancer model for use in the study and treatment of human cancer.


Automated multiple structure alignment and detection of a common substructural motif.
While a number of approaches have been geared toward multiple sequence alignments, to date there have been very few approaches to multiple structure alignment and detection of a recurring substructural motif. Among these, none performs both multiple structure comparison and motif detection simultaneously. Further, none considers all structures at the same time, rather than initiating from pairwise molecular comparisons. We present such a multiple structural alignment algorithm. Given an ensemble of protein structures, the algorithm automatically finds the largest common substructure (core) of C(alpha) atoms that appears in all the molecules in the ensemble. The detection of the core and the structural alignment are done simultaneously. Additional structural alignments also are obtained and are ranked by the sizes of the substructural motifs, which are present in the entire ensemble. The method is based on the geometric hashing paradigm. As in our previous structural comparison algorithms, it compares the structures in an amino acid sequence order-independent way, and hence the resulting alignment is unaffected by insertions, deletions and protein chain directionality. As such, it can be applied to protein surfaces, protein-protein interfaces and protein cores to find the optimally, and suboptimally spatially recurring substructural motifs. There is no predefinition of the motif. We describe the algorithm, demonstrating its efficiency. In particular, we present a range of results for several protein ensembles, with different folds and belonging to the same, or to different, families. Since the algorithm treats molecules as collections of points in three-dimensional space, it can also be applied to other molecules, such as RNA, or drugs.


Network-Based Identification of Altered Stem Cell Pluripotency and Calcium Signaling Pathways in Metastatic Melanoma.
Malignancy of cancer has been linked to distinct subsets of stem-like cells, the so-called cancer stem cells (CSCs), which persist during treatment and seem to lead to drug-resistant recurrence. Metastatic spread of cancer cells is one of the hallmarks of malignancy and contributes to most human melanoma-related deaths. Recently, overlapping groups of proteins and pathways were shown to regulate stem cell migration and cancer metastasis, raising the question of whether genes/proteins involved in stem cell pluripotency may have important implications when applied to the biology of cancer metastasis. Furthermore, it is well known that ion channels and receptors, particularly those responsible for calcium (Ca2+) signal generation, are critical in determining the cellular fate of stem cells (SCs). In the present study, we searched for evidence of altered stem cell pluripotency and Ca2+ signaling-related genes in the context of melanoma metastasis. We did this by using network analysis of gene expression in tissue biopsies from three different independent datasets of patients. First, we created an in silico network model ("STEMCa" interactome) showing the landscape of interactions between stem cell pluripotency and Ca2+ signaling-related genes/proteins, and demonstrated that around 51% (151 out of 294) of the genes within this model displayed significant changes of expression (False Discovery Rate (FDR), corrected p-value < 0.05) in at least one of the datasets of melanoma metastasis when compared with primary tumor biopsies (controls). Analysis of the properties (degree and betweenness) of the topological network revealed 27 members as the most central hub (HB) and nonhub-bottlenecks (NH-B) among the 294 genes/proteins of the whole interactome. From those representative genes, CTNNB1, GNAQ, GSK3B, GSTP1, MAPK3, PPP1CC, PRKACA, and SMAD4 showed equal up- or downregulation (corrected p-value < 0.05) in at least 2 independent datasets of melanoma metastases samples and PTPN11 showed upregulation (corrected p-value < 0.05) in three of them when compared with control samples. We postulate that altered expression of stem cell pluripotency and Ca2+ signaling pathway-related genes may contribute to the metastatic transformation, with these central members being an optimal candidate group of biomarkers and in silico therapeutic targets for melanoma metastasis, which deserve further investigation.


Complementary and alternative medicine (CAM) use among men with a history of prostate cancer.
Complementary and alternative medicine (CAM) has been commonly used among Americans; however, less is known about its use among men with a history of prostate cancer. This study used the 2002 National Health Interview Survey (NHIS) to explore the amount and type of CAM use among 218 Black and White men with a history of prostate cancer. Over 90% of men reported having ever used any form of CAM and most men used biologically-based and mind-body therapies. Nurses are in a unique position to discuss, to assess needs and practices, and perhaps, to act as intermediaries for physicians and other healthcare professionals and prostate cancer survivors who use CAM.


[Questionnaire survey about NSAIDs use in late pregnancy for pharmacists and physicians].
It has been reported the use of nonsteroid anti-inflammatory drugs (NSAIDs) in late pregnancy was associated with potentially fetal toxicity (contraction of fetal ductus areteriosus). According to the package inserts in Japan, many oral NSAIDs are contraindicated to women in late pregnancy, but several oral and topical NSAIDs with case reports of fetal toxicity are not. In the present study, a web-based questionnaire survey was conducted in pharmacists/physicians to determine their awareness of fetal toxicity caused by NSAIDs, as well as their attitudes regarding the use of NSAIDs in late pregnancy. Responses were obtained from 427 pharmacists, 22 obstetricians, and 160 non-obstetric physicians. Of the non-obstetric respondents, more than 40% had no knowledge of fetal ductus arteriosus contraction caused by oral ibuprofen, and most of them were not aware of the relevant warning statement on the package insert. In contrast, these were familiar to nearly 100% of the obstetricians. As for ketoprofen tape, only 20-40% of the pharmacists/physicians were aware of the warning statement, and nearly all respondents did not confirm whether the patient was in late pregnancy. The majority of the respondents answered that oral ibuprofen, ketoprofen tape and NSAID-containing OTC drugs should not be used in late pregnancy after they knew the warning statements in late pregnancy. This survey suggests that the fetal toxicity of NSAIDs is not well recognized by pharmacists/physicians. It would be necessary to make it thoroughly known to them through such as enrichment of safety information on the package inserts, accompanying with the evidence.


Influence of different prosthodontic rehabilitation options on oral health-related quality of life, orofacial esthetics and chewing function based on patient-reported outcomes.
The aim was to assess influence of different prosthodontic rehabilitation options on improvement of orofacial esthetics, chewing function (CF) and oral health-related quality of life. Patients treated with 70 conventional complete dentures (CDs), 38 implant-supported mandibular complete dentures opposed to maxillary CDs, 56 conventional removable partial dentures, 15 implant-supported removable partial dentures, 25 conventional fixed partial dentures (FPDs) and 59 implant-supported fixed partial dentures (IFPDs) were included. The survey was conducted using the three questionnaires: the OHIP-CRO14, the Orofacial Esthetic Scale (OES-CRO) and the Chewing Function Questionnaire (CFQ), and administrated twice: at the baseline prior the therapy and 3 months after prosthodontic rehabilitation had been finished. The after-treatment scores were significantly better than the baseline scores (p < 0.001) for the OES, OHIP14 and CF questionnaires in all types of treatments. The two-factor ANOVA showed no significant difference for the OES after-treatment scores between different rehabilitation options and implant presence, but the OHIP14 and CFQ after-treatment scores were significantly better in FPD and IFPDs than in removable implant and conventional denture wearers. The score change was significantly higher in all implant removable denture patients for the OES, OHIP and CFQ. The lowest score change was registered in the FPD wearers. (p < 0.01). Removable denture implant patients most benefited from implant support, but IFPD and FPD had the best after-treatment scores. The assessed clinical parameters may help dentists in choice of the best rehabilitation option with the highest treatment effect.


Synthetic bioresorbable poly-α-hydroxyesters as peripheral nerve guidance conduits; a review of material properties, design strategies and their efficacy to date.
Implantable tubular devices known as nerve guidance conduits (NGCs) have drawn considerable interest as an alternative to autografting in the repair of peripheral nerve injuries. At present, there exists a lack of biodegradable, biocompatible materials for the fabrication of NGCs with physical properties which suitably match the native nerve tissue. Most of the existing reports have been confined to the traditional synthetic aliphatic polyesters due to their naturally-occurring degradation by-products, suitably slow in vivo resorption timeframes and relatively diverse and tailorable range of material properties. Moreover, these thermoplastic polymers can be processed into NGCs from various methods and further tweaking of physical properties can be achieved during fabrication. Although there have been many successful reports of nerve gap repair using NGCs made from these materials, the majority have been confined to basic tubular designs across short to medium nerve gaps with at best equivalent outcomes to autografts. This article reviews the performance of poly-α-hydroxyester tubes to date (including modifications to basic hollow conduits) and is intended to aid researchers as they aim to create biomimetic NGCs capable of bridging larger nerve gaps with superior results to autografting. Based on the existing reports, a next-generation bioresorbable NGC should involve a highly flexible poly-α-hydroxyester outer tube, most suitably from a lactide-caprolactone co-polymer, with some combination of internal lumen contact guidance and bioactive neurotrophic factors. However, detailed further experimentation and an interdisciplinary approach will be required to arrive at an ideal final configuration.


Sarcopenia in the prognosis of cirrhosis: Going beyond the MELD score.
Estimating the prognosis of patients with cirrhosis remains challenging, because the natural history of cirrhosis varies according to the cause, presence of portal hypertension, liver synthetic function, and the reversibility of underlying disease. Conventional prognostic scoring systems, including the Child-Turcotte-Pugh score or model for end-stage liver diseases are widely used; however, revised models have been introduced to improve prognostic performance. Although sarcopenia is one of the most common complications related to survival of patients with cirrhosis, the newly proposed prognostic models lack a nutritional status evaluation of patients. This is reflected by the lack of an optimal index for sarcopenia in terms of objectivity, reproducibility, practicality, and prognostic performance, and of a consensus definition for sarcopenia in patients with cirrhosis in whom ascites and edema may interfere with body composition analysis. Quantifying skeletal muscle mass using cross-sectional abdominal imaging is a promising tool for assessing sarcopenia. As radiological imaging provides direct visualization of body composition, it is useful to evaluate sarcopenia in patients with cirrhosis whose body mass index, anthropometric measurements, or biochemical markers are inaccurate on a nutritional assessment. Sarcopenia defined by cross-sectional imaging-based muscular assessment is prevalent and predicts mortality in patients with cirrhosis. Sarcopenia alone or in combination with conventional prognostic systems shows promise for a cirrhosis prognosis. Including an objective assessment of sarcopenia with conventional scores to optimize the outcome prediction for patients with cirrhosis needs further research.


Practical algorithm to inform clinical decision-making in the topical treatment of atopic dermatitis.
Atopic dermatitis is a chronic relapsing, inflammatory skin disorder associated with skin barrier dysfunction, the prevalence of which has increased dramatically in developing countries. In this article, we propose a treatment algorithm for patients with mild-to-moderate and severe atopic dermatitis flares in daily clinical practice. An international panel of 15 dermatology and allergy experts from eight countries was formed to develop a practical algorithm for the treatment of patients with atopic dermatitis, with a particular focus on topical therapies. In cases of mild-to-moderate atopic dermatitis involving sensitive skin areas, the topical calcineurin inhibitor pimecrolimus should be applied twice daily at the first signs of atopic dermatitis. For other body locations, patients should apply a topical calcineurin inhibitor, either pimecrolimus or tacrolimus, twice daily at the first signs of atopic dermatitis, such as pruritus, or twice weekly in previously affected skin areas. Emollients should be used regularly. Patients experiencing acute atopic dermatitis flares in sensitive skin areas should apply a topical corticosteroid twice daily or alternate once-daily topical corticosteroid/topical calcineurin inhibitor until symptoms improve. Following improvement, topical corticosteroid therapy should be discontinued and patients switched to a topical calcineurin inhibitor. Maintenance therapy should include the use of pimecrolimus once daily for sensitive areas and tacrolimus for other body locations. This treatment algorithm can help guide clinical decision-making in the treatment of atopic dermatitis.


Impact of thoracic surgery on esophageal motor function-Evaluation by high resolution manometry.
Alteration of esophageal function is a potential risk factor for postoperative complications in thoracic surgery. This prospective study investigates esophageal motility and function during and after thoracic procedures via high resolution manometry (HRM) and impedance technology with spatiotemporal representation of pressure data. Twelve consecutive patients eligible for elective thoracic surgery underwent preoperative and postoperative (48 hours and 7 days) esophageal HRM. Swallowing acts were carried out with 5 mL of water, 10 mL of water and 1 cm3 bread in physiological posture to evaluate distal contraction integral (DCI). Length and location of contractile integrity breaks were measured by investigators blinded to the form of surgical intervention. The impact of surgical procedures on esophageal motility was quantified according to current Chicago Classification (CC) criteria. Pre-, intra- and postoperative 24-hour multi-channel impedance pH-metry (MII-pH) was performed to further analyze gastroesophageal reflux patterns. All patients were investigated 48 hours prior to and 7 days after thoracic procedures, with a total of n=675 swallowing acts being included in our study. Increased motility patterns of the tubular esophagus occurred temporally 48 hours postoperatively. DCI 48 hours after surgery increased significantly (5 mL, P=0.049; solid, P=0.014) and returned to baseline values after seven days (5 mL, P=0.039; solid, P=0.039). Break length was significantly reduced 48 hours postoperatively, especially in the proximal esophageal segment (transition zone). Follow-up measurements after another week were comparable to preoperative baseline findings. The perioperative MII-pH measurement showed numerous artifacts caused by intubation and ventilation during surgery also with increasing short and frequent acidic reflux episodes. Thoracic procedures cause a transient modulation of esophageal peristalsis with postoperative increased contractility of the tubular esophagus, presumably without affecting intraesophageal reflex arcs. Although limited by the number of patients, we can conclude on our data that postoperative esophageal hypomotility is unlikely to promote secondary pulmonary complications.


Effect of Single-Dose Dexmedetomidine on Intraoperative Hemodynamics and Postoperative Recovery during Pediatric Adenotonsillectomy.
In children undergoing adenotonsillectomy, smooth recovery from anesthesia without any respiratory compromise and excessive sedation or pain is always desirable. In this placebo-controlled study, we examined the effect of single dose of dexmedetomidine on intraoperative hemodynamics and postoperative recovery profile such as emergence agitation (EA), pain, and sedation in children undergoing adenotonsillectomy. Sixty American Society of Anesthesiologists I or II children in the age group of 5-10 years, undergoing adenotonsillectomy were randomly assigned to receive dexmedetomidine 1 μg/kg (Group D) or volume-matched saline (placebo) (Group C), 10 min before induction of anesthesia. Intraoperative heart rate (HR) and mean blood pressure (MBP), duration of surgery, time to extubation, EA using Paediatric Anaesthesia Emergence Delirium (PAED) scale, level of sedation in postanesthesia care unit using Ramsay sedation score (RSS), and postoperative visual analog score (VAS) for pain were recorded and compared. Dexmedetomidine group had lower HR and stable MBP, compared to the control group (P < 0.05). Postoperatively, the agitation score (PAED scale score) was statistically lower in Group D compared to Group C (13.84 ± 1.39; median 14 in Group C vs. 9.37 ± 1.33; median 9.5 in Group D; P < 0.001). All patients in Group C had PAED scale score >12, while only 6.67% of patients in Group D had PAED scale score of 12. The patients in Group D had higher RSS (2.62 ± 0.49 in Group D vs. 1.60 ± 0.50, P = 0.004); none of the patients were excessively sedated or had RSS >3. No significant difference was found in VAS score of the groups at all times, except at 0 h (P = 0.002). Time to extubation was significantly longer in the dexmedetomidine group (7.70 ± 1.62 min in Group D vs. 5.23 ± 1.91 min in Group C; P = 0.001). Premedication of dexmedetomidine at the dose of 1 μg/kg in children undergoing adenotonsillectomy resulted in favorable effect on intraoperative hemodynamics, significant decrease in postoperative EA without causing any excessive sedation, desaturation, or any other drug-related adverse events.


Metal-in-metal localized surface plasmon resonance.
Anomalous strong resonances in silver and gold nanoporous thin films which conduct are found to arise from isolated metal nano-islands separated from the surrounding percolating metal network by a thin loop of insulator. This observed resonant optical response is modelled. The observed peak position is in agreement with the observed average dimensions of the silver core and insulator shell. As the insulating ring thickness shrinks, the resonance moves to longer wavelengths and strengthens. This structure is the Babinet's principle counterpart of dielectric core-metal shell nanoparticles embedded in dielectric. Like for the latter, tuning of resonant absorption is possible, but here the matrix reflects rather than transmits, and tuning to longer wavelengths is more practical. A new class of metal mirror occurring as a single thin layer is identified using the same resonances in dense metal mirrors. Narrow band deep localized dips in reflectance result.


Risk factors for gestational diabetes in black population.
In a long-term longitudinal study of gestational diabetes mellitus in Black women, risk factors that were identified were age, obesity, a family history of diabetes, and the presence of hypertension. Poor predictors were a history of a previous large-for-date infant, parity, and age at first pregnancy. The prevalence of smooth muscle and nuclear autoantibodies was higher in gestational diabetic subjects. Gestational diabetic subjects who required insulin for glycemic control were more obese, had a lower frequency of the Bf-F phenotype and a higher frequency of the Bf-F1 phenotype, and had a lower frequency of the type 2 allele at the polymorphic locus adjacent to the insulin gene. Restriction-fragment-length polymorphisms flanking the insulin and apolipoprotein A-I and C-III genes, although not associated with gestational diabetes mellitus, may be associated with hyperlipidemia and subsequent atherosclerosis.


A Successful Treatment of Ostraceous Psoriasis Associated with Psoriatic Arthritis in Children: A Case Report.
Psoriasis may manifest as severe hyperkeratotic lesions resembling an oyster shell called ostraceous psoriasis (OP). This type of psoriasis is extremely rare and is often associated with psoriatic arthritis (PA). Cases of OP associated with PA in children have never been reported before. We reported a 9-year-old girl with hyperkeratotic lesions resembling an oyster shell all over the body accompanied with swelling on joints of both fingers, knee joints, and ankle. Histopathological examination supported the diagnosis of OP. The diagnosis of PA was established according to the Classification Criteria for Psoriatic Arthritis (CASPAR). Significant improvements of the skin lesions and joints involved were observed within 44 days after the beginning of treatment with cyclosporine and a combination of high potent topical steroid with emollient. OP associated with PA is uncommonly seen in children. High potent corticosteroid combined with emollient showed good result in skin improvement with low side effects. In addition, cyclosporine can be a good choice of systemic therapy for OP with PA in children.


Extracellular superoxide dismutase (SOD3) regulates oxidative stress at the vitreoretinal interface.
Oxidative stress is a pathogenic feature in vitreoretinal disease. However, the ability of the inner retina to manage metabolic waste and oxidative stress is unknown. Proteomic analysis of antioxidants in the human vitreous, the extracellular matrix opposing the inner retina, identified superoxide dismutase-3 (SOD3) that localized to a unique matrix structure in the vitreous base and cortex. To determine the role of SOD3, Sod3-/- mice underwent histological and clinical phenotyping. Although the eyes were structurally normal, at the vitreoretinal interface Sod3-/- mice demonstrated higher levels of 3-nitrotyrosine, a key marker of oxidative stress. Pattern electroretinography also showed physiological signaling abnormalities within the inner retina. Vitreous biopsies and epiretinal membranes collected from patients with diabetic vitreoretinopathy (DVR) and a mouse model of DVR showed significantly higher levels of nitrates and/or 3-nitrotyrosine oxidative stress biomarkers suggestive of SOD3 dysfunction. This study analyzes the molecular pathways that regulate oxidative stress in human vitreous substructures. The absence or dysregulation of the SOD3 antioxidant at the vitreous base and cortex results in increased oxidative stress and tissue damage to the inner retina, which may underlie DVR pathogenesis and other vitreoretinal diseases.


The development of a comprehensive medical-surgical distribution agreement.
The selection of a medical-surgical distributor has become one of the most important decisions made by a hospital materiel manager today. It is therefore critical that before a distributor is selected a clearly defined development process and master plan be established. This master plan should contain, at a minimum, (1) a comprehensive strategic plan, (2) a detailed request for proposal, and (3) a detailed project implementation schedule. A well-structured, well-executed plan will help to ensure that the best distributor is selected and that the best possible distribution agreement is designed.


Capacitative calcium entry deficits and elevated luminal calcium content in mutant presenilin-1 knockin mice.
Dysregulation of calcium signaling has been causally implicated in brain aging and Alzheimer's disease. Mutations in the presenilin genes (PS1, PS2), the leading cause of autosomal dominant familial Alzheimer's disease (FAD), cause highly specific alterations in intracellular calcium signaling pathways that may contribute to the neurodegenerative and pathological lesions of the disease. To elucidate the cellular mechanisms underlying these disturbances, we studied calcium signaling in fibroblasts isolated from mutant PS1 knockin mice. Mutant PS1 knockin cells exhibited a marked potentiation in the amplitude of calcium transients evoked by agonist stimulation. These cells also showed significant impairments in capacitative calcium entry (CCE, also known as store-operated calcium entry), an important cellular signaling pathway wherein depletion of intracellular calcium stores triggers influx of extracellular calcium into the cytosol. Notably, deficits in CCE were evident after agonist stimulation, but not if intracellular calcium stores were completely depleted with thapsigargin. Treatment with ionomycin and thapsigargin revealed that calcium levels within the ER were significantly increased in mutant PS1 knockin cells. Collectively, our findings suggest that the overfilling of calcium stores represents the fundamental cellular defect underlying the alterations in calcium signaling conferred by presenilin mutations.


Breast biopsies: the content of the surgical pathology report.
In the context of recent developments, the role of the surgical pathologist in evaluating and reporting breast cancer specimens has become more important. The pathologist must not only diagnose carcinoma in a given patient, but must also document a set of morphologic features that have been shown to be important in determining prognosis and guiding therapy.


Extensive repetitive DNA facilitates prokaryotic genome plasticity.
Prokaryotic genomes are substantially diverse, even when from closely related species, with the resulting phenotypic diversity representing a repertoire of adaptations to specific constraints. Within the microbial population, genome content may not be fixed, as changing selective forces favor particular phenotypes; however, organisms well adapted to particular niches may have evolved mechanisms to facilitate such plasticity. The highly diverse Helicobacter pylori is a model for studying genome plasticity in the colonization of individual hosts. For H. pylori, neither point mutation, nor intergenic recombination requiring the presence of multiple colonizing strains, is sufficient to fully explain the observed diversity. Here we demonstrate that H. pylori has extensive, nonrandomly distributed repetitive chromosomal sequences, and that recombination between identical repeats contributes to the variation within individual hosts. That H. pylori is representative of prokaryotes, especially those with smaller (<2 megabases) genomes, that have similarly extensive direct repeats, suggests that recombination between such direct DNA repeats is a widely conserved mechanism to promote genome diversification.


Sid4p is required to localize components of the septation initiation pathway to the spindle pole body in fission yeast.
A mutation in the Schizosaccharomyces pombe sid4(+) (septation initiation defective) gene was isolated in a screen for mutants defective in cytokinesis. We have cloned sid4(+) and have found that sid4(+) encodes a previously unknown 76.4-kDa protein that localizes to the spindle pole body (SPB) throughout the cell cycle. Sid4p is required for SPB localization of key regulators of septation initiation, including the GTPase Spg1p, the protein kinase Cdc7p, and the GTPase-activating protein Byr4p. An N-terminally truncated Sid4p mutant does not localize to SPBs and when overproduced acts as a dominant-negative mutant by titrating endogenous Sid4p and Spg1p from the SPB. Conversely, the Sid4p N-terminal 153 amino acids are sufficient for SPB localization. Biochemical studies demonstrate that Sid4p interacts with itself, and yeast two-hybrid analysis shows that its self-interaction domain lies within the C-terminal half of the protein. Our data indicate that Sid4p SPB localization is a prerequisite for the execution of the Spg1p signaling cascade.


Quick cytogenetic screening of breeding bulls using flow cytometric sperm DNA histogram analysis.
The aim of the present study was to test the FXCycle PI/RNase kit for routine DNA analyses in order to detect breeding bulls and/or insemination doses carrying cytogenetic aberrations. In a series of experiments we first established basic DNA histogram parameters of cytogenetically healthy breeding bulls by measuring the intraspecific genome size variation of three animals, then we compared the histogram profiles of bulls carrying cytogenetic defects to the baseline values. With the exception of one case the test was able to identify bulls with cytogenetic defects. Therefore, we conclude that the assay could be incorporated into the laboratory routine where flow cytometry is applied for semen quality control.


Three-dimensional visualization of neurovascular compression: presurgical use of virtual endoscopy created from magnetic resonance imaging.
To assess the usefulness of presurgical simulation of microvascular decompression (MVD) by virtual endoscopy (VE), a new tool to analyze three-dimensionally reconstructed magnetic resonance data sets in patients with trigeminal neuralgia or hemifacial spasm (HFS). In 17 patients (10 with trigeminal neuralgia and seven with HFS) determined to be candidates for MVD, we performed presurgical simulation of MVD using VE. We used constructive interference in steady-state imaging and magnetic resonance angiography to obtain the original images. VE findings were compared with surgical findings. The three-dimensional relations between visible structures seen on VE were consistent with intraoperative findings in all patients. In total, 20 (91%) of 22 neurovascular compression sites in all 17 patients were correctly delineated on VE, with the exception of two small branches identified as offending vessel in two patients with HFS. Perforators that were not apparent on VE limited our ability to accomplish transpositioning of the offending vessels as simulated. The positions of structures that can affect individual surgical approaches, such as the petrosal vein, cerebellar flocculus, and vertebral artery, were also adequately predicted on VE. All patients had excellent surgical outcomes. Presurgical VE in patients with trigeminal neuralgia or HFS is a novel technique that provides excellent visualization of the three-dimensional relations between neurovascular structures and allows simulation of MVD.