Genetic Variants Contributing to Early Recurrent Pregnancy Loss Etiology Identified by Sequencing Approaches.
Recurrent pregnancy loss (RPL) affects up to 5% of couples. It is believed that genetic factors contribute to the disease's etiology and pathophysiology. Hundreds of genes represent coherent RPL candidates due to mammalian implantation's inherent complexity. Sanger sequencing (direct sequencing) of candidate genes has identified potential RPL causative genes (and variants), including those regulating embryo implantation and pregnancy maintenance. Although this approach is a reliable technique, the simultaneous analysis of large genomic regions is challenging. Next-generation sequencing (NGS) technology has thus emerged as a useful alternative for determining genetic variants and transcriptomic disturbances contributing to monogenic and polygenic diseases pathogenesis. However, interpreting results remains challenging as NGS experiments provide an enormous amount of complex data. The molecular aspects of specific diseases must be fully understood for accurate interpretation of NGS data. This review was thus aimed at describing (for the first time) the most relevant studies involving Sanger and NGS sequencing, leading to the description of variants related to RPL pathogenesis. Successful RPL-related NGS initiatives (including RNAseq-based studies) and future challenges are discussed. We consider that the information given here should be useful for clinicians, scientists, and students to enable a better understanding of RPL etiology. It may also provide a basis for the development of diagnostic/prognostic approaches contributing toward translational medicine.


[Spa therapy in rheumatology. Indications based on the clinical guidelines of the French National Authority for health and the European League Against Rheumatism, and the results of 19 randomized clinical trials].
The objective of this work was to update the rheumatologic indications of spa therapy, based on clinical practice guidelines published by the French National Authority for Health (HAS) and the European League Against Rheumatism (EULAR), and on the results of randomized clinical trials (RCT) METHODOLOGY: We first examined the indications for which spa therapy is mentioned and/or recommended in HAS and EULAR guidelines. We then identified RCTs in spa therapy and rheumatology by using the key words spa therapy, balneology, balneotherapy, hydrotherapy, mud therapy and mineral water in the Pubmed, Pascal and Embase databases. Only RCTs including a statistical analysis of between-group outcomes were retained We also examined the possible contribution of RCTs not listed in the bibliography of the guidelines. spa therapy is recommended by HAS for chronic lower back pain, rank B and for stabilized rheumatoid arthritis, rank C. In ankylosing spondylitis, EULAR classifies spa therapy along with physiotherapy, rank A. In fibromyalgia, EULAR recommends hot-water balneology, an important component of spa therapy, rank B, based on five RCTs, of which three were carried out in thermal springs. Nineteen RCTs that comprised a statistical comparison of between-group outcomes were identified Sixteen studies indicated a persistent improvement (at least twelve weeks) in pain, analgesic and non-steroidal antiinflammatory drug consumption, functional capacity and/or quality of life, in the following indications: chronic lower back pain, knee osteoarthritis, hand osteoarthritis, fibromyalgia, ankylosing spondylitis andrheumatoidarthritis (PR). Spa therapy, or hot-water balneology, appears to be indicated for chronic low back pain, stabilized rheumatoid arthritis, ankylosing spondylitis and fibromyalgia. RCT findings suggest that patients with knee and hand osteoarthritis might also benefit.


Women treated for gynaecological cancer during young adulthood - A mixed-methods study of perceived psychological distress and experiences of support from health care following end-of-treatment.
To investigate the prevalence and predictors of cancer-related distress in younger women treated for gynaecological cancer, and to explore women's needs and experiences of psychosocial support following end-of-treatment. Data were collected from 337 gynaecological cancer survivors, 19-39years at diagnosis, using a study-specific questionnaire and the Swedish Quality Register of Gynaecologic Cancer. Predictors of distress were investigated with multivariable logistic regression analysis. Open-ended questions were analysed with content analysis. The prevalence of cancer-related distress was 85% (n=286) including fear of cancer-recurrence (n=175, 61%), anxiety (n=152, 53%), depression (n=145, 51%), fear of death (n=91, 32%), concerns regarding sexuality (n=87, 34%) and fertility (n=78, 27%), and changed body image (n=78, 27%). Multi-modal treatment (OR 2.25, 95% CI 1.13-4.49) and a history of psychological distress (OR 3.44, 95% CI 1.41-8.39) predicted cancer-related distress. The majority of women experiencing distress also reported a need for support after end-of-treatment (n=205, 71%). One-third of those receiving support reported the received support as inadequate (n=55, 34%). Eight categories described reasons for not seeking support, e.g., lacked strength to seek professional support and too busy managing every-day life and, wanted help but did not know who to turn to. Four categories described reasons for not receiving sought support e.g., found it difficult to openly express feelings, psychosocial care was under-dimensioned, insufficient and unprofessional. Results identify the importance of support and longer-term follow-up for young survivors of gynaecological cancer. The support needs to be organised to meet this group's specific needs.


MO-A-213AB-07: Evaluation of Distal Dose Surface with In-Room PET for Proton Therapy Monitoring.
The objective of this study is to evaluate the feasibility of proton beam treatment verification using in-room PET. As of February 2012, four patients have been studied in a clinical trial. In addition, we suggest a new method comparing the distal surface of the measured and simulated PET activities to verify the location of the distal dose surface. Patients were scanned for 20 minutes with an in-room PET positioned next to the proton treatment head in a gantry room for beam delivery using passive scattering. The time between end of treatment and the start of the scan was within about 2 minutes. The predicted distribution of the PET activities and the proton dose distributions in the patients were also calculated using Monte Carlo (MC). Along the beam direction, the 50% fall-off positions of the maximum PET activity at each line profile were compared with the MC simulated and the measured PET images, and then the differences were assessed with root-mean-square deviation (RMSD) and mapped in the beam's eye view. The measured PET images showed a good spatial correlation with the simulated PET images and the proton dose distributions even though the treated volumes and locations varied between patients. The RMSD values, representing the surface differences between the measured and simulated PET, were assessed to be 4.3-5.1 mm for four patients. Some region including the penumbra showed larger differences but was excluded. We have explored the potential of the in-room PET for proton therapy monitoring through a clinical trial. The PET image analysis method based on MC simulations showed that the distal dose surface could be determined within a few millimeters but not within the aimed accuracy of 2-3 mm. Improvements in PET-CT image registration and biological washout modeling will most likely increase the accuracy further. NIH/NCI P01 CA021239.


Sexual and reproductive health considerations among transgender and gender-expansive youth.
Sexual and reproductive health are an integral part of all youths' health and wellbeing, including youth who are transgender and gender-expansive. This article will discuss general approaches to the sexual and reproductive health care of transgender and gender-expansive youth, and review the topics of contraception and menstrual suppression, fertility preservation and family building, and the prevention and treatment of sexually transmitted infections and HIV in this population. Although transgender youth on testosterone therapy often become amenorrheic, ovulation and pregnancy can still occur, and thus all youth on testosterone therapy should be counseled on the potential for pregnancy and have access to effective contraception. Many forms of hormonal contraceptives are both safe and efficacious when used by youth on testosterone therapy. Hormonal contraceptives may also be used to provide menstrual suppression for those experiencing dysphoria from unwanted uterine bleeding. All transgender youth should receive counseling on fertility preservation and reproductive options prior to starting pubertal blockers and/or gender-affirming hormones, therapies that have varying effects on long-term fertility potential. Several different methods of fertility preservation exist, however there are numerous barriers to transgender youth receiving fertility preservation services, and rates of utilization of these services is low. Transgender individuals suffer from a disproportionate burden of HIV compared to their peers-thought to result from stigma, marginalization, and lack of access to appropriate care. All providers caring for youth should be informed about HIV pre-exposure prophylaxis (PrEP) and HIV post-exposure prophylaxis (PEP), which may help to prevent HIV acquisition.


Multiple sensors provide spatiotemporal oxygen regulation of gene expression in a Rhizobium-legume symbiosis.
Regulation by oxygen (O2) in rhizobia is essential for their symbioses with plants and involves multiple O2 sensing proteins. Three sensors exist in the pea microsymbiont Rhizobium leguminosarum Rlv3841: hFixL, FnrN and NifA. At low O2 concentrations (1%) hFixL signals via FxkR to induce expression of the FixK transcription factor, which activates transcription of downstream genes. These include fixNOQP, encoding the high-affinity cbb3-type terminal oxidase used in symbiosis. In free-living Rlv3841, the hFixL-FxkR-FixK pathway was active at 1% O2, and confocal microscopy showed hFixL-FxkR-FixK activity in the earliest stages of Rlv3841 differentiation in nodules (zones I and II). Work on Rlv3841 inside and outside nodules showed that the hFixL-FxkR-FixK pathway also induces transcription of fnrN at 1% O2 and in the earliest stages of Rlv3841 differentiation in nodules. We confirmed past findings suggesting a role for FnrN in fixNOQP expression. However, unlike hFixL-FxkR-FixK, Rlv3841 FnrN was only active in the near-anaerobic zones III and IV of pea nodules. Quantification of fixNOQP expression in nodules showed this was driven primarily by FnrN, with minimal direct hFixL-FxkR-FixK induction. Thus, FnrN is key for full symbiotic expression of fixNOQP. Without FnrN, nitrogen fixation was reduced by 85% in Rlv3841, while eliminating hFixL only reduced fixation by 25%. The hFixL-FxkR-FixK pathway effectively primes the O2 response by increasing fnrN expression in early differentiation (zones I-II). In zone III of mature nodules, near-anaerobic conditions activate FnrN, which induces fixNOQP transcription to the level required for wild-type nitrogen fixation activity. Modelling and transcriptional analysis indicates that the different O2 sensitivities of hFixL and FnrN lead to a nuanced spatiotemporal pattern of gene regulation in different nodule zones in response to changing O2 concentration. Multi-sensor O2 regulation is prevalent in rhizobia, suggesting the fine-tuned control this enables is common and maximizes the effectiveness of the symbioses.


Abnormal calcium handling by platelets in thrombotic disorders.
This study presents a quantitative comparison of the free cytoplasmic calcium concentration ([Ca2+]cyt) and the free concentration in the lumen of the dense tubules of the human platelet. The former was measured by the fluorescence of the high affinity indicator quin2 and latter by the fluorescence of chlorotetracycline (CTC). The CTC technique monitors calcium-CTC complex accumulation in the lumen of dense tubules and mitochondria when washed platelets were incubated in 2 mM Ca2+. Resting cytoplasmic and dense tubular Ca2+ concentrations were studied in platelets from patients suffering from venous and arterial thrombosis. Compared with normal controls (0.40 +/- 0.10, n = 54), the values of the calcium-CTC ratios were 0.68 +/- 0.19 (n = 16, p less than 0.005) in venous thrombosis; 0.75 +/- 0.18 (n = 14, p less than 0.005) in cardiovascular accident; 0.84 +/- 0.18 (n = 6, p less than 0.005) in occlusive peripheral vascular diseases; and 0.42 +/- 0.10 (n = 21, p greater than 0.1) in patient controls. The dense tubular Ca2+ levels for both patients and controls were perfectly correlated with the cytoplasmic levels using an equation that assumes that the dense tubular free calcium concentration ([Ca2+]dt) has a second power dependence on [Ca2+]cyt. The abnormal Ca2+ handling of platelets obtained from thrombotic patients could be completely reversed by preincubation with the calcium channel blocker verapamil. These observations suggest that the primary Ca2+ handling defect is the leakage through activated channels in the plasma membrane. The defect and the elevated resting [Ca2+]cyt and [Ca2+]dt are adequate to explain the observation of increased rates of collagen-activated aggregation in the above-mentioned group of patients. The results can be explained by platelets from thrombosis patients being exposed to activating factors in the circulation, resulting in Ca2+ channel activation. Channel activation persists through the process of platelet isolation and washing and is manifested in higher measured values of [Ca2+]cyt and [Ca2+]dt in the "resting state." This would bring the platelet closer to its aggregation when aggregation-inducing agents are added. The CTC test is shown to be a useful and convenient means of detecting this abnormality.


Exploration of Multiple Signaling Pathways Through Which Sodium Tanshinone IIA Sulfonate Attenuates Pathologic Remodeling Experimental Infarction.
The level of maladaptive myocardial remodeling consistently contributes to the poor prognosis of patients following a myocardial infarction (MI). In this study, we investigated whether and how sodium tanshinone IIA sulfonate (STS) would attenuate the post-infarct cardiac remodeling in mice model of MI developing after surgical ligation of the left coronary artery. All mice subjected to experimental MI or to the sham procedure were then treated for the following 4 weeks, either with STS or with a vehicle alone. Results of our studies indicated that STS treatment of MI mice prevented the left ventricular dilatation and improved their cardiac function. Results of further tests, aimed at mechanistic explanation of the beneficial effects of STS, indicated that treatment with this compound enhanced the autophagy and, at the same time, inhibited apoptosis of the cardiomyocytes. Meaningfully, we have also established that myocardium of STS-treated mice displayed significantly higher levels of adenosine monophosphate kinase than their untreated counterparts and that this effect additionally associated with the significantly diminished activities of apoptotic promoters: mammalian target of rapamycin and P70S6 kinase. Moreover, we also found that additional administration of the adenosine monophosphate kinase inhibitor (compound C) or autophagy inhibitor (chloroquine) practically eliminated the observed beneficial effects of STS. In conclusion, we suggest that the described multistage mechanism triggered by STS treatment enhanced autophagy, thereby attenuating pathologic remodeling of the post-infarct hearts.


Patterns of atrophy differ among specific subtypes of mild cognitive impairment.
In most patients, mild cognitive impairment (MCI) represents the clinically evident prodromal phase of dementia. This is most well established in amnestic MCI, which is most commonly a precursor to Alzheimer disease (AD). It follows, however, that subjects with MCI who have impairment in nonmemory domains may progress to non-AD degenerative dementias. To investigate patterns of cerebral atrophy associated with specific subtypes of MCI. Case-control study. Community-based sample at a tertiary referral center. One hundred forty-five subjects with MCI and 145 age- and sex-matched cognitively normal control subjects. Mild cognitive impairment was classified as amnestic, single cognitive domain; amnestic, multiple domain; nonamnestic, single domain; and nonamnestic, multiple domain. Subjects with nonamnestic single-domain MCI were classified into language, attention/executive, and visuospatial subgroups on the basis of specific cognitive impairment. Patterns of gray matter loss in the MCI groups compared with control subjects, assessed using voxel-based morphometry. Subjects in the amnestic single- and multiple-domain groups showed loss in the medial and inferior temporal lobes compared with control subjects, and those in the multiple-domain group also had involvement of the posterior temporal lobe, parietal association cortex, and posterior cingulate. Subjects in the nonamnestic single-domain group with language impairment showed loss in the left anterior inferior temporal lobe. The group with attention/executive deficits showed loss in the basal forebrain and hypothalamus. No coherent patterns of loss were observed in the other subgroups. The pattern of atrophy in the amnestic MCI groups is consistent with the concept that MCI in most of these subjects represents prodromal AD. However, the varying patterns in the language and attention/executive subgroups suggest that these subjects may have a different underlying disorder.


Misclassification of Calcium Status Based on Albumin-Adjusted Calcium: Studies in a Tertiary Hospital Setting.
Clinical laboratories measure total calcium and adjust for albumin concentrations to predict calcium status. We compared total and adjusted calcium (Adj-Ca) with ionized calcium (Ca2+) for correct assignment of calcium status. The effect of restriction of Adj-Ca reporting in patients with hypoalbuminemia was determined on the basis of frequency of misclassifications. Extraction of laboratory results was performed for 24 months. Adj-Ca was calculated from a modified Payne formula. A further prospective data set for 6 months was collected after stopping reporting of Adj-Ca for patients with an albumin <3.0 g/dL. The agreement between Ca2+ and Adj-Ca or total Ca was assessed with Cohen's kappa statistic. In 5553 hospitalized patients, 13604 paired Ca2+ results were analyzed retrospectively. Prospective collection in 1113 paired samples was from 450 patients. Adj-Ca was a poor predictor of calcium status compared to the Ca2+ reference standard in both data sets (agreement 56.9% in the first, 65.6% in the second data set). Renal failure and low albumin concentrations were associated with worse agreement between Adj-Ca and Ca2+. Restriction of reporting of Adj-Ca to albumin concentrations >3.0g/dL improved correct classification of calcium status from 65.6% to 77.6% (P < 0.0001). Total Ca performed better than Adj-Ca for low albumin (<3.0g/dL) and performed similarly in samples with albumin >3.0g/dL. Adj-Ca is unreliable for the classification of calcium status in hospital patients when compared to Ca2+. Adj-Ca overestimates calcium for patients with renal impairment and albumin concentrations <3.0g/dL. Restriction of reporting Adj-Ca for albumin below 3.0 g/dL reduces the number of misclassified patients.


Angiotensin receptors in Dupuytren's disease: a target for pharmacological treatment?
Attempts at the pharmacological treatment of Dupuytren's disease have so far been unsuccessful, and the disease is not yet fully understood on a cellular level. The Renin-Angiotensin System has long been understood to play a circulating hormonal role. However, there is much evidence showing Angiotensin II to play a local role in wound healing and fibrosis, with ACE inhibitors being widely used as an anti-fibrotic agent in renal and cardiac disease. This study was designed to investigate the presence of Angiotensin II receptors 1 (AT1) and 2 (AT2) in Dupuytren's tissue to form a basis for further study into the pharmacological treatment of this condition. Tissue was harvested from 11 patients undergoing surgery for Dupuytren's disease. Each specimen was processed into frozen sections and immunostaining was employed to identify AT1 and AT2 receptors. Immunostaining for AT1 receptors was mildly positive in one patient and negative in all the remaining patients. However, all specimens stained extensively for AT2 receptors. This suggests that the expression of AT2 receptors is more prominent than AT1 receptors in Dupuytren's disease. These findings have opened a new avenue for future research involving ACE inhibitors, AT2 agonists, and AT2 antagonists in Dupuytren's disease.


Risk and Return in Village Economies.
This paper provides a theory-based empirical framework for understanding the risk and return on productive capital assets and their allocation across activities in an economy characterized by idiosyncratic and aggregate risk and thin formal markets for real and financial assets. We apply our framework to households running business enterprises in Thai villages with extensive networks, taking advantage of panel data: income, assets, consumption, gifts, and loans. We decompose risk and estimate the risk premia faced by households, distinguishing aggregate risk from idiosyncratic, potentially diversifiable risk. This distinction matters for estimating measures of underlying productivity and has important policy implications.


Multicompartment Polymeric Nanoreactors for Non-Orthogonal Cascade Catalysis.
Spatial confinement of multiple catalysts presents an effective strategy for performing sequential or tandem chemical transformations in a one-pot reaction. These methods may be used to catalyze numerous reactions in conditions that are otherwise incompatible between catalyst and solvent, different catalysts, or reagents. Appropriate site isolation or support structure design will lead to significant advantages in atom economy, purification, and costs; the development of the interface between a catalyst and its confined microenvironment is paramount for realizing the next generation of nanoreactors. Polymer scaffolds can create tailor-made microenvironments resulting in catalyst compartmentalization. Through the optimization of a number of variables such as size, solubility, functionality, and morphology of the nanoreactor, catalyst activity and selectivity can be tuned. In this feature article, design principles and early strategies for polymer supports for catalyst site-isolation are introduced, and current strategies toward multicompartment polymer nanoreactors for non-orthogonal cascade catalysis are discussed. Future design trends in this burgeoning field are outlined in the conclusion.


Peritoneal dialysis as a life-saving procedure in an extremely low birth weight infant: case report and review of the literature.
Acute kidney injury (AKI) is a common condition in the neonatal intensive care unit (NICU), particularly in preterm infants. Management of AKI in neonates is challenging. Peritoneal dialysis (PD) has been preferred as the most applicable modality in neonates when medical therapy fails. A female infant was born at 24 and 4/7 weeks with a birth weight of 460 grams after an emergency cesarian section from a preeclamptic pregnacy. She developed AKI secondary to sepsis. A neonatal, straight single-cuff Tenckhoff catheter was inserted and PD was started on day 12. PD was discontinued after 6 days, on day 18 with adequate urine output and normalization of kidney function tests. However, the patient died on day 152 secondary to a nosocomial infection. To the best of our knowlegde, our case is the smallest infant in whom PD was performed succesfully with a PD catheter. PD is a relatively safe, effective and a feasible therapy in the neonatal population even in the smallest infants. PD may be a live-saving procedure in extremely low birth weight infants with severe AKI.


Manufacturing of Human Tissues as off-the-Shelf Grafts Programmed to Induce Regeneration.
Design criteria for tissue-engineered materials in regenerative medicine include robust biological effectiveness, off-the-shelf availability, and scalable manufacturing under standardized conditions. For bone repair, existing strategies rely on primary autologous cells, associated with unpredictable performance, limited availability and complex logistic. Here, a conceptual shift based on the manufacturing of devitalized human hypertrophic cartilage (HyC), as cell-free material inducing bone formation by recapitulating the developmental process of endochondral ossification, is reported. The strategy relies on a customized human mesenchymal line expressing bone morphogenetic protein-2 (BMP-2), critically required for robust chondrogenesis and concomitant extracellular matrix (ECM) enrichment. Following apoptosis-driven devitalization, lyophilization, and storage, the resulting off-the-shelf cartilage tissue exhibits unprecedented osteoinductive properties, unmatched by synthetic delivery of BMP-2 or by living engineered grafts. Scalability and pre-clinical efficacy are demonstrated by bioreactor-based production and subsequent orthotopic assessment. The findings exemplify the broader paradigm of programming human cell lines as biological factory units to engineer customized ECMs, designed to activate specific regenerative processes.


Spectrum of Phenylalanine Hydroxylase Gene Mutations in Hamadan and Lorestan Provinces of Iran and Their Associations with Variable Number of Tandem Repeat Alleles.
Phenylketonuria (PKU) is one of the most common known inherited metabolic diseases. The present study aimed to investigate the status of molecular defects in phenylalanine hydroxylase (PAH) gene in western Iranian PKU patients (predominantly from Kermanshah, Hamadan, and Lorestan provinces) during 2014-2016. Additionally, the results were compared with similar studies in Iran. Nucleotide sequence analysis of all 13 exons and their flanking intronic regions of the PAH gene was performed in 18 western Iranian PKU patients. Moreover, a variable number of tandem repeat (VNTR) located in the PAH gene was studied. The results revealed a mutational spectrum encompassing 11 distinct mutations distributed along the PAH gene sequence on 34 of the 36 mutant alleles (diagnostic efficiency of 94.4%). Also, four PAH VNTR alleles (with repeats of 3, 7, 8 and 9) were detected. The three most frequent mutations were IVS9+5G>A, IVS7-5T>C, and p.P281L with the frequency of 27.8%, 11%, and 11%, respectively. The results showed that there is not only a consanguineous relation, but also a difference in PAH characters of mutations between Kermanshah and the other two parts of western Iran (Hamadan and Lorestan). Also, it seems that the spectrum of mutations in western Iran is relatively distinct from other parts of the country, suggesting that this region might be a special PAH gene distribution region. Moreover, our findings can be useful in the identification of genotype to phenotype relationship in patients, and provide future abilities for confirmatory diagnostic testing, prognosis, and predict the severity of PKU patients.


Secondary infection as a risk factor for dengue hemorrhagic fever/dengue shock syndrome: an historical perspective and role of antibody-dependent enhancement of infection.
Today, dengue viruses are the most prevalent arthropod-borne viruses in the world. Since the 1960s, numerous reports have identified a second heterologous dengue virus (DENV) infection as a principal risk factor for severe dengue disease (dengue hemorrhagic fever/dengue shock syndrome, DHF/DSS). Modifiers of dengue disease response include the specific sequence of two DENV infections, the interval between infections, and contributions from the human host, such as age, ethnicity, chronic illnesses and genetic background. Antibody-dependent enhancement (ADE) of dengue virus infection has been proposed as the early mechanism underlying DHF/DSS. Dengue cross-reactive antibodies raised following a first dengue infection combine with a second infecting virus to form infectious immune complexes that enter Fc-receptor-bearing cells. This results in an increased number of infected cells and increased viral output per cell. At the late illness stage, high levels of cytokines, possibly the result of T cell elimination of infected cells, result in vascular permeability, leading to shock and death. This review is focused on the etiological role of secondary infections (SI) and mechanisms of ADE.


Assessing the genomic evidence for conserved transcribed pseudogenes under selection.
Transcribed pseudogenes are copies of protein-coding genes that have accumulated indicators of coding-sequence decay (such as frameshifts and premature stop codons), but nonetheless remain transcribed. Recent experimental evidence indicates that transcribed pseudogenes may regulate the expression of homologous genes, through antisense interference, or generation of small interfering RNAs (siRNAs). Here, we assessed the genomic evidence for such transcribed pseudogenes of potential functional importance, in the human genome. The most obvious indicators of such functional importance are significant evidence of conservation and selection pressure. A variety of pseudogene annotations from multiple sources were pooled and filtered to obtain a subset of sequences that have significant mid-sequence disablements (frameshifts and premature stop codons), and that have clear evidence of full-length mRNA transcription. We found 1750 such transcribed pseudogene annotations (TPAs) in the human genome (corresponding to approximately 11.5% of human pseudogene annotations). We checked for syntenic conservation of TPAs in other mammals (rhesus monkey, mouse, rat, dog and cow). About half of the human TPAs are conserved in rhesus monkey, but strikingly, very few in mouse (approximately 3%). The TPAs conserved in rhesus monkey show evidence of selection pressure (relative to surrounding intergenic DNA) on: (i) their GC content, and (ii) their rate of nucleotide substitution. This is in spite of distributions of Ka/Ks (ratios of non-synonymous to synonymous substitution rates), congruent with a lack of protein-coding ability. Furthermore, we have identified 68 human TPAs that are syntenically conserved in at least two other mammals. Interestingly, we observe three TPA sequences conserved in dog that have intermediate character (i.e., evidence of both protein-coding ability and pseudogenicity), and discuss the implications of this. Through evolutionary analysis, we have identified candidate sequences for functional human transcribed pseudogenes, and have pinpointed 68 strong candidates for further investigation as potentially functional transcribed pseudogenes across multiple mammal species.


The epidemiology of bacterial vaginosis in relation to sexual behaviour.
Bacterial vaginosis (BV) has been most consistently linked to sexual behaviour, and the epidemiological profile of BV mirrors that of established sexually transmitted infections (STIs). It remains a matter of debate however whether BV pathogenesis does actually involve sexual transmission of pathogenic micro-organisms from men to women. We therefore made a critical appraisal of the literature on BV in relation to sexual behaviour. G. vaginalis carriage and BV occurs rarely with children, but has been observed among adolescent, even sexually non-experienced girls, contradicting that sexual transmission is a necessary prerequisite to disease acquisition. G. vaginalis carriage is enhanced by penetrative sexual contact but also by non-penetrative digito-genital contact and oral sex, again indicating that sex per se, but not necessarily coital transmission is involved. Several observations also point at female-to-male rather than at male-to-female transmission of G. vaginalis, presumably explaining the high concordance rates of G. vaginalis carriage among couples. Male antibiotic treatment has not been found to protect against BV, condom use is slightly protective, whereas male circumcision might protect against BV. BV is also common among women-who-have-sex-with-women and this relates at least in part to non-coital sexual behaviours. Though male-to-female transmission cannot be ruled out, overall there is little evidence that BV acts as an STD. Rather, we suggest BV may be considered a sexually enhanced disease (SED), with frequency of intercourse being a critical factor. This may relate to two distinct pathogenetic mechanisms: (1) in case of unprotected intercourse alkalinisation of the vaginal niche enhances a shift from lactobacilli-dominated microflora to a BV-like type of microflora and (2) in case of unprotected and protected intercourse mechanical transfer of perineal enteric bacteria is enhanced by coitus. A similar mechanism of mechanical transfer may explain the consistent link between non-coital sexual acts and BV. Similar observations supporting the SED pathogenetic model have been made for vaginal candidiasis and for urinary tract infection. Though male-to-female transmission cannot be ruled out, overall there is incomplete evidence that BV acts as an STI. We believe however that BV may be considered a sexually enhanced disease, with frequency of intercourse being a critical factor.


Interaction of insulin and prostacyclin production in the rat.
The effects of hyperinsulinemia on production of prostacyclin (PGI2), a potent inhibitor of platelet aggregation, was studied in vitro in the rat. Aortic rings following 1-h preincubation at 37 degrees C and 1 h at 4 degrees C were incubated with and without purified porcine insulin in Krebs' glucose at 37 degrees C for 5 min and immediately percent inhibition of platelet aggregation was determined. PGI2 production in ng/mg aorta was estimated from a curve using PGI2 standard. The mean PGI2 production was significantly decreased in those rings incubated with insulin in concentration of 2500, 500, and 250 microunits/ml. Likewise, incubation of rings at 22 degrees C for 30 min resulted in at least ten times less PGI2 with insulin. Since PGI2 appears to exert its antiaggregatory effect through cyclic AMP, theophylline was added to the incubation medium resulting in potentiation of inhibition of aggregation which was decreased to control levels when insulin was also added to the medium. Pancreatic slices yielded no significant change in insulin obtained when incubated with and without 5 ng of PGI2 in 2 ml of 2.8 mM glucose, but in a high glucose medium (28 mM) the PGI2-treated slices yielded significantly less insulin. Since PGI2 may play a role in the formation of atherosclerotic plaques, these results suggest a possible deleterious effect of elevated insulin levels in type II and in insulin-treated type I diabetics with regard to macrovascular disease. Suppression of insulin production in presence of PGI2 in high glucose medium resembles the action of other prostaglandins and suggests it may inhibit insulin secretion after a glucose load.


Mid-frequency song and low-frequency calls of sei whales in the Falkland Islands.
Although sei whales (Balaenoptera borealis) are distributed throughout the globe, their behaviour and vocal repertoire are poorly described. We used passive acoustic monitoring to describe the vocal behaviour of sei whales in the Falkland Islands, between December 2018 and April 2019. We isolated more than 2000 low-frequency calls for manual classification, of which 510 calls with high signal-to-noise ratio were quantitatively measured. Five categories of stereotyped call types in the 15-230 Hz range were described, some with multiple subcategories. These included some similar to previously described calls (e.g. downsweeps), but others that were novel in acoustic structure and frequency band. In the mid-frequency range, we documented a highly stereotyped, hierarchically structured and rhythmically repetitive song display. Songs were arranged in phrases with a structure composed of repetitive sub-phrases, and a diverse variety of sounds in the 1-5 kHz range. Singing commenced in late February, despite the presence of whales and calls since early December, and continued through April. These acoustic properties and behavioural characteristics indicate that this is likely a male breeding display similar to songs and singing of other balaenopterids. This is the first detailed description of a song display for sei whales, highlighting the importance of the Falkland Islands.


The perceptual response to treadmill exercise using the Eston-Parfitt scale and marble dropping task, in children age 7 to 8 years.
This study assessed the nature of the perceived exertion response to treadmill running in 14 healthy 7-8 year-old children, using the Eston-Parfitt (E-P) Ratings of Perceived Exertion (RPE) scale and a marble dropping task. For the E-P scale and the marble dropping task, the relationships between the RPE and work rate were best described as linear (R2 = .96) and curvilinear (R2 = .94), respectively. This study further suggests that individual respiratory-metabolic cues (oxygen uptake: O2, heart rate: HR, ventilation: VE) may significantly influence the overall RPE to varying degrees in young children. The E-P scale provides an intuitively meaningful and valid means of quantifying the overall perception of exertion in young, healthy children during treadmill running. The marble dropping task is a useful secondary measure of perceived exertion, which provides further insight into the nature of the perceived exertion response to exercise in young children.


Real-time, aptamer-based tracking of circulating therapeutic agents in living animals.
A sensor capable of continuously measuring specific molecules in the bloodstream in vivo would give clinicians a valuable window into patients' health and their response to therapeutics. Such technology would enable truly personalized medicine, wherein therapeutic agents could be tailored with optimal doses for each patient to maximize efficacy and minimize side effects. Unfortunately, continuous, real-time measurement is currently only possible for a handful of targets, such as glucose, lactose, and oxygen, and the few existing platforms for continuous measurement are not generalizable for the monitoring of other analytes, such as small-molecule therapeutics. In response, we have developed a real-time biosensor capable of continuously tracking a wide range of circulating drugs in living subjects. Our microfluidic electrochemical detector for in vivo continuous monitoring (MEDIC) requires no exogenous reagents, operates at room temperature, and can be reconfigured to measure different target molecules by exchanging probes in a modular manner. To demonstrate the system's versatility, we measured therapeutic in vivo concentrations of doxorubicin (a chemotherapeutic) and kanamycin (an antibiotic) in live rats and in human whole blood for several hours with high sensitivity and specificity at subminute temporal resolution. We show that MEDIC can also obtain pharmacokinetic parameters for individual animals in real time. Accordingly, just as continuous glucose monitoring technology is currently revolutionizing diabetes care, we believe that MEDIC could be a powerful enabler for personalized medicine by ensuring delivery of optimal drug doses for individual patients based on direct detection of physiological parameters.


Impact of electroacupuncture on quality of life for patients with Relapsing-Remitting Multiple Sclerosis under treatment with immunomodulators: a randomized study.
Multiple sclerosis (MS) is a complex autoimmune disease mediated by an immune response to central nervous system antigens. Modern immunomodulatory therapies, however, do not ameliorate many of the symptoms, such as pain and depression. Patients thus seek alternative treatments, such as acupuncture, although the benefits of such treatments have not been objectively evaluated. The present study was thus designed to evaluate the effect of the use of acupuncture in the alleviation of the symptoms of patients with MS. Thirty-one patients with Relapsing-Remitting Multiple Sclerosis undergoing treatment with immunomodulators were randomly distributed into sex-stratified experimental and placebo groups in a patient- and evaluator-blind design; they received either true or sham electroacupuncture during regular visits to the doctor in the university hospital outpatient clinic. Standardized questionnaires were used to evaluate the effect of electroacupuncture on the quality of life of these patients. Initial and follow-up assessment included the evaluation of clinical status (Expanded Disability Status Scale), pain (Visual Analogue Scale) and quality of life (Functional Assessment of multiple Sclerosis) to ascertain the impact of electroacupuncture on the quality of life of these patients. Electroacupuncture improved various aspects of quality of life, including a reduction in pain and depression. The self-report scales were more sensitive to improvement than was the more objective clinical measure. This paper provides evidence that electroacupuncture can significantly improve the quality of life of such patients. The results suggest that the routine use of a self-report scale evaluating quality of life should be included in regular clinical evaluations in order to detect changes more rapidly. RBR-58yq52.


The evolution of Clostridium difficile infection in cancer patients: epidemiology, pathophysiology, and guidelines for prevention and management.
Clostridium difficile infection (CDI) has emerged as a significant challenge to the healthcare system. The availability of anti-cancer chemotherapeutic regimens has contemporaneously resulted in a larger population of patients who are susceptible to CDI. The outbreak of a novel, hypervirulent, resistant strain, NAP-1/027 as well as resistance to antibiotic therapy have further contributed to an increase in prevalence as well as in disease severity. Recent data show high fatality rates in cancer patients with CDI. In this review, we have discussed the incidence, epidemiology, pathophysiology, clinical signs and symptoms and therapeutic guidelines for patients who are on chemotherapy and present with CDI and highlighted clinical reports documenting severe CDI associated with chemotherapeutic agents such as methotrexate, 5FU, cisplatin, carboplatin, paclitaxel, vinorelbine and cyclophosphamide. The review article also has the discussion of patents pertaining to infections caused by Clostridium difficile in cancer patients. We underscore the urgent need for early recognition and diagnosis of CDI in cancer patients and for the design and implementation of randomized clinical trials of new treatment modalities in the management of chemotherapy- associated CDI.


Design analysis of doped-silicon surface plasmon resonance immunosensors in mid-infrared range.
This paper reports the design analysis of a microfabricatable mid-infrared (mid-IR) surface plasmon resonance (SPR) sensor platform. The proposed platform has periodic heavily doped profiles implanted into intrinsic silicon and a thin gold layer deposited on top, making a physically flat grating SPR coupler. A rigorous coupled-wave analysis was conducted to prove the design feasibility, characterize the sensor's performance, and determine geometric parameters of the heavily doped profiles. Finite element analysis (FEA) was also employed to compute the electromagnetic field distributions at the plasmon resonance. Obtained results reveal that the proposed structure can excite the SPR on the normal incidence of mid-IR light, resulting in a large probing depth that will facilitate the study of larger analytes. Furthermore, the whole structure can be microfabricated with well-established batch protocols, providing tunability in the SPR excitation wavelength for specific biosensing needs with a low manufacturing cost. When the SPR sensor is to be used in a Fourier-transform infrared (FTIR) spectroscopy platform, its detection sensitivity and limit of detection are estimated to be 3022 nm/RIU and ~70 pg/mm(2), respectively, at a sample layer thickness of 100 nm. The design analysis performed in the present study will allow the fabrication of a tunable, disposable mid-IR SPR sensor that combines advantages of conventional prism and metallic grating SPR sensors.


Rapid prototyping of nanofluidic systems using size-reduced electrospun nanofibers for biomolecular analysis.
Biomolecular transport in nanofluidic confinement offers various means to investigate the behavior of biomolecules in their native aqueous environments, and to develop tools for diverse single-molecule manipulations. Recently, a number of simple nanofluidic fabrication techniques has been demonstrated that utilize electrospun nanofibers as a backbone structure. These techniques are limited by the arbitrary dimension of the resulting nanochannels due to the random nature of electrospinning. Here, a new method for fabricating nanofluidic systems from size-reduced electrospun nanofibers is reported and demonstrated. As it is demonstrated, this method uses the scanned electrospinning technique for generation of oriented sacrificial nanofibers and exposes these nanofibers to harsh, but isotropic etching/heating environments to reduce their cross-sectional dimension. The creation of various nanofluidic systems as small as 20 nm is demonstrated, and practical examples of single biomolecular handling, such as DNA elongation in nanochannels and fluorescence correlation spectroscopic analysis of biomolecules passing through nanochannels, are provided.


The S. aureus 4-oxalocrotonate tautomerase SAR1376 enhances immune responses when fused to several antigens.
A persistent goal of vaccine development is the enhancement of the immunogenicity of antigens while maintaining safety. One strategy involves alteration of the presentation of the antigen by combining antigens with a multimeric scaffold. Multi-antigen vaccines are under development, and there are presently far more candidate antigens than antigen scaffolding strategies. This is potentially problematic, since prior immunity to a scaffold may inhibit immune responses to the antigen-scaffold combination. In this study, a series of domains from S. aureus which have been shown to crystallise into multimeric structures have been examined for their scaffolding potential. Of these domains, SAR1376, a 62 amino acid member of the 4-oxalocrotonate tautomerase (4-OT) family, was pro-immunogenic in mice when fused to a range of pathogen antigens from both S. aureus and P. falciparum, and delivered by either DNA vaccination, viral vector vaccines or as protein-in-adjuvant formulations. The adjuvant effect did not depend on enzymatic activity, but was abrogated by mutations disrupting the hexameric structure of the protein. We therefore propose that SAR1376, and perhaps other members of the 4-OT protein family, represent very small domains which can be fused to a wide range of antigens, enhancing immune responses against them.


Association studies of novel obesity-related gene variants with quantitative metabolic phenotypes in a population-based sample of 6,039 Danish individuals.
Genome-wide association studies have identified novel WHR and BMI susceptibility loci. The aim of this study was to elucidate if any of these loci had an effect on quantitative measures of glucose homeostasis, including estimates of insulin release and insulin sensitivity in an epidemiological setting. By applying an additive genetic model, 14 WHR-associated gene variants and 18 BMI-associated variants were investigated for their relationships with glucose-related metabolic traits in treatment-naive individuals from the population-based Inter99 study sample (n = 6,039). Of the variants associated with BMI, the QPCTL rs2287019 C allele was associated with an increased insulinogenic index of 7.4% per risk allele (p = 4.0 × 10⁻⁷) and increased disposition index of 5.6% (p = 6.4 × 10⁻⁵). The LRP1B rs2890652 C allele was associated with insulin resistance, showing a 3.3% increase (p = 0.0011) using the HOMA-insulin resistance (HOMA-IR) index and a 2.2% reduction (p = 0.0014) with the Matsuda index. Of the variants associated with WHR, LYPLAL1/SLC30A10 rs4846567 G allele carriers showed a 5.2% lower HOMA-IR (p = 0.00086) in women, indicating improved insulin sensitivity. Female carriers of the VEGFA rs6905288 A allele were insulin resistant, with a 3.7% increase in HOMA-IR (p = 0.00036) and 4.0% decrease in Matsuda index (p = 2 × 10⁻⁴). Our correlative findings from analysing single-locus data suggest that some variation in validated BMI and WHR loci are associated with either increased or decreased insulin sensitivity and thereby potentially with metabolically healthy or metabolically unhealthy subsets of obesity. The results call for testing in larger study samples and for further physiological exploration of the possible metabolic implications of these loci.


CAEP 2016 Academic Symposium: A Writer's Guide to Key Steps in Producing Quality Medical Education Scholarship.
A key skill for successful clinician educators is the effective dissemination of scholarly innovations and research. Although there are many ways to disseminate scholarship, the most accepted and rewarded form of educational scholarship is publication in peer-reviewed journals. This paper provides direction for emergency medicine (EM) educators interested in publishing their scholarship via traditional peer-reviewed avenues. It builds upon four literature reviews that aggregated recommendations for writing and publishing high-quality quantitative and qualitative research, innovations, and reviews. Based on the findings from these literature reviews, the recommendations were prioritized for importance and relevance to novice clinician educators by a broad community of medical educators. The top items from the expert vetting process were presented to the 2016 Canadian Association of Emergency Physicians (CAEP) Academic Symposium Consensus Conference on Education Scholarship. This community of EM educators identified the highest yield recommendations for junior medical education scholars. This manuscript elaborates upon the top recommendations identified through this consensus-building process.


Insulin resistance as a marker for the immune-metabolic subtype of depression.
Insulin resistance (IR), a marker of metabolic dysregulation and pro-inflammatory state, moderates the antidepressant treatment effect in patients with type 2 diabetes (T2D) and is therefore a potential marker for personalized treatment. Based on data from a light therapy trial (NTR4942), we aimed to evaluate whether 1) depression symptoms differ according to the level of IR, and 2) improvement of specific depression symptoms drive the positive effects of light therapy in those with higher IR. This secondary analysis in 59 individuals with depression and T2D explored differences in depressive symptom profile (30-item Inventory of Depressive Symptomatology (IDS)) at baseline and in response to light therapy (versus placebo), between lower and higher IR individuals, using Likelihood Ratio tests and Linear-by-linear association. IR was measured using the gold standard, a hyperinsulinemic-euglycaemic clamp. At baseline, higher IR individuals reported more symptoms of irritability (p=0.024) anhedonia (no interest in people and activities: p=0.011; absence of pleasure and enjoyment: p=0.021), fatigue (fatigue: p=0.036; physical fatigue: p=0.035) and hypersomnia (p=0.029) relative to persons with lower IR, who reported more insomnia (nightly awakening: p=0.041; early morning awakening: p=0.012). Light therapy led to an improvement across IDS symptoms in higher IR individuals, while in lower IR individuals, light therapy improved early morning awakening (p=0.005) and interest in people and activities (p=0.015), but worsened mood (feeling sad: p=0.001; feeling irritable: p=0.002; interpersonal sensitivity: p=0.014). Results add to the hypothesis of an immune-metabolic subtype of depression, and suggest that IR might be a promising focus for precision medicine.


Evaluation of Matrix Tablets Based on Eudragit®E100/Carbopol®971P Combinations for Controlled Release and Improved Compaction Properties of Water Soluble Model Drug Paracetamol.
The purpose of this work was to investigate the influence of Eudragit®E100 polymer in modifying the release rates and compaction properties of water soluble model drug paracetamol from Carbopol®971P NF polymer matrix tablets prepared by direct compression. The effects of the ratio of the two polymers, the total polymeric content, and the tablets mechanical strength on paracetamol release rates were investigated. Dissolution studies were conducted using USP XX Π rotating paddle apparatus at 50 rpm and 37°C at three different stages (pH 1.2, 4.8, and 6.8). Results showed that the polymers combination improved significantly the compaction properties of paracetamol tablets as evident by the higher crushing strengths (8.3 ± 0.4 Kp) compared to polymer-free tablets (3.4 ± 0.2 Kp) at intermediate compression pressure of 490 MPa. When combined with Carbopol®971P NF, Eudragit®E100 was found to be capable of extending paracetamol release for more than 12 h compared to 1 h for polymers-free tablets. The combined polymers were able to control paracetamol release in a pH independent pattern. The f2 (similarity factor) analysis showed that the ratio between the polymers and the total polymer concentration exhibited significant impact on drug release rates. In conclusion, Eudragit®E100 when combined with Carbopol®971P NF was capable of improving the compaction and sustained release properties of paracetamol. Korsmeyer-Peppas model was found to be the most suitable for fitting drug release data. The polymer combinations can potentially be used to control the release rates of highly water soluble drugs.


[The frontiers of medicalization: tensions surrounding the identification and appreciation of child malnutrition in a primary healthcare center of the city of Buenos Aires].
The medicalization of life and its implications for the production of subjectivities are phenomena that have been highlighted by the human sciences in the study of health and disease. Nevertheless, the analysis of its local expressions has been insufficiently covered. The scope of this paper is to explore this field by an ethnographical study of the medicalization process of child malnutrition in a primary healthcare center of the city of Buenos Aires. We will describe analytically the singularities involved in the body perception and the alimentary context by health professionals and their patients. We emphasize that the criteria of perception and moral values that encourage social positions of health professionals and recipients of their actions precluded the institutionalization of a medical vision. We conclude that the process analyzed highlights the need to exceed the medicalization approaches dealing exclusively from the angle of imposition. The social history of the groups involved and ways of establishing relationships in local settings, are essential to understand the peculiarities of these processes.


Repurposing Thioridazine (TDZ) as an anti-inflammatory agent.
Nuclear factor-kB (NF-kB) is a crucial transcription factor in the signal transduction cascade of the inflammatory signaling. Activation of NF-κB depends on the phosphorylation of IκBα by IκB kinase (IKKβ) followed by subsequent ubiquitination and degradation. This leads to the nuclear translocation of the p50- p65 subunits of NF-κB, and further triggers pro-inflammatory cytokine gene expression. Thus, in the need of a more effective therapy for the treatment of inflammatory diseases, specific inhibition of IKKβ represents a rational alternative strategy to the current therapies. A computer-aided drug identification protocol was followed to identify novel IKKβ inhibitors from a database of over 1500 Food and Drug Administration (FDA) drugs. The best scoring compounds were compared with the already known high-potency IKKβ inhibitors for their ability to bind and inhibit IKKβ by evaluating their docking energy. Finally, Thioridazinehydrochloride (TDZ), a potent antipsychotic drug against Schizophrenia was selected and its efficiency in inhibiting IκBα protein degradation and NF-κB activation was experimentally validated. Our study has demonstrated that TDZ blocks IκBα protein degradation and subsequent NF-κB activation to inhibit inflammation. Thus, it is a potential repurposed drug against inflammation.


The Nutritional Risk Screening 2002 tool for detecting malnutrition risk in hospitalised patients: perspective from a developing country.
To verify the validity of the Nutritional Risk Screening (NRS) 2002 test in a Turkish population. We prospectively investigated 2566 patients at a tertiary referral hospital. Nutritional status was screened using NRS 2002, and the length of the stay (LOS) was the main outcome measure. Hospital stays >10 days were accepted as prolonged LOS. NRS scores ≥3 were accepted as indicating risk for malnutrition. Statistical analyses were performed to determine the independent risk factors for malnutrition risk and prolonged LOS. The mean age of patients was 56.6±16.9 years. According to the NRS 2002, 964 patients (37.6%) were without risk, 1320 (51.4%) warranted surveillance and 282 (11%) were at high risk for malnutrition. Malnutrition rate was the highest in the intensive care unit (22.01%). Prolonged LOS was seen in 24.4% of patients. Intensive care unit stay [odds ratio (OR): 0.585; confidence interval (CI): 1.45-2.22; p<0.001] and an NRS score ≥3 (OR: 0.88; CI: 1.87-3.13; p<0.001) were independent risk factors for prolonged LOS. Improving healthcare outcomes while avoiding preventable healthcare costs is an important goal of healthcare provision in developing countries. NRS 2002 was predictive of LOS, and thus, of patient prognosis. Further community-based studies are warranted to assess the impact of NRS 2002 on reducing healthcare costs.


Psychiatric rehabilitation of emotional disorders.
Emotional disorder is psychological and behavioral problems of emotional domain that is different from cognitive domain, such as thought and memory. Typical emotional disorders are anxiety disorder, depression, and bipolar disorder. In the present study, we discussed on the symptoms, progression, and treatment for the anxiety disorder (panic disorder, social phobia, and obsessive compulsive disorder), depression, and bipolar disorder. The goal of treatment for the emotional disorder is removal of symptoms. In spite of the development of brain science, removal of symptoms, prevention of recurrence, and coming back to normal life require patience and effort.


Test of the recommended dialysis dose on one-year mortality of nondiabetic maintenance hemodialysis patients; observations from a single dialysis unit.
The optimal delivered dialysis dose has been of a great interest for the last three decades, though a clear cut point has not been reached yet. We aimed to evaluate the relationship between one-year mortality and the delivered dialysis dose, which was recommended by Kidney Disease Outcomes Quality Initiative (KDOQI), in our maintenance hemodialysis (MHD) patients. This was a single center, prospective observational study with one year of follow-up. Patients with extremes of age, BMI, residual renal function, diabetes mellitus, severe infection malignancy, and recent hospitalization within the last three months were excluded. Demographic, anthropometric, laboratory, and outcome data (mortality as the primary) were prospectively collected. Patients were classified into two groups according to baseline spKt/V levels; group 1 (n = 20): spKt/V ≤ 1.4, group 2 (n = 60): spKt/V > 1.4. Median (IQR) age and hemodialysis vintage of all patients (M/F: 41/39) were 49.5 (29) years and 60 (94) months, respectively. Both groups had similar characteristics, with the exception of significantly higher BMI (24 vs. 21.7, p = 0.012), serum creatinine and uric acids, and lower spKt/V (1.30 vs. 1.71, p < 0.001) in group 1. Overall death occurred in seven (8.75%) patients (5 from group 1 and 2 from group 2). Patients in group 1 had significantly higher one-year mortality rate and shorter survival time (25% vs. 3.3%, p = 0.003 and 43.9 vs. 47.3 weeks, p = 0.003, respectively). Higher spKt/V (>1.4) was associated with a lower one-year mortality in this small cohort of patients.


An integrated optic ethanol vapor sensor based on a silicon-on-insulator microring resonator coated with a porous ZnO film.
Optical structures fabricated on silicon-on-insulator technology provide a convenient platform for the implementation of highly compact, versatile and low cost devices. In this work, we demonstrate the promise of this technology for integrated low power and low cost optical gas sensing. A room temperature ethanol vapor sensor is demonstrated using a ZnO nanoparticle film as a coating on an SOI micro-ring resonator of 5 microm in radius. The local coating on the ring resonators is prepared from colloidal suspensions of ZnO nanoparticles of around 3 nm diameter. The porous nature of the coating provides a large surface area for gas adsorption. The ZnO refractive index change upon vapor adsorption shifts the microring resonance through evanescent field interaction. Ethanol vapor concentrations down to 100 ppm are detected with this sensing configuration and a detection limit below 25 ppm is estimated.


Health-related quality of life in outpatients with schizophrenia: factors that determine changes over time.
The objective of this study was to analyze the clinical factors associated with changes in HRQoL in outpatients with schizophrenia using both generic and condition-specific HRQoL scales. Adult outpatients with schizophrenia at least 18 years of age who did not have an acute psychotic exacerbation in the 3 months prior to baseline were recruited. PANSS dimensions were calculated based on Lindenmayer et al.'s five factors. HRQoL data were assessed by patients using the Schizophrenia Quality of Life Scale (SQLS), the Short Form-36 (SF-36), and the EuroQol-5 Dimension (EQ-5D) questionnaires. Out of the 1345 patients included at baseline, 1196 (89%) were evaluated at 12 months. Regression models showed that the factor most consistently associated with HRQoL at endpoint was change in the PANSS negative symptoms score. A decrease in the PANSS negative symptoms score from baseline to 1 year was associated with a decrease in HRQoL during the same period. There were also significant associations of the change in PANSS excitatory factor with all the HRQoL scales except the SF-36 PCS. Female gender was associated with a decrease in all HRQoL ratings. There was also a relationship between years since onset and HRQoL. The longer the time since illness onset, the larger the decrease in HRQoL. This study has found that, in outpatients with schizophrenia, changes in negative and excitement symptoms may have a greater an association with HRQoL than changes in positive, cognitive and depressive symptoms.


Senescence as a main mechanism of Ritonavir and Ritonavir-NO action against melanoma.
The main focus of this study is exploring the effect and mechanism of two HIV-protease inhibitors: Ritonavir and Ritonavir-nitric oxide (Ritonavir-NO) on in vitro growth of melanoma cell lines. NO modification significantly improved the antitumor potential of Ritonavir, as the IC50 values of Ritonavir-NO were approximately two times lower than IC50 values of the parental compound. Our results showed for the first time, that both compounds induced senescence in primary and metastatic melanoma cell lines. This transformation was manifested as a change in cell morphology, enlargement of nuclei, increased cellular granulation, upregulation of β-galactosidase activity, lipofuscin granules appearance, higher production of reactive oxygen species and persistent inhibition of proliferation. The expression of p53, as one of the key regulators of senescence, was upregulated after 48 hours of Ritonavir-NO treatment only in metastatic B16F10 cells, ranking it as a late-response event. The development of senescent phenotype was consistent with the alteration of the cytoskeleton-as we observed diminished expression of vinculin, α-actin, and β-tubulin. Permanent inhibition of S6 protein by Ritonavir-NO, but not Ritonavir, could be responsible for a stronger antiproliferative potential of the NO-modified compound. Taken together, induction of senescent phenotype may provide an excellent platform for developing therapeutic approaches based on selective killing of senescent cells.


Two cell division cycle mutants of Saccharomyces cerevisiae are defective in transmission of mitochondria to zygotes.
Mutations in CDC genes of S. cerevisiae disrupt the cell cycle at specific stages. The experiments reported here demonstrate that two CDC genes, CDC5 and CDC27, are necessary for mitochondrial segregation as well as for nuclear division. The defect in the transmission of mitochondria was revealed by the examination of uninucleate and binucleate progeny of transient heterokaryons generated by using the kar1-1 mutation that disrupts nuclear fusion. One of the parents lacked mitochondrial DNA (rho(0)) whereas the other parent had functional mitochondria (rho(+)). When the parents of the heterokaryon were both wild-type (CDC), nearly all progeny received mitochondria at 21 degrees and at 34 degrees . Thirty-four of the 36 cdc mutations tested had no defect in transmission of mitochondria to zygotic progeny in crosses in which one parent was a cdc mutant and the other parent was not (CDC). However, the cdc5 and cdc27 mutations prevented the transmission of mitochondria to cdc progeny at 34 degrees but not at 21 degrees ; CDC progeny received mitochondria at either temperature. This defect was observed in crosses of cdc5 or cdc27 by wild-type cells regardless of which parent donated mitochondria to the zygote. The defect in mitochondrial transmission cosegregated in meiotic tetrads with the defect in mitosis demonstrating that both are likely to be caused by the same temperature-sensitive mutation. These results indicate that the CDC5 and CDC27 gene products are essential in two motility-related processes: mitochondrial movement from the zygote to the progeny and in mitosis.-Furthermore, the results suggest that the function performed by the CDC5 and CDC27 gene products for mitochondrial transmission differ in some fundamental way from the function performed for mitosis. The function necessary for mitosis can be supplied to the cdc5 (or cdc27) nucleus by the CDC5 (or CDC27) nucleus in the same heterokaryon but the function necessary for mitochondrial transmission cannot. Perhaps the function needed for mitochondrial transmission must be performed in the cell cycle preceding the actual segregation of mitochondria whereas the function needed for nuclear segregation can be performed at the time that mitosis occurs.


Cortical Dopamine Transmission as Measured with the [11C]FLB 457 - Amphetamine PET Imaging Paradigm Is Not Influenced by COMT Genotype.
Basic investigations link a Val158Met polymorphism (rs4680) in the catechol-O-methyltransferase (COMT) gene to not only its enzymatic activity, but also to its dopaminergic tone in the prefrontal cortex. Previous PET studies have documented the relationship between COMT Val158Met polymorphism and D1 and D2/3 receptor binding potential (BP), and interpreted them in terms of dopaminergic tone. The use of baseline dopamine D1 and D2/3 receptor binding potential (BPND) as a proxy for dopaminergic tone is problematic because they reflect both endogenous dopamine levels (a change in radiotracer's apparent affinity) and receptor density. In this analysis of 31 healthy controls genotyped for the Val158Met polymorphism (Val/Val, Val/Met, and Met/Met), we used amphetamine-induced displacement of [11C]FLB 457 as a direct measure of dopamine release. Our analysis failed to show a relationship between COMT genotype status and prefrontal cortical dopamine release. COMT genotype was also not predictive of baseline dopamine D2/3 receptor BPND.


Expression of TNF-α and CD44 is implicated in poor prognosis, cancer cell invasion, metastasis and resistance to the sunitinib treatment in clear cell renal cell carcinomas.
Tumor necrosis factor-α (TNF-α) is involved in epithelial-mesenchymal transition (EMT) and expression of CD44, a cancer stem cell marker, in several cancers. This study was performed to clarify the significance of TNF-α and CD44 in clear cell renal cell carcinomas (ccRCCs). Expression of TNF-α and CD44 was examined by immunohistochemistry in 120 ccRCCs. Involvement of TNF-α in EMT and induction of CD44 was analyzed by monitoring expression of EMT-related genes and CD44, and invasion in cultured ccRCC cell lines. TNF-α and CD44 were immunolocalized mainly to carcinoma cells of high-grade ccRCCs with positive correlations with primary tumor stage. A positive correlation was also obtained between TNF-α and CD44 expression, and co-upregulation of TNF-α and CD44 was associated with primary tumor stage, distant metastasis, and poor prognosis. TNF-α enhanced migration and invasion of ccRCC cells together with down-regulation of E-cadherin expression and up-regulation of matrix metalloproteinase 9 and CD44 expression. TNF-α also up-regulated the expression of TNF-α itself in ccRCC cells. Among the 25 ccRCC patients treated with sunitinib for metastatic disease, high CD44 expression was associated with poor treatment outcome. Importantly, residual carcinoma cells in the sunitinib-treated metastatic ccRCCs were strongly positive for CD44, and the CD44 expression was significantly higher in the tumors from the sunitinib-treated patients than in those from untreated ones. Our data show that TNF-α plays an important role in progression of ccRCCs by inducing EMT and CD44 expression, and suggest that CD44 induced by TNF-α may be involved in the resistance to the sunitinib treatment.


Deletion of Irs2 reduces amyloid deposition and rescues behavioural deficits in APP transgenic mice.
As impaired insulin signalling (IIS) is a risk factor for Alzheimer's disease we crossed mice (Tg2576) over-expressing human amyloid precursor protein (APP), with insulin receptor substrate 2 null (Irs2(-/-)) mice which develop insulin resistance. The resulting Tg2576/Irs2(-/-) animals had increased tau phosphorylation but a paradoxical amelioration of Abeta pathology. An increase of the Abeta binding protein transthyretin suggests that increased clearance of Abeta underlies the reduction in plaques. Increased tau phosphorylation correlated with reduced tau-phosphatase PP2A, despite an inhibition of the tau-kinase glycogen synthase kinase-3. Our findings demonstrate that disruption of IIS in Tg2576 mice has divergent effects on pathological processes-a reduction in aggregated Abeta but an increase in tau phosphorylation. However, as these effects are accompanied by improvement in behavioural deficits, our findings suggest a novel protective effect of disrupting IRS2 signalling in AD which may be a useful therapeutic strategy for this condition.


Identification of chlorinated solvents degradation zones in clay till by high resolution chemical, microbial and compound specific isotope analysis.
The degradation of chlorinated ethenes and ethanes in clay till was investigated at a contaminated site (Vadsby, Denmark) by high resolution sampling of intact cores combined with groundwater sampling. Over decades of contamination, bioactive zones with degradation of trichloroethene (TCE) and 1,1,1-trichloroethane (1,1,1-TCA) to 1,2-cis-dichloroethene (cis-DCE) and 1,1-dichloroethane, respectively, had developed in most of the clay till matrix. Dehalobacter dominated over Dehalococcoides (Dhc) in the clay till matrix corresponding with stagnation of sequential dechlorination at cis-DCE. Sporadically distributed bioactive zones with partial degradation to ethene were identified in the clay till matrix (thickness from 0.10 to 0.22 m). In one sub-section profile the presence of Dhc with the vcrA gene supported the occurrence of degradation of cis-DCE and VC, and in another enriched δ(13)C for TCE, cis-DCE and VC documented degradation. Highly enriched δ(13)C for 1,1,1-TCA (25‰) and cis-DCE (-4‰) suggested the occurrence of abiotic degradation in a third sub-section profile. Due to fine scale heterogeneity the identification of active degradation zones in the clay till matrix depended on high resolution subsampling of the clay till cores. The study demonstrates that an integrated approach combining chemical analysis, molecular microbial tools and compound specific isotope analysis (CSIA) was required in order to document biotic and abiotic degradations in the clay till system.


Human resource and funding constraints for essential surgery in district hospitals in Africa: a retrospective cross-sectional survey.
There is a growing recognition that the provision of surgical services in low-income countries is inadequate to the need. While constrained health budgets and health worker shortages have been blamed for the low rates of surgery, there has been little empirical data on the providers of surgery and cost of surgical services in Africa. This study described the range of providers of surgical care and anesthesia and estimated the resources dedicated to surgery at district hospitals in three African countries. We conducted a retrospective cross-sectional survey of data from eight district hospitals in Mozambique, Tanzania, and Uganda. There were no specialist surgeons or anesthetists in any of the hospitals. Most of the health workers were nurses (77.5%), followed by mid-level providers (MLPs) not trained to provide surgical care (7.8%), and MLPs trained to perform surgical procedures (3.8%). There were one to six medical doctors per hospital (4.2% of clinical staff). Most major surgical procedures were performed by doctors (54.6%), however over one-third (35.9%) were done by MLPs. Anesthesia was mainly provided by nurses (39.4%). Most of the hospital expenditure was related to staffing. Of the total operating costs, only 7% to 14% was allocated to surgical care, the majority of which was for obstetric surgery. These costs represent a per capita expenditure on surgery ranging from US$0.05 to US$0.14 between the eight hospitals. African countries have adopted different policies to ensure the provision of surgical care in their respective district hospitals. Overall, the surgical output per capita was very low, reflecting low staffing ratios and limited expenditures for surgery. We found that most surgical and anesthesia services in the three countries in the study were provided by generalist doctors, MLPs, and nurses. Although more information is needed to estimate unmet need for surgery, increasing the funds allocated to surgery, and, in the absence of trained doctors and surgeons, formalizing the training of MLPs appears to be a pragmatic and cost-effective way to make basic surgical services available in underserved areas. Please see later in the article for the Editors' Summary.


Research resource: Comprehensive expression atlas of the fibroblast growth factor system in adult mouse.
Although members of the fibroblast growth factor (FGF) family and their receptors have well-established roles in embryogenesis, their contributions to adult physiology remain relatively unexplored. Here, we use real-time quantitative PCR to determine the mRNA expression patterns of all 22 FGFs, the seven principal FGF receptors (FGFRs), and the three members of the Klotho family of coreceptors in 39 different mouse tissues. Unsupervised hierarchical cluster analysis of the mRNA expression data reveals that most FGFs and FGFRs fall into two groups the expression of which is enriched in either the central nervous system or reproductive and gastrointestinal tissues. Interestingly, the FGFs that can act as endocrine hormones, including FGF15/19, FGF21, and FGF23, cluster in a third group that does not include any FGFRs, underscoring their roles in signaling between tissues. We further show that the most recently identified Klotho family member, Lactase-like, is highly and selectively expressed in brown adipose tissue and eye and can function as an additional coreceptor for FGF19. This FGF atlas provides an important resource for guiding future studies to elucidate the physiological functions of FGFs in adult animals.


Investigations on the aetiology of pinching off syndrome in four white-tailed sea eagles (Haliaeetus albicilla) from Germany.
The purpose of this study was to investigate the aetiology of the pinching off syndrome (POS), a generalized feather abnormality affecting free-living nestling of the white-tailed sea eagle (Haliaeetus albicilla) in Europe. For the first time, extensive clinical, haematological, biochemical, virological, bacteriological, nutritional, histopathological, parasitological and electron microscopical examinations were performed on three females and one male suffering from POS. Early and increased cytokeratin formation at the base of regenerating feathers and their follicle was observed in affected birds. Ultrathin sections of the feather papillae revealed an extended stratum transitivum and a compact, thickened keratinized stratum corneum. The transitional cells in POS feathers contained vacuoles often associated with the nucleus. Lipofuscin accumulations in neurons, glial cells and islet cells of the pancreas were found in all examined birds. It was not clear whether there is an association between the occurrence of lipofuscin and POS. No evidence was found to suggest that infectious agents (parasites, bacteria, fungi or viruses), malnutrition or hormonal imbalances are involved in the aetiology of POS in white-tailed sea eagles. It remains unclear whether there is a genetic background of POS.


Phylogenetic analysis of viral haemorrhagic septicaemia virus (VHSV) isolates from France (1971-1999).
The nucleotide sequences of a specific region of the glycoprotein gene were compared among 63 strains of viral haemorrhagic septicaemia virus (VHSV) isolated from fish in France between 1971 and 1999. The analysis was performed on a region corresponding to amino acids 238 to 331 of the glycoprotein gene, also designated the V2 region and previously shown to accumulate most of the mutations. The sequences of many VHSV isolates were found to be identical or very conserved. An isolate, designated L59X, obtained from elver in the Loire estuary, depicted a higher degree of divergence compared to the other French isolates. The deduced amino-acid sequences were analysed together with the results of neutralisation tests performed using monoclonal antibody 168m4 specific to serotype 1. Non-neutralised VHSV strains had mutations in the region corresponding to the previously described 168m4 epitope. Phylogenetic analysis showed that all the VHSV isolates studied, except L59X, belong to genotype I, previously described as containing VHSV strains isolated from continental Europe. Most of the VHSV isolates studied were found to be genetically related to one of the previously described VHSV strains representative of the major serotypes. Isolate L59X, which was the only French marine strain studied, was found to belong to genotype II, previously shown to encompass the VHSV strains isolated from the British Isles coastal waters. Overall there was a good correlation between the geographical origin of the studied isolates and their genetic characteristics.


Incorporation of web-based applications and online resources in undergraduate medical education in the Irish Republic. Can new changes be incorporated in the current medical curriculum?
Significant change has been happening in the introduction of technology in medical teaching all over the world. We aim to determine if the undergraduate medical students and teachers are open to incorporating changes in the current medical curriculum or if there is a need for the same in the Republic of Ireland. A cross-sectional study involving 202 participants of whom 152 were medical students and 50 medical professionals (teachers and hospital doctors) were carried out involving three different medical universities namely; University College Cork (UCC), University College Dublin (UCD), and National University of Ireland in Galway (NUIG). Participants were requested to answer a series of 15 questions designed incorporating various fields of technology necessary for the study. The data was collected and analyzed using Statistical Package for Social Sciences (SPSS) software to determine statistical significance. The participants overall had a positive attitude toward the utility of modern technology and web-based applications in current medical curriculum. Ninety-one percent of the participants preferred the introduction of modern technology into medical education and 7% were against the idea and a further 2% of them remained undecided. There seems to be a "technology gap" in the current undergraduate medical curriculum in Ireland. A large-scale study involving more participants from all the medical schools in Ireland is recommended. We believe, changes can be brought into the current medical teaching and learning to make the process more fruitful and successful.


Effects of Self-Massage Using a Foam Roller on Ankle Range of Motion and Gastrocnemius Fascicle Length and Muscle Hardness: A Pilot Study.
Several studies have reported that self-massage using a foam roller (FR) increased joint range of motion (ROM) immediately. However, the mechanism of increasing ROM by the FR intervention has not been elucidated. To clarify the mechanism by investigating properties and morphological changes of muscles targeted by the FR intervention. An interventional study. An athletic training laboratory. Ten male college volunteers with no injuries in their lower limbs (mean [SD]: age 23.8 [3.2] y, height 173.2 [4.9] cm, weight 69.5 [8.6] kg). The FR intervention on the right plantar flexors for 3 minutes. Maximum ankle ROM, muscle hardness, and fascicle length of the gastrocnemius muscle at the neutral (0°), maximum dorsiflexion, and maximum plantar flexion positions. All measurements were conducted before (PRE) and after (POST) the FR intervention. Dorsiflexion ROM increased significantly at POST (PRE: 13.6° [8.0°], POST: 16.6° [8.4°]; P < .001), although plantar flexion ROM did not change significantly between PRE and POST (PRE: 40.0° [6.1°], POST: 41.1° [4.9°]). There was no significant difference in muscle hardness and fascicle length between PRE and POST in any of the angles. Dorsiflexion ROM increased significantly by the FR intervention in the present study; however, muscle hardness and fascicle length did not change. FR may affect not only the muscle but also the fascia, tendon, and muscle-tendon unit. The FR protocol of the present study can be applied in clinical situations, because it was found to be effective to increase ROM.


Should weight loss and maintenance programmes be designed differently for men? A systematic review of long-term randomised controlled trials presenting data for men and women: The ROMEO project.
We systematically reviewed the randomised controlled trial (RCT) evidence for long-term (≥12 months) weight management interventions for obese men in contrast to women to help understand whether programmes should be designed differently for men. We searched 11 databases up to October 2014. Twenty-two RCTs reported data separately for men and women in weight loss or weight maintenance interventions. We found men were under-represented in RCTs of weight loss interventions open to both sexes. Men comprised 36% of participants (4771 from 13,305 participants). Despite this, men were 11% (95% CI 8-14%, p<0.001) more likely to be trial completers compared to women. The trials did not report service user consultation and none were designed to investigate whether men and women responded differently to given interventions. Our meta-analysis of 13 trials showed no significant difference in weight loss between men and women, either for weight loss in kg (p=0.90) or percentage weight loss (p=0.78), although men tended to lose more weight with intensive low fat reducing diets, with or without meal replacements, and structured physical activity/exercise programmes than women. Orlistat was less beneficial for men for weight maintenance. Individual support and tailoring appeared more helpful for men than women. We found evidence that men and women respond differently to, and have different preferences for, varying types of weight management programme. We suggest that it is important to understand men's views on weight loss, as this is likely to also improve the uptake and effectiveness of programmes for men.


Multiple intracellular routes in the cross-presentation of a soluble protein by murine dendritic cells.
Soluble heat shock fusion proteins (Hsfp) stimulate mice to produce CD8+ CTL, indicating that these proteins are cross-presented by dendritic cells (DC) to naive CD8 T cells. We report that cross-presentation of these proteins depends upon their binding to DC receptors, likely belonging to the scavenger receptor superfamily. Hsfp entered DC by receptor-mediated endocytosis that was either inhibitable by cytochalasin D or not inhibitable, depending upon aggregation state and time. Most endocytosed Hsfp was transported to lysosomes, but not the small cross-presented fraction that exited early from the endocytic pathway and required access to proteasomes and TAP. Naive CD8 T cell (2C and OT-I) responses to DC incubated with Hsfp at 1 microM were matched by incubating DC with cognate octapeptides at 1-10 pM, indicating that display of very few class I MHC-peptide complexes per DC can be sufficient for cross-presentation. With an Hsfp (heat shock protein-OVA) having peptide sequences for both CD4+ (OT-II) and CD8+ (OT-I) cells, the CD4 cells responded far more vigorously than the CD8 cells and many more class II MHC-peptide than class I MHC-peptide complexes were displayed.


Edentulism and Trajectories of Cognitive Functioning Among Older Adults: The Role of Dental Care Service Utilization.
Objective: This study examined the associations between edentulism, dental care service utilization, and cognitive functioning trajectories among older adults. Method: Longitudinal data from the Health and Retirement Study (2006-2014) were employed to examine individuals aged 51 and older who were identified as having normal cognition at baseline (N = 12,405). Cognitive functioning was measured with a modified version of the Telephone Interview for Cognition Status. Edentulism was self-reported as total tooth loss at baseline. Dental care service utilization was measured by self-report of having visited a dentist at least once during the previous 2 years. Results: The results indicated that edentulism and dental care service utilization were independently associated with cognitive decline during the observation period. Findings also showed that dental care service utilization moderated the association between edentulism and cognitive decline. Discussion: The findings suggested that providing access to dental services may promote cognitive health and potentially reduce health care expenditures.


[Chorionicity and adverse perinatal outcome].
Considering the highest rate of morbidity and mortality in diamniotic monochorionic twins, the authors evaluated and compared the adverse obstetric and perinatal outcome in twin pregnancies according to chorionicity. A retrospective study was conducted in all twin deliveries that occurred in the Obstetric Unit of Maternidade Bissaya-Barreto, for a period of tree years (from the 1st of January 1999 until the 31st of December 2001). From de 140 diamniotic twin pregnancies studied, we considered two groups according to the chorionicity: monochorionic and dichorionic. We compared multiple parameters as, epidemiologic data, adverse obstetric outcome, gestacional delivery age, type of delivery and the morbidity, the mortality and the follow-up of the newborn. The statistic tests used were the X2 and the t student. From the 140 twin pregnancies included in the study, 66% (92 cases) presented dichorionic placentation and 34% (48 cases) were monochorionic. In the group of monochorionic pregnancies, we observed highly difference related to pathology of amniotic fluid (14.5% vs 2.2%), discordant fetal growth (41.6% vs 22.8%) and rate of preterm delivery (66.6% vs 32.6%). Related to the newborn we verified that they had a lower average birth weight (1988g vs 2295g), a highly rate of weight discordancy (23% vs 15.3%), intraventricular haemorrhage (2.2% vs 0%) and IUGR (6.6% vs 1.6%), statistically significant in the monochorionic group. Also the perinatal mortality rate was significantly higher in the monochorionic pregnancies (93.7 per thousand vs 21.7 per thousand). The high rate of morbidity and mortality related to the monochorionic twin pregnancies, implies the need of a correct identification of the type of chorionicity and also a high standard of prenatal surveillance in prenatal specialised health centers.


The analgesic effect of odour and music upon dressing change.
Vascular wounds may require frequent dressing changes over a long period of time, often involving pain, which may not be adequately controlled with conventional analgesia. Complementary analgesia may be beneficial as an adjunctive therapy. This pilot study presented eight patients with two odour therapies, lavender and lemon, two music therapies, relaxing and preferred music and a control condition, during vascular wound dressing changes. Although the therapies did not reduce the pain intensity during the dressing change there was a significant reduction in pain intensity for the lavender therapy and a reduction in pain intensity for the relaxing music therapy after the dressing change. This supports the use of these complementary therapies, which are inexpensive, easy to administer and have no known side effects, as adjunctive analgesia in this patient population. Earlier administration before dressing change may enhance these effects. Further research is required to ascertain why certain complementary therapies are more effective than others at relieving pain.


PrP(C) expression in the peripheral nervous system is a determinant of prion neuroinvasion.
Transmissible spongiform encephalopathies are often propagated by extracerebral inoculation. The mechanism of spread from peripheral portals of entry to the central nervous system (neuroinvasion) is complex: while lymphatic organs typically show early accumulation of prions, and B-cells and follicular dendritic cells are required for efficient neuroinvasion, actual entry into the central nervous system occurs probably via peripheral nerves and may utilize a PrP(C)-dependent mechanism. This study shows that transgenic mice overexpressing PrP(C) undergo rapid and efficient neuroinvasion upon intranerval and footpad inoculation of prions. These mice exhibited deposition of the pathological isoform of the prion protein (PrP(Sc)) and infectivity in specific portions of the central and peripheral sensory pathways, but almost no splenic PrP(Sc) accumulation. In contrast, wild-type mice always accumulated splenic PrP(Sc), and had widespread deposition of PrP(Sc) throughout the central nervous system even when prions were injected directly into the sciatic nerve. These results indicate that a lympho-neural sequence of spread occurs in wild-type mice even upon intranerval inoculation, while overexpression of PrP(C) leads to substantial predilection of intranerval over lymphoreticular spread. The rate of transport of infectivity in peripheral nerves was ca. 0.7 mm per day, and prion infectivity titres of sciatic nerves were much higher in tga20 than in wild-type mice, suggesting that overexpression of PrP(C) modulates the capacity for intranerval transport.


Diffusion-Weighted Imaging for Pretreatment Evaluation and Prediction of Treatment Effect in Patients Undergoing CT-Guided Injection for Lumbar Disc Herniation.
To determine whether a change in apparent diffusion coefficient (ADC) value could predict early response to CT-guided Oxygen-Ozone (O2-O3) injection therapy in patients with unilateral mono-radiculopathy due to lumbar disc herniation. A total of 52 patients with unilateral mono-radiculopathy received a single intradiscal (3 mL) and periganglionic (5 mL) injection of an O2-O3 mixture. An ADC index of the involved side to the intact side was calculated using the following formula: pre-treatment ADC index = ([ADC involved side - ADC intact side] / ADC intact side) × 100. We analyzed the relationship between the pre-treatment Oswestry Disability Index (ODI) and the ADC index. In addition, the correlation between ODI recovery ratio and ADC index was investigated. The sensitivity and specificity of the ADC index for predicting response in O2-O3 therapy was determined. Oswestry Disability Index and the ADC index was not significantly correlated (r = -0.125, p = 0.093). The ADC index and ODI recovery ratio was significantly correlated (r = 0.819, p < 0.001). When using 7.10 as the cut-off value, the ADC index obtained a sensitivity of 86.3% and a specificity of 82.9% for predicting successful response to therapy around the first month of follow-up. This preliminary study demonstrates that the patients with decreased ADC index tend to show poor improvement of clinical symptoms. The ADC index may be a useful indicator to predict early response to CT-guided O2-O3 injection therapy in patients with unilateral mono-radiculopathy due to lumbar disc herniation.


Multidetector computed tomography myocardial perfusion imaging during adenosine stress.
The purpose of this study is to validate the accuracy of multidetector computed tomography (MDCT) to measure differences in regional myocardial perfusion during adenosine stress in a canine model of left anterior descending (LAD) artery stenosis, during first-pass, contrast-enhanced helical MDCT. Myocardial perfusion imaging by MDCT may have significant implications in the diagnosis and treatment of coronary artery disease. Eight dogs were prepared with a LAD stenosis, and contrast-enhanced MDCT imaging was performed 5 min into adenosine infusion (0.14 to 0.21 mg/kg/min). Images were analyzed using a semiautomated approach to define the regional signal density (SD) ratio (myocardial SD/left ventricular blood pool SD) in stenosed and remote territories, and then compared with microsphere myocardial blood flow (MBF) measurements. Mean MBF in stenosed versus remote territories was 1.37 +/- 0.46 ml/g/min and 1.29 +/- 0.48 ml/g/min at baseline (p = NS) and 2.54 +/- 0.93 ml/g/min and 8.94 +/- 5.74 ml/g/min during adenosine infusion, respectively (p < 0.05). Myocardial SD was 92.3 +/- 39.5 HU in stenosed versus 180.4 +/- 41.9 HU in remote territories (p < 0.001). There was a significant linear association of the SD ratio with MBF in the stenosed territory (R = 0.98, p = 0.001) and between regional myocardial SD ratio and MBF <8 ml/g/min, slope = 0.035, SE = 0.007, p < 0.0001. Overall, there was a significant non-linear relationship over the range of flows studied (LR chi-square [2 degrees of freedom] = 31.8, p < 0.0001). Adenosine-augmented MDCT myocardial perfusion imaging provides semiquantitative measurements of myocardial perfusion during first-pass MDCT imaging in a canine model of LAD stenosis.


Prospective audit comparing ambulatory day surgery with inpatient surgery for treating cataracts.
To compare the cost effectiveness and safety of inpatient cataract surgery (with one night in hospital postoperatively) with ambulatory day case surgery under local anaesthesia. Prospective study of patients receiving inpatient (group 1) or day case (group 2) surgery. One ophthalmic surgical firm. 100 patients in each group, excluding those with coexisting ocular conditions, contraindications to local or request for general anaesthesia, ill health, or lack of agreed minimum social care; four patients died during follow up. Envelope method and implantation of the posterior chamber lens into the capsular sac in both groups. Perioperative complications, operating and turnover times, visual outcome at three to six days and 10 weeks to six months after operation, patient satisfaction (according to self administered questionnaire) at three to six days, and total costs (1989 salaries) for both groups. Patients in both groups did not differ significantly in age or sex, perioperative complications, visual outcome (6/9 or better in 78 patients in group 1 and 75 in group 2 at one month after operation and 6/12 or better in 92/98 in group 1, 90/98 in group 2 at final follow up), or patient satisfaction. The mean total cost per patient for group 1 patients was 365.99 pounds and for group 2, 221.62 pounds. Day case surgery for cataract is safe and more cost effective. Day case surgery should be recommended to increase availability of cataract surgery and thereby improve quality of life for more patients.