Compact tomato seedlings and plants upon overexpression of a tomato chromatin remodelling ATPase gene.
Control of plant growth is an important aspect of crop productivity and yield in agriculture. Overexpression of the AtCHR12/23 genes in Arabidopsis thaliana reduced growth habit without other morphological changes. These two genes encode Snf2 chromatin remodelling ATPases. Here, we translate this approach to the horticultural crop tomato (Solanum lycopersicum). We identified and cloned the single tomato ortholog of the two Arabidopsis Snf2 genes, designated SlCHR1. Transgenic tomato plants (cv. Micro-Tom) that constitutively overexpress the coding sequence of SlCHR1 show reduced growth in all developmental stages of tomato. This confirms that SlCHR1 combines the functions of both Arabidopsis genes in tomato. Compared to the wild type, the transgenic seedlings of tomato have significantly shorter roots, hypocotyls and reduced cotyledon size. Transgenic plants have a much more compact growth habit with markedly reduced plant height, severely compacted reproductive structures with smaller flowers and smaller fruits. The results indicate that either GMO-based or non-GMO-based approaches to modulate the expression of chromatin remodelling ATPase genes could develop into methods to control plant growth, for example to replace the use of chemical growth retardants. This approach is likely to be applicable and attractive for any crop for which growth habit reduction has added value.


Protective Effect of Procyanidin B2 on Acute Liver Injury Induced by Aflatoxin B 1 in Rats.
This study aimed to explore the protective effect of procyanidin B2 (PCB2) on acute liver injury induced by aflatoxin B 1 (AFB 1) in rats. Forty Sprague Dawley rats were randomly divided into control, AFB 1, AFB 1 + PCB2, and PCB2 groups. The latter two groups were administrated PCB2 intragastrically (30 mg/kg body weight) for 7 d, whereas the control and AFB 1 groups were given the same dose of double distilled water intragastrically. On the sixth day of treatment, the AFB 1 and AFB 1 + PCB2 groups were intraperitoneally injected with AFB 1 (2 mg/kg). The control and PCB2 groups were intraperitoneally administered the same dose of dimethyl sulfoxide (DMSO). On the eighth day, all rats were euthanized: serum and liver tissue were isolated for further examination. Hepatic histological features were assessed by hematoxylin and eosin-stained sections. Weight, organ coefficient (liver, spleen, and kidney), liver function (serum alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, total bilirubin, and direct bilirubin), oxidative index (catalase, glutathione, superoxide dismutase, malondialdehyde, and 8-hydroxy-2'-deoxyguanosine), inflammation factor [hepatic interleukin-6 (IL-6) mRNA expression and serum IL-6], and bcl-2/bax ratio were measured. AFB 1 significantly caused hepatic histopathological damage, abnormal liver function, oxidative stress, inflammation, and bcl-2/bax ratio reduction compared with DMSO-treated controls. Our results indicate that PCB2 treatment can partially reverse the adverse liver conditions induced by AFB 1. Our findings indicate that PCB2 exhibits a protective effect on acute liver injury induced by AFB 1.


Measuring Frailty Can Help Emergency Departments Identify Independent Seniors at Risk of Functional Decline After Minor Injuries.
This study aims to (i) describe frailty in the subgroup of independent community-dwelling seniors consulting emergency departments (EDs) for minor injuries, (ii) examine the association between frailty and functional decline 3 months postinjury, (iii) ascertain the predictive accuracy of frailty measures and emergency physicians' for functional decline. Prospective cohort in 2011-2013 among 1,072 seniors aged 65 years or older, independent in basic daily activities, evaluated in Canadian EDs for minor injuries.Frailty was assessed at EDs using the Canadian Study of Health and Aging-Clinical Frailty scale (CSHA-CFS) and the Study of Osteoporotic Fracture frailty index (SOF). Functional decline was defined as a loss ≥2/28 on the Older American Resources Services scale 3 months postinjury. Generalized mixed models were used to explore differences in functional decline across frailty levels. Areas under the receiver operating characteristic curve were used to ascertain the predictive accuracy of frailty measures and emergency physicians' clinical judgment. The SOF and CSHA-CFS were available in 342 and 1,058 participants, respectively. The SOF identified 55.6%, 32.7%, 11.7% patients as robust, prefrail, and frail. These CSHA-CFS (n = 1,058) proportions were 51.9%, 38.3%, and 9.9%. The 3-month incidence of functional decline was 12.1% (10.0%-14.6%). The Areas under the receiver operating characteristic curves of the CSHA-CFS and the emergency physicians' were similar (0.548-0.777), while the SOF was somewhat higher (0.704-0.859). Measuring frailty in community-dwelling seniors with minor injuries in EDs may enhance current risk screening for functional decline. However, before implementation in usual care, feasibility issues such as inter-rater reliability and acceptability of frailty tools in the EDs have to be addressed.


Smooth muscle gap-junctions allow propagation of intercellular Ca2+ waves and vasoconstriction due to Ca2+ based action potentials in rat mesenteric resistance arteries.
The role of vascular gap junctions in the conduction of intercellular Ca2+ and vasoconstriction along small resistance arteries is not entirely understood. Some depolarizing agents trigger conducted vasoconstriction while others only evoke a local depolarization. Here we use a novel technique to investigate the temporal and spatial relationship between intercellular Ca2+ signals generated by smooth muscle action potentials (APs) and vasoconstriction in mesenteric resistance arteries (MA). Pulses of exogenous KCl to depolarize the downstream end (T1) of a 3 mm long artery increased intracellular Ca2+ associated with vasoconstriction. The spatial spread and amplitude of both depended on the duration of the pulse, with only a restricted non-conducting vasoconstriction to a 1 s pulse. While blocking smooth muscle cell (SMC) K+ channels with TEA and activating L-type voltage-gated Ca2+ channels (VGCCs) with BayK 8644 spread was dramatically facilitated, so the 1 s pulse evoked intercellular Ca2+ waves and vasoconstriction that spread along an entire artery segment 3000 μm long. Ca2+ waves spread as nifedipine-sensitive Ca2+ spikes due to SMC action potentials, and evoked vasoconstriction. Both intercellular Ca2+ and vasoconstriction spread at circa 3 mm s-1 and were independent of the endothelium. The spread but not the generation of Ca2+ spikes was reversibly blocked by the gap junction inhibitor 18β-GA. Thus, smooth muscle gap junctions enable depolarization to spread along resistance arteries, and once regenerative Ca2+-based APs occur, spread along the entire length of an artery followed by widespread vasoconstriction.


Viewpoints of fertile women on gestational surrogacy in East Azerbaijan Province, Iran.
The aim of this descriptive, cross-sectional study was to investigate the viewpoint of fertile Iranian women on gestational surrogacy. A convenience sample of 230 fertile women was invited to participate in the study and 185 consented. Data were collected via a 22-item scale that assessed the viewpoints of the participants in five domains related to gestational surrogacy. The viewpoints reported by the women were positive. However, a significant percentage of them believed that commissioning couples are not the biological owners of the baby, religious barriers need to be overcome prior to legal barriers, children born through surrogacy may face emotional issues, and the adoption of children may be a better option than surrogacy. The negative views of the women on some key aspects make it clear that public education is needed to increase the acceptability of gestational surrogacy.


A study of the dermo-epidermal junction in dystrophic epidermolysis bullosa using the periodic acid-thiosemicarbazide-silver proteinate technique.
Dermo-epidermal separation in dystrophic epidermolysis bullosa (DEB) is thought to results from an abnormality of anchoring fibrils which, in normal skin, are stained selectively by the periodic acid-thiosemicarbazide-silver proteinate technique. This method was applied to non-lesional skin from four patients with generalized recessive DEB, five with localized recessive DEB and one with dominant DEB. No anchoring fibrils were present in the subjects with generalized recessive DEB, but they were morphologically normal in the case of dominant DEB and in three patients with mild localized recessive DEB. Two patients with a more severe form of localized recessive DEB possessed attenuated anchoring fibrils which lacked the normal banding of the mid-portion. The lamina densa, normally unlabelled, was consistently stained in patients with generalized recessive DEB, suggesting a biochemical abnormality of this structure.


Correlates of certification in family medicine in the billing patterns of Ontario general practitioners.
There is conflicting evidence as to whether physicians who are certified in family medicine practise differently from their noncertified colleagues and what those differences are. We examined the extent to which certification in family medicine is associated with differences in the practice patterns of primary care physicians as reflected in their billing patterns. Billing data for 1986 were obtained from the Ontario Health Insurance Plan for 269 certified physicians and 375 noncertified physicians who had graduated from Ontario medical schools between 1972 and 1983 and who practised as general practitioners or family physicians in Ontario. As a group, certificants provided fewer services per patient and billed less per patient seen per month. They were more likely than noncertificants to include counselling, psychotherapy, prenatal and obstetric care, nonemergency hospital visits, surgical services and visits to chronic care facilities in their service mix and to bill in more service categories. Certificants billed more for prenatal and obstetric care, intermediate assessments, chronic care and nonemergency hospital visits and less for psychotherapy and after-hours services than noncertificants. Many of the differences detected suggest a practice style consistent with the objectives for training and certification in family medicine. However, whether the differences observed in our study and in previous studies are related more to self-selection of physicians for certification or to the types of educational experiences cannot be directly assessed.


Molecular breeding of thermo-sensitive genic male sterile (TGMS) lines of rice for blast resistance using Pi2 gene.
Blast disease caused by the fungal pathogen Magnaporthe oryzae is one of the big problems in rice production in China, especially for high yield hybrid varieties made from a two-line system in which thermo-sensitive genic male sterile (TGMS) lines are used. In this study, we report the introgression of a rice blast resistance gene Pi2 from VE6219 into C815S, an elite rice TGMS line, leading to the development of blast resistant TGMS lines through marker assisted selection (MAS) and phenotypic selection approaches. Four new TGMS lines with blast resistance gene Pi2 were developed from C815S (an elite TGMS line susceptible to the blast, used as recurrent parent) and VE6219 (a blast resistant line harboring Pi2, used as donor parent). The pathogenicity assays inoculated with 53 blast prevalent isolates in glasshouse showed that the blast resistant frequency of the four TGMS lines was 94.3%-98.1% that is equivalent to blast resistant donor parent VE6219. The field evaluation of the new lines and hybrids made from them at a blast epidemic site also showed high resistant levels against the blast. The genetic background of the newly developed TGMS lines were examined using a whole-genome single nucleotide polymorphism (SNP) array (RICE6K) that turned out more than 83% of the genomic markers were derived from the recurrent parent. The critical temperature points of fertility-sterility alteration of the new TGMS lines were between 22°C and 23°C of daily mean temperature, which is similar to that of C815S. The complete male sterility under natural growth conditions at Wuhan last more than 80 days. Their agronomic and grain quality traits meet the requirement for two-line hybrid rice production. The broad-spectrum and durable rice blast resistant gene Pi2 was introgressed into the elite TGMS line C815S background. The newly developed TGMS lines can be practically used for two-line hybrid rice breeding and must play an important role in sustainable rice production in China.


The Interplay between Wnt Mediated Expansion and Negative Regulation of Growth Promotes Robust Intestinal Crypt Structure and Homeostasis.
The epithelium of the small intestinal crypt, which has a vital role in protecting the underlying tissue from the harsh intestinal environment, is completely renewed every 4-5 days by a small pool of stem cells at the base of each crypt. How is this renewal controlled and homeostasis maintained, particularly given the rapid nature of this process? Here, based on the recent observations from in vitro "mini gut" studies, we use a hybrid stochastic model of the crypt to investigate how exogenous niche signaling (from Wnt and BMP) combines with auto-regulation to promote homeostasis. This model builds on the sub-cellular element method to account for the three-dimensional structure of the crypt, external regulation by Wnt and BMP, internal regulation by Notch signaling, as well as regulation by internally generated diffusible signals. Results show that Paneth cell derived Wnt signals, which have been observed experimentally to sustain crypts in cultured organs, have a dramatically different influence on niche dynamics than does mesenchyme derived Wnt. While this signaling can indeed act as a redundant backup to the exogenous gradient, it introduces a positive feedback that destabilizes the niche and causes its uncontrolled expansion. We find that in this setting, BMP has a critical role in constraining this expansion, consistent with observations that its removal leads to crypt fission. Further results also point to a new hypothesis for the role of Ephrin mediated motility of Paneth cells, specifically that it is required to constrain niche expansion and maintain the crypt's spatial structure. Combined, these provide an alternative view of crypt homeostasis where the niche is in a constant state of expansion and the spatial structure of the crypt arises as a balance between this expansion and the action of various sources of negative regulation that hold it in check.


Effect of constant-release implants of melatonin on seasonal cycles in reproduction, prolactin secretion and moulting in rams.
Seasonal cycles in the size of the testes, blood plasma concentration of testosterone, FSH and prolactin, intensity of the sexual skin flush, timing of rutting behaviour and moulting of the body coat were recorded in Soay rams after s.c. implantation of melatonin contained in a Silastic envelope which increased the circulating blood levels of melatonin to 200-600 pg/ml for many months. Two groups of 8 adult rams were held under alternating periods of short days (8L:16D) and long days (16L:8D) to drive the seasonal cycles and the treatments with melatonin were initiated during the long or short days, and one group of 8 ram lambs was kept out of doors and given implants during the long days of summer (4 melatonin-implanted and 4 control (empty implants) rams per group). The treatments demonstrated that melatonin implants during exposure to long days resulted in a rapid 'switch on' of reproductive redevelopment similar to that produced by exposure to short days melatonin implants prevented the rams from showing the normal responses to changes in the prevailing photoperiod rendering them nonphotoperiodic; and long-term cyclic changes in testicular activity, prolactin secretion and other characteristics occurred in the melatonin-implanted rams; the pattern was similar to that previously observed in rams exposed to prolonged periods of short days. The overall results are consistent with the view that melatonin is the physiological hormone that relays the effects of changing photoperiod on reproduction and other seasonal features, and that continuous exogenous melatonin from an implant interferes with the normal 'signal' and produces an over-riding short-day response.


PLS/OPLS models in metabolomics: the impact of permutation of dataset rows on the K-fold cross-validation quality parameters.
Among all the software packages available for discriminant analyses based on projection to latent structures (PLS-DA) or orthogonal projection to latent structures (OPLS-DA), SIMCA (Umetrics, Umeå Sweden) is the more widely used in the metabolomics field. SIMCA proposes many parameters or tests to assess the quality of the computed model (the number of significant components, R2, Q2, pCV-ANOVA, and the permutation test). Significance thresholds for these parameters are strongly application-dependent. Concerning the Q2 parameter, a significance threshold of 0.5 is generally admitted. However, during the last few years, many PLS-DA/OPLS-DA models built using SIMCA have been published with Q2 values lower than 0.5. The purpose of this opinion note is to point out that, in some circumstances frequently encountered in metabolomics, the values of these parameters strongly depend on the individuals that constitute the validation subsets. As a result of the way in which the software selects members of the calibration and validation subsets, a simple permutation of dataset rows can, in several cases, lead to contradictory conclusions about the significance of the models when a K-fold cross-validation is used. We believe that, when Q2 values lower than 0.5 are obtained, SIMCA users should at least verify that the quality parameters are stable towards permutation of the rows in their dataset.


A lumped parameter model of cerebral blood flow control combining cerebral autoregulation and neurovascular coupling.
Cerebral blood flow regulation is based on a variety of different mechanisms, of which the relative regulatory role remains largely unknown. The cerebral regulatory system expresses two regulatory properties: cerebral autoregulation and neurovascular coupling. Since partly the same mechanisms play a role in cerebral autoregulation and neurovascular coupling, this study aimed to develop a physiologically based mathematical model of cerebral blood flow regulation combining these properties. A lumped parameter model of the P2 segment of the posterior cerebral artery and its distal vessels was constructed. Blood flow regulation is exerted at the arteriolar level by vascular smooth muscle and implements myogenic, shear stress based, neurogenic, and metabolic mechanisms. In eight healthy subjects, cerebral autoregulation and neurovascular coupling were challenged by squat-stand maneuvers and visual stimulation using a checkerboard pattern, respectively. Cerebral blood flow velocity was measured using transcranial Doppler, whereas blood pressure was measured by finger volume clamping. In seven subjects, the model proposed fits autoregulation and neurovascular coupling measurement data well. Myogenic regulation is found to dominate the autoregulatory response. Neurogenic regulation, although only implemented as a first-order mechanism, describes neurovascular coupling responses to a great extent. It is concluded that our single, integrated model of cerebral blood flow control may be used to identify the main mechanisms affecting cerebral blood flow regulation in individual subjects.


Quantitative Evaluation of Rabbit Brain Injury after Cerebral Hemisphere Radiation Exposure Using Generalized q-Sampling Imaging.
Radiation therapy is widely used for the treatment of brain tumors and may result in cellular, vascular and axonal injury and further behavioral deficits. The non-invasive longitudinal imaging assessment of brain injury caused by radiation therapy is important for determining patient prognoses. Several rodent studies have been performed using magnetic resonance imaging (MRI), but further studies in rabbits and large mammals with advanced magnetic resonance (MR) techniques are needed. Previously, we used diffusion tensor imaging (DTI) to evaluate radiation-induced rabbit brain injury. However, DTI is unable to resolve the complicated neural structure changes that are frequently observed during brain injury after radiation exposure. Generalized q-sampling imaging (GQI) is a more accurate and sophisticated diffusion MR approach that can extract additional information about the altered diffusion environments. Therefore, herein, a longitudinal study was performed that used GQI indices, including generalized fractional anisotropy (GFA), quantitative anisotropy (QA), and the isotropic value (ISO) of the orientation distribution function and DTI indices, including fractional anisotropy (FA) and mean diffusivity (MD) over a period of approximately half a year to observe long-term, radiation-induced changes in the different brain compartments of a rabbit model after a hemi-brain single dose (30 Gy) radiation exposure. We revealed that in the external capsule, the GFA right to left (R/L) ratio showed similar trends as the FA R/L ratio, but no clear trends in the remaining three brain compartments. Both the QA and ISO R/L ratios showed similar trends in the all four different compartments during the acute to early delayed post-irradiation phase, which could be explained and reflected the histopathological changes of the complicated dynamic interactions among astrogliosis, demyelination and vasogenic edema. We suggest that GQI is a promising non-invasive technique and as compared with DTI, it has better potential ability in detecting and monitoring the pathophysiological cascades in acute to early delayed radiation-induced brain injury by using clinical MR scanners.


Detrimental Role of miRNA-144-3p in Intracerebral Hemorrhage Induced Secondary Brain Injury is Mediated by Formyl Peptide Receptor 2 Downregulation Both In Vivo and In Vitro.
Although microRNA-144-3p (miRNA-144-3p) has been shown to suppress tumor proliferation and invasion, its function in intracerebral hemorrhage (ICH)-induced secondary brain injury (SBI) remains unclear. Thus, this study was designed to investigate the role of miRNA-144-3p in ICH. To accomplish this, we used adult male Sprague-Dawley rats to establish an in vivo ICH model by injecting autologous blood, while cultured primary rat cortical neurons were exposed to oxyhemoglobin (OxyHb) to mimic ICH in vitro. To examine the role of miRNA-144-3p in ICH-induced SBI, we used an miRNA-144-3p mimic and inhibitor both in vivo and in vitro. Following ICH induction, we found miRNA-144-3p expression to increase. Additionally, we predicted the formyl peptide receptor 2 (FPR2) to be a potential miRNA-144-3p target, which we validated experimentally, with FPR2 expression downregulated when miRNA-144-3p was upregulated. Furthermore, elevated miRNA-144-3p levels aggravated brain edema and neurobehavioral disorders and induced neuronal apoptosis via the downregulation of FPR2 both in vivo and in vitro. We suspected that these beneficial effects provided by FPR2 were associated with the PI3K/AKT pathway. We validated this finding by overexpressing FPR2 while inhibiting PI3K/AKT in vitro and in vivo. In conclusion, miRNA-144-3p aggravated ICH-induced SBI by targeting and downregulating FPR2, thereby contributing to neurological dysfunction and neural apoptosis via PI3K/AKT pathway activation. These findings suggest that inhibiting miRNA-144-3p may offer an effective approach to attenuating brain damage incurred after ICH and a potential therapy to improve ICH-induced SBI.


[Molecular diagnosis as a strategy for differential diagnosis and at early ages of neurofibromatosis type 1 (NF1)].
Neurofibromatosis type 1 (NF1), is a haploinsufficient and multisystemic disease, caused by inherited or sporadic mutations in the NF1 gene. Its incidence is one in 2,500 to 3,000 individuals, it has an autosomal dominant pattern of inheritance, high clinical variability, complete penetrance and age-dependent complications. Neurofibromin is the product of the NF1 gene and is believed to act as a tumor suppressor since the loss of its function has been associated with benign and malignant tumors in neural crest-derived tissues. Only two correlations between clinical phenotype and mutant alleles in the NF1 gene have been observed. The established criteria for disease diagnosis are very efficient in adults and children older than 3 years of age, but not for children under this age. Mutational analysis is therefore recommended to confirm the disease in young children with a negative family history. A pathogenic mutation in the NF1 should be added to the list of diagnostic criteria. Mutational analysis is also recommended for differential diagnosis and for prenatal or pre-implantation genetic diagnosis, taking into consideration the family history and the type of method to be applied. Molecular studies of this disease using different complimentary molecular techniques and bioinformatics tools have characterized NF1 gene mutations at both the DNA and mRNA levels, increasing the mutational spectrum. Consequently, about 1,289 defects have been reported to date, mainly nonsense/missense mutations, deletions and splice site defects.


Murine T cell determination of pregnancy outcome: I. Effects of strain, alphabeta T cell receptor, gammadelta T cell receptor, and gammadelta T cell subsets.
T cells bearing alphabeta T cell receptor (TcR) and gammadelta TcR are present at the fetomaternal interface, and the latter, which express surface activation markers, can react with fetal trophoblast cell antigens. What is the role of these cells? Using stress-abortion-prone DBA/2-mated CBA/J and abortion-resistant C57/B16 mice, alphabeta, gammadelta, and CD8+/- T cell subsets were measured in spleen and uterine decidua. The effect of immunization against abortion and administration of anti-TcR antibody in vivo was examined. Cytokine synthesis was measured by intracellular staining of Brefeldin A-treated cells. Abortion-prone matings showed an unexpected accumulation of gammadelta T cells beginning in the peri-implantation period and this was suppressed by immunization against abortion. The immunization deleted gammadelta T cells producing the abortogenic cytokines, TNF-alpha and gamma-interferon, and increased production of the anti-abortive cytokines, IL-10 and transforming growth factor-beta2 (TGF-beta2). Immunization also boosted the number of alphabeta T cells which were present in the decidua as early as 2 days after implantation. In vivo injection of GL4 (anti-delta) depleted gammadelta T cells producing Th1 cytokines in the peri-implantation period, and prevented abortions, whereas H57 (anti-beta) decreased the number of alphabeta T cells and led to 100% abortions. CD8+ T cells present in peri-implant decidua before onset of abortions were mostly alphabeta TcR+, although some were gammadelta+. Changes in gammadelta and alphabeta T cells in pregnancy were most dramatic in uterine tissue. Although decidual gammadelta T cells after formation of a distinct placenta and fetus produce anti-abortive TGF-beta2-like molecules and IL-10, prior events can lead to abortion. High local production of TNF-alpha and gamma-interferon develop during the peri-implantation phase because of an excessive increase in the Th1 cytokine+ subset of gammadelta cells; these cytokines may be contributed by other tissues in decidua, and the contribution of bioactive factors by gammadelta T cells may augment the cytokine pool. In contrast, alphabeta T cells (which may be inactivated by stress that causes abortions) may mediate the anti-abortive effect of alloimmunization. Alloimmunization involves a shift from a Th1 to a Th2 pattern in the gammadelta T cells in decidua.


Roquin binds microRNA-146a and Argonaute2 to regulate microRNA homeostasis.
Roquin is an RNA-binding protein that prevents autoimmunity and inflammation via repression of bound target mRNAs such as inducible costimulator (Icos). When Roquin is absent or mutated (Roquin(san)), Icos is overexpressed in T cells. Here we show that Roquin enhances Dicer-mediated processing of pre-miR-146a. Roquin also directly binds Argonaute2, a central component of the RNA-induced silencing complex, and miR-146a, a microRNA that targets Icos mRNA. In the absence of functional Roquin, miR-146a accumulates in T cells. Its accumulation is not due to increased transcription or processing, rather due to enhanced stability of mature miR-146a. This is associated with decreased 3' end uridylation of the miRNA. Crystallographic studies reveal that Roquin contains a unique HEPN domain and identify the structural basis of the 'san' mutation and Roquin's ability to bind multiple RNAs. Roquin emerges as a protein that can bind Ago2, miRNAs and target mRNAs, to control homeostasis of both RNA species.


Utilization of Diagnostic Testing for Renal Anomalies and Congenital Heart Disease in Patients with Microtia.
Congenital ear anomalies are associated with congenital cardiac and renal defects. Renal ultrasounds, electrocardiogram, and echocardiogram can be utilized for diagnosis of these concurrent defects. No standard of care exists for the workup of patients with microtia. The goals of this study were to describe the utilization of diagnostic testing for cardiac and renal anomalies and to identify their prevalence in patients with microtia. Case series with chart review. Children's Hospital of Pittsburgh of the University of Pittsburgh Medical Center. This study is an Institutional Review Board-approved retrospective review of consecutive patients born between 2002 and 2016 who were diagnosed with microtia and seen in the otolaryngology clinic at a tertiary care children's hospital. Demographics, sidedness and grade of microtia, comorbid diagnoses, and details of renal and cardiovascular evaluations were recorded. Factors associated with retroperitoneal ultrasound and cardiac testing were assessed with logistic regression. Microtia was present in 102 patients, and 98 patients were included as they received follow-up. Microtia was associated with craniofacial syndrome in 34.7% of patients. Renal ultrasound was performed in 64.3% of patients, and 12.9% of patients with ultrasounds had renal aplasia. Cardiac workup (electrocardiogram or echocardiogram) was completed in 60.2% of patients, and of this subset, 54.2% had a congenital heart defect. Diagnostic testing revealed renal anomalies and cardiac defects in patients with isolated microtia at a higher rate than in the general population. This suggests the need for further evaluation of the role of routine screening in patients with microtia.


The inhibition of free radical generation by preparations of Harpagophytum procumbens in vitro.
Harpagophytum procumbens (Hp), commonly known as Devil's Claw has been used as a traditional treatment for a variety of illnesses for centuries. Since the early twentieth century, it has become a popular antiinflammatory and analgesic preparation amongst European herbalists for supportive or adjuvant treatment of degenerative joint diseases. Extracts of Hp tubers have demonstrated antiinflammatory and analgesic effects in animal models of inflammation and in human trials. The mechanism(s) of action responsible for these attributes, however, remain to be elucidated. Reactive oxygen species generated in acute and chronic inflammatory diseases are known to be cytotoxic and can cause tissue damage. In this study, a root tuber extract (Hp extract) and commercially available tincture (Hp tincture) were investigated for antioxidant characteristics using in vitro test systems. Both preparations were found to effectively scavenge DPPH radical, inhibit nitrite levels in supernatants harvested from LPS-stimulated RAW 264.7 macrophages, and cause dose-dependent suppressions in the detection of fMLP- and AA-induced neutrophil MPO. The antioxidant effects demonstrated for both preparations of Hp may contribute to the antiinflammatory and analgesic properties observed for the plant.


Detection of a novel mutation in the CACNA1A gene.
Familial hemiplegic migraine (FHM) is a rare autosomal dominant subtype of migraine with aura. It is divided into three subtypes FHM1, FHM2 and FHM3, which are caused by mutations in the CACNA1A, ATP1A2 and SCN1A genes respectively. As part of a regular diagnostic service, we investigated 168 patients with FHM symptoms. Samples were tested for mutations contained within the CACNA1A gene. Some tested samples (4.43%) showed an FHM1 mutation, with five of the mutations found in exon 5, one mutation in exon 16 and one in exon 17. Four polymorphisms were also detected, one of which occurred in a large percentage of samples (14.88%). The exon 16 2094G>A polymorphism, however, has been found to occur in healthy Caucasian control populations up to a frequency of 16% and is not considered to be significantly associated with FHM. A finding of significance, found in a single patient, was the detection of a novel mutation in exon 5 that results in a P225H change. The affected individual was an 8-year-old female. The exact phenotypic effect of this mutation is unknown, and further studies are needed to understand the pathophysiology of this mutation in FHM1. New information will allow for diagnostic procedures to be constantly updated, thus improving accuracy of diagnosis. It is possible that new information will also aid the development of new therapeutic agents for the treatment of FHM.


Does smooth muscle in an intact airway undergo length adaptation during a sustained change in transmural pressure?
In isolated airway smooth muscle (ASM) strips, an increase or decrease in ASM length away from its current optimum length causes an immediate reduction in force production followed by a gradual time-dependent recovery in force, a phenomenon termed length adaptation. In situ, length adaptation may be initiated by a change in transmural pressure (Ptm), which is a primary physiological determinant of ASM length. The present study sought to determine the effect of sustained changes in Ptm and therefore, ASM perimeter, on airway function. We measured contractile responses in whole porcine bronchial segments in vitro before and after a sustained inflation from a baseline Ptm of 5 cmH2O to 25 cmH2O, or deflation to -5 cmH2O, for ∼50 min in each case. In one group of airways, lumen narrowing and stiffening in response to electrical field stimulation (EFS) were assessed from volume and pressure signals using a servo-controlled syringe pump with pressure feedback. In a second group of airways, lumen narrowing and the perimeter of the ASM in situ were determined by anatomical optical coherence tomography. In a third group of airways, active tension was determined under isovolumic conditions. Both inflation and deflation reduced the contractile response to EFS. Sustained Ptm change resulted in a further decrease in contractile response, which returned to baseline levels upon return to the baseline Ptm. These findings reaffirm the importance of Ptm in regulating airway narrowing. However, they do not support a role for ASM length adaptation in situ under physiological levels of ASM lengthening and shortening.


Predicting protein-protein interactions from protein domains using a set cover approach.
One goal of contemporary proteome research is the elucidation of cellular protein interactions. Based on currently available protein-protein interaction and domain data, we introduce a novel method, Maximum Specificity Set Cover (MSSC), for the prediction of protein-protein interactions. In our approach, we map the relationship between interactions of proteins and their corresponding domain architectures to a generalized weighted set cover problem. The application of a greedy algorithm provides sets of domain interactions which explain the presence of protein interactions to the largest degree of specificity. Utilizing domain and protein interaction data of S. cerevisiae, MSSC enables prediction of previously unknown protein interactions, links that are well supported by a high tendency of coexpression and functional homogeneity of the corresponding proteins. Focusing on concrete examples, we show that MSSC reliably predicts protein interactions in well-studied molecular systems, such as the 26S proteasome and RNA polymerase II of S. cerevisiae. We also show that the quality of the predictions is comparable to the Maximum Likelihood Estimation while MSSC is faster. This new algorithm and all data sets used are accessible through a Web portal at http://ppi.cse.nd.edu.


Hydrogen and Formate Oxidation Coupled to Dissimilatory Reduction of Iron or Manganese by Alteromonas putrefaciens.
The ability of Alteromonas putrefaciens to obtain energy for growth by coupling the oxidation of various electron donors to dissimilatory Fe(III) or Mn(IV) reduction was investigated. A. putrefaciens grew with hydrogen, formate, lactate, or pyruvate as the sole electron donor and Fe(III) as the sole electron acceptor. Lactate and pyruvate were oxidized to acetate, which was not metabolized further. With Fe(III) as the electron acceptor, A. putrefaciens had a high affinity for hydrogen and formate and metabolized hydrogen at partial pressures that were 25-fold lower than those of hydrogen that can be metabolized by pure cultures of sulfate reducers or methanogens. The electron donors for Fe(III) reduction also supported Mn(IV) reduction. The electron donors for Fe(III) and Mn(IV) reduction and the inability of A. putrefaciens to completely oxidize multicarbon substrates to carbon dioxide distinguish A. putrefaciens from GS-15, the only other organism that is known to obtain energy for growth by coupling the oxidation of organic compounds to the reduction of Fe(III) or Mn(IV). The ability of A. putrefaciens to reduce large quantities of Fe(III) and to grow in a defined medium distinguishes it from a Pseudomonas sp., which is the only other known hydrogen-oxidizing, Fe(III)-reducing microorganism. Furthermore, A. putrefaciens is the first organism that is known to grow with hydrogen as the electron donor and Mn(IV) as the electron acceptor and is the first organism that is known to couple the oxidation of formate to the reduction of Fe(III) or Mn(IV). Thus, A. putrefaciens provides a much needed microbial model for key reactions in the oxidation of sediment organic matter coupled to Fe(III) and Mn(IV) reduction.


Effect of short-term ingestion of konjac glucomannan on serum cholesterol in healthy men.
The effects of the soluble fiber konjac glucomannan (GM) on serum cholesterol concentrations were investigated in 63 healthy men in a double-blind crossover, placebo-controlled study. After a 2-wk baseline period, the subjects were given 3.9 g GM or placebo daily for 4 wk. After a washout period of 2 wk, crossover took place, followed by another 4 wk of treatment. The subjects were encouraged not to change their ordinary diets or general lifestyle during the investigation. GM fibers reduced total cholesterol (TC) concentrations by 10% (P < 0.0001), low-density-lipoprotein cholesterol (LDL-C) concentrations by 7.2% (P < 0.007), triglycerides by 23% (P < 0.03), and systolic blood pressure by 2.5% (P < 0.02). High-density-lipoprotein cholesterol (HDL-C) and the ratio of LDL-C to HDL-C did not change significantly. No change in diastolic blood pressure or body weight was observed. No adverse effects were observed. The results of this study show that GM is an effective cholesterol-lowering dietary adjunct.


Treatment of Fuchs Endothelial Dystrophy by Descemet Stripping Without Endothelial Keratoplasty.
To evaluate the effect of deliberate removal of the central Descemet membrane on endothelial function and morphology in patients with Fuchs endothelial dystrophy (FED) and cataract undergoing phacoemulsification. In this retrospective case series, patients with FED and visually significant cataract underwent phacoemulsification in an academic cornea practice in Boston, MA. Four millimeters of the central Descemet membrane was stripped and removed after intraocular lens insertion. Vision, corneal pachymetry, and confocal imaging of the endothelial anatomy were performed before surgery and at 1, 3, 6, and 12 months after surgery. Patients were classified as fast responders, responders, slow responders, and nonresponders on the basis of postoperative time to resolution of corneal edema with visible central endothelial mosaic. Eleven patients (13 eyes) aged 51 to 91 years were included in the study. No eyes had countable central endothelial cells by confocal imaging before surgery. Preoperative visual acuity ranged from 20/25 to 20/400. All corneas showed stromal and microcystic edema in the area of Descemet stripping at days 1 and 7 after surgery. Four eyes demonstrated resolution of corneal edema with visible central endothelial cell mosaic (range: 410-864 cells/mm) by postoperative month 1 with visual acuity ranging between 20/25 and 20/40. Four additional eyes demonstrated a similar response by postoperative month 3 and an additional 2 eyes had resolution of corneal edema with an intact central endothelial mosaic at postoperative month 6 or later. Cell counts (range: 428-864 cells/mm) were maintained in all 10 responders at the last follow-up visit (range: postoperative months 6-24). Final vision ranged from 20/15 to 20/20 in these 10 eyes with the exception of 2 eyes with retinal pathology. Three eyes required endothelial keratoplasty. Repopulation of the central corneal endothelium with corneal deturgescence can occur after deliberate central Descemet stripping in patients with FED who underwent cataract removal. This may offer a novel treatment for patients with FED that could reduce the need for endothelial transplantation. Further studies are needed to delineate the optimal patient population for Descemet stripping because not all patients will respond to this intervention.


Deidentification of free-text medical records using pre-trained bidirectional transformers.
The ability of caregivers and investigators to share patient data is fundamental to many areas of clinical practice and biomedical research. Prior to sharing, it is often necessary to remove identifiers such as names, contact details, and dates in order to protect patient privacy. Deidentification, the process of removing identifiers, is challenging, however. High-quality annotated data for developing models is scarce; many target identifiers are highly heterogenous (for example, there are uncountable variations of patient names); and in practice anything less than perfect sensitivity may be considered a failure. As a result, patient data is often withheld when sharing would be beneficial, and identifiable patient data is often divulged when a deidentified version would suffice. In recent years, advances in machine learning methods have led to rapid performance improvements in natural language processing tasks, in particular with the advent of large-scale pretrained language models. In this paper we develop and evaluate an approach for deidentification of clinical notes based on a bidirectional transformer model. We propose human interpretable evaluation measures and demonstrate state of the art performance against modern baseline models. Finally, we highlight current challenges in deidentification, including the absence of clear annotation guidelines, lack of portability of models, and paucity of training data. Code to develop our model is open source, allowing for broad reuse.


Predictors of uncontrolled hypertension and antihypertensive medication nonadherence.
Although hypertension is, in most cases, a controllable major risk factor in the development of cardiovascular disease, studies have demonstrated that hypertension remains poorly controlled in Portugal. Our aim was to evaluate the covariates associated with poor blood pressure (BP) control in a Portuguese hypertensive population. We conducted a cross-sectional survey in a hospital hypertension outpatient clinic, located in the Eastern Central Region of Portugal. Patients attending the clinic from July to September 2009 were asked to participate in a structured interview including medication adherence and knowledge about hypertension. Eligible participants were all adults aged 18 or over with an established diagnosis of arterial hypertension and had been on antihypertensive drug treatment for at least 6 months. Exclusion criteria were dementia, pregnancy, and breastfeeding. Detailed clinical information was prospectively obtained from medical records. A total of 197 patients meeting the inclusion criteria and consenting to participate completed the interview. Of these, only 33.0% had their BP controlled according to the JNC 7 guidelines. Logistic regression analysis revealed three independent predictors of poor BP control: living alone (OR = 5.3, P = 0.004), medication nonadherence (OR = 4.8, P < 0.001), and diabetes (OR = 4.4, P = 0.011). Predictors of medication nonadherence were: unawareness of target BP values (OR = 3.7, P < 0.001), a report of drug side effects (OR = 3.7, P = 0.002), lack of BP monitoring (OR = 2.5, P = 0.015) and unawareness of medication indications (OR = 2.4, P = 0.021), and of hypertension risks (OR = 2.1, P = 0.026). Poor medication adherence, lack of information about hypertension, and side effects should be considered as possible underlying causes of uncontrolled BP and must be addressed in any intervention aimed to improve BP control.


Self-sustainable, high-power-density bio-solar cells for lab-on-a-chip applications.
A microfluidic lab-on-a-chip system that generates its own power is essential for stand-alone, independent, self-sustainable point-of-care diagnostic devices to work in limited-resource and remote regions. Miniaturized biological solar cells (or micro-BSCs) can be the most suitable power source for those lab-on-a-chip applications because the technique resembles the earth's natural ecosystem - living organisms work in conjunction with non-living components of their environment to create a self-assembling and self-maintaining system. Micro-BSCs can continuously generate electricity from microbial photosynthetic and respiratory activities over day-night cycles, offering a clean and renewable power source with self-sustaining potential. However, the promise of this technology has not been translated into practical applications because of its relatively low power (∼nW cm-2) and current short lifetimes (∼a couple of hours). In this work, we enabled high-performance, self-sustaining, long-life micro-BSCs by using fundamental breakthroughs of device architectures and electrode materials. A 3-D biocompatible, conductive, and porous anode demonstrated great microbial biofilm formation and a high rate of bacterial extracellular electron transfer, which led to greater power generation. Furthermore, our micro-BSCs promoted gas exchange to the bacteria through a gas-permeable PDMS membrane in a well-controlled, tightly enclosed micro-chamber, substantially enhancing sustainability. Through photosynthetic reactions of the cyanobacteria Synechocystis sp. PCC 6803 without additional organic fuel, the 90 μL single-chambered bio-solar cell generated a maximum power density of 43.8 μW cm-2 and sustained consistent power production of ∼18.6 μW cm-2 during the day and ∼11.4 μW cm-2 at night for 20 days, which is the highest and longest reported success of any existing micro-scale bio-solar cells.


Characterisation of pathogen-specific regions and novel effector candidates in Fusarium oxysporum f. sp. cepae.
A reference-quality assembly of Fusarium oxysporum f. sp. cepae (Foc), the causative agent of onion basal rot has been generated along with genomes of additional pathogenic and non-pathogenic isolates of onion. Phylogenetic analysis confirmed a single origin of the Foc pathogenic lineage. Genome alignments with other F. oxysporum ff. spp. and non pathogens revealed high levels of syntenic conservation of core chromosomes but little synteny between lineage specific (LS) chromosomes. Four LS contigs in Foc totaling 3.9 Mb were designated as pathogen-specific (PS). A two-fold increase in segmental duplication events was observed between LS regions of the genome compared to within core regions or from LS regions to the core. RNA-seq expression studies identified candidate effectors expressed in planta, consisting of both known effector homologs and novel candidates. FTF1 and a subset of other transcription factors implicated in regulation of effector expression were found to be expressed in planta.


Content of phenolic compounds and antioxidant capacity in fruits of apricot genotypes.
Research on natural compounds is increasingly focused on their effects on human health. In this study, we were interested in the evaluation of nutritional value expressed as content of total phenolic compounds and antioxidant capacity of new apricot (Prunus armeniaca L.) genotypes resistant against Plum pox virus (PPV) cultivated on Department of Fruit Growing of Mendel University in Brno. Fruits of twenty one apricot genotypes were collected at the onset of consumption ripeness. Antioxidant capacities of the genotypes were determined spectrometrically using DPPH• (1,1-diphenyl-2-picryl-hydrazyl free radicals) scavenging test, TEAC (Trolox Equivalent Antioxidant Capacity), and FRAP (Ferric Reducing Antioxidant Power)methods. The highest antioxidant capacities were determined in the genotypes LE-3228 and LE-2527, the lowest ones in the LE-985 and LE-994 genotypes. Moreover, close correlation (r = 0.964) was determined between the TEAC and DPPH assays. Based on the antioxidant capacity and total polyphenols content, a clump analysis dendrogram of the monitored apricot genotypes was constructed. In addition, we optimized high performance liquid chromatography coupled with tandem electrochemical and spectrometric detection and determined phenolic profile consisting of the following fifteen phenolic compounds: gallic acid, 4-aminobenzoic acid, chlorogenic acid, ferulic acid, caffeic acid, procatechin, salicylic acid, p-coumaric acid, the flavonols quercetin and quercitrin, the flavonol glycoside rutin, resveratrol, vanillin, and the isomers epicatechin, (-)- and (+)- catechin.


Influence of the growth substrate on ester-linked phospho- and glycolipid fatty acids of PAH-degrading Mycobacterium sp. LB501T.
The influences of poorly water-soluble anthracene on ester-linked phospholipid fatty acid (PLFA) and glycolipid fatty acid (GLFA) profiles of Mycobacterium sp. LB501T were studied. Bacteria were cultivated on either anthracene or glucose (one culture with successively amended small doses of this substrate and one with excess concentrations) to distinguish between influences of the chemical structure and the bioavailability of the growth substrate. Results revealed that GLFA and PLFA profiles of M. sp. LB501T depended on the availability and the structure of the carbon source. Fatty acid profiles obtained with anthracene differed from those obtained with excess glucose. They were interpreted as a specific adaptation to this poorly bioavailable polycyclic aromatic hydrocarbon (PAH). In contrast, profiles obtained with low glucose concentrations showed clear signs of starvation stress. Stable carbon isotopic ratios (delta13C) of GLFA and PLFA of M. sp. LB501T were analysed to characterize the 13C-fractionation during the biosynthesis of individual fatty acids and to evaluate their value as markers for substrate usage. Although the delta13C values of PLFA and GLFA showed differential isotope fractionation during anthracene- and glucose-degradation, they were sufficiently distinct to be used as signatures of bacterial substrate usage.


Psychopathology and attrition in the Baltimore ECA 15-year follow-up 1981-1996.
Predictors of non-response were investigated in a 15-year follow-up (1981-1996) of 3,481 individuals in a probability sample from the household population of East Baltimore. Demographics (age, sex, race, education, marital status, and unemployment), household factors (living arrangements, household income, household size, and number of children), cultural variables (ancestral ethnicity and foreign language), social variables (social support and networks, committing felony, carrying a weapon, using an alias, and wandering), health factors (physical illness, health insurance, medical assistance, Medicare, receiving disability benefits, social security, and welfare), interviewer's observation, and psychopathologic variables (mental disorders, suicide behavior, comorbidity, and drug use) were collected at baseline in 1981 and in 1982, then linked to follow-up data between 1993 and 1996. A tracing process involving mail, phone, criss-cross directories, motor vehicle administration records, a commercial credit bureau, the state criminal justice system, hospital records, the US National Death Index, and field tracing were used to locate the original sample. A total of 3,066 respondents of the original sample (88.1%) were traced. Non-response was categorized into Sample Mortality (that part of the original sample that died during follow-up), Sample Loss (that part of the original sample that survived but could not be found) and Refusal (that part of the original sample that survived and was found but refused to participate). Stratified analysis and adjusted multiple logistic regression modeling found sample mortality and sample loss were strongly influenced by individual and household variables and by psychopathology. Sample mortality was influenced by specific mental disorders or conditions as mania, drug abuse/dependency, antisocial personality, cognitive impairment, alcohol abuse/dependency, phobia, drug use (except PCP), and comorbidity. Household factors protective against mortality include higher household income, not living as extended members in a married couple family, and living with children in the household. Persons who were unemployed, widowed or single, without high school education, male, and 65 years of age or older were more likely to die. Sample loss was influenced by cognitive impairment, antisocial personality, and cocaine use. Household factors linked to sample loss include living in female-headed families, or non-family households, and living alone. Young nonwhite, divorced/separated, without high school education, and unemployed were also harder to find. Refusal was associated with being white, with incomplete elementary education, living as a spouse in traditional married couple families, or as a child in female-headed families. Psychopathology did not influence refusal.


tRNA ligase is required for regulated mRNA splicing in the unfolded protein response.
The accumulation of unfolded proteins in the endoplasmic reticulum (ER) triggers an intracellular signaling pathway, the unfolded protein response (UPR), that leads to increased transcription of genes encoding ER-resident proteins. Transcriptional activation is mediated by a dedicated transcription factor, Hac1p, whose activity is controlled by regulated splicing of its mRNA. We have identified a mutation in tRNA ligase that disrupts the UPR in the yeast Saccharomyces cerevisiae. In this mutant, splicing of HAC1 mRNA, but not tRNA, is blocked. In contrast, HAC1 mRNA splicing is not impaired in cells that are blocked in spliceosome-mediated mRNA splicing. Furthermore, the splice junctions of HAC1 mRNA do not conform to the consensus sequences of other yeast pre-mRNAs. Our results suggest that the regulated splicing of HAC1 mRNA occurs by a novel pathway, involving tRNA ligase and bypassing the spliceosome.


Distinct metal-exchange pathways of doped Ag25 nanoclusters.
Atomically precise metal nanoclusters (NCs) containing more than one type of metal atom (i.e., doped or alloyed), due to synergistic effects, open new avenues for engineering the catalytic and optical properties of NCs in a manner that homometal NCs cannot. Unfortunately, it is still a major challenge to controllably introduce multimetallic dopants in NCs, understanding the dopants' positions, mechanism, and synergistic effects. To overcome these challenges, we designed a metal-exchange approach involving NCs as molecular templates and metal ions as the source of the incoming dopant. In particular, two structurally similar monodoped silver-rich NCs, [MAg24(SR)18]2- (M = Pd/Pt and SR: thiolate), were synthesized as templates to study their mechanistic transformation in response to the introduction of gold atoms. The controllable incorporation of Au atoms into the MAg24 framework facilitated the elucidation of distinct doping pathways through high-resolution mass spectrometry, optical spectroscopy and elemental analysis. Interestingly, gold replaced the central Pd atom of [PdAg24(SR)18]2- clusters to produce predominantly bimetallic [AuAg24(SR)18]- clusters along with a minor product of an [Au2Ag23(SR)18]- cluster. In contrast, the central Pt atom remained intact in [PtAg24(SR)18]2- clusters, and gold replaced the non-central Ag atoms to form trimetallic [AuxPtAg24-x(SR)18]2- NCs, where x = 1-2, with a portion of the starting [PtAg24(SR)18]2- NCs remaining. This study reveals some of the unusual metal-exchange pathways of doped NCs and the important role played by the initial metal dopant in directing the position of a second dopant in the final product.


Circulating insulin-like growth factor binding protein-1 and the risk of pancreatic cancer.
Insulin-like growth factor (IGF)-I has growth-promoting effects on pancreatic cancer cells, and elevated fasting serum insulin has been linked to pancreatic cancer risk. IGF binding protein-1 (IGFBP-1) is a downstream target of insulin and inhibits IGF-I activity. To investigate whether prediagnostic plasma levels of IGFBP-1 are associated with pancreatic cancer risk, we did a prospective, case-control study nested within the Health Professionals Follow-up Study, the Nurses' Health Study, the Physicians' Health Study, and the Women's Health Initiative. We assayed circulating IGFBP-1 among 144 pancreatic cancer cases that occurred >or=4 years after plasma collection and in 429 controls, matched for date of birth, prospective cohort, smoking status, and fasting status. When compared with participants in the three highest quartiles of plasma IGFBP-1, those in the lowest quartile experienced a relative risk (RR) for pancreatic cancer of 2.07 [95% confidence intervals (95% CI), 1.26-3.39], after adjusting for other risk factors, including circulating IGF-I, IGF binding protein-3, and C-peptide. Only participants in the lowest quartile of plasma IGFBP-1 showed an elevated risk of pancreatic cancer. The influence of low plasma IGFBP-1 became progressively stronger with time; among cases diagnosed >or=8 years after blood collection, the adjusted RR was 3.47 (95% CI, 1.48-8.14), comparing the bottom versus the top three quartiles. The influence of plasma IGFBP-1 was most marked among participants who never smoked cigarettes (RR, 3.30; 95% CI, 1.48-7.35). Among participants in four U.S. prospective cohort studies, low plasma IGFBP-1 levels significantly predicted an increased risk of pancreatic cancer.


Interactions of Streptomyces griseus aminopeptidase with amino acid reaction products and their implications toward a catalytic mechanism.
Streptomyces griseus aminopeptidase (SGAP) is a double-zinc exopeptidase with a high preference toward large hydrophobic amino-terminus residues. It is a monomer of a relatively low molecular weight (30 kDa), it is heat stable, it displays a high and efficient catalytic turnover, and its activity is modulated by calcium ions. The small size, high activity, and heat stability make SGAP a very attractive enzyme for various biotechnological applications, among which is the processing of recombinant DNA proteins and fusion protein products. Several free amino acids, such as phenylalanine, leucine, and methionine, were found to act as weak inhibitors of SGAP and hence were chosen for structural studies. These inhibitors can potentially be regarded as product analogs because one of the products obtained in a normal enzymatic reaction is the cleaved amino terminal amino acid of the substrate. The current study includes the X-ray crystallographic analysis of the SGAP complexes with methionine (1.53 A resolution), leucine (1.70 A resolution), and phenylalanine (1.80 A resolution). These three high-resolution structures have been used to fully characterize the SGAP active site and to identify some of the functional groups of the enzyme that are involved in enzyme-substrate and enzyme-product interactions. A unique binding site for the terminal amine group of the substrate (including the side chains of Glu131 and Asp160, as well as the carbonyl group of Arg202) is indicated to play an important role in the binding and orientation of both the substrate and the product of the catalytic reaction. These studies also suggest that Glu131 and Tyr246 are directly involved in the catalytic mechanism of the enzyme. Both of these residues seem to be important for substrate binding and orientation, as well as the stabilization of the tetrahedral transition state of the enzyme-substrate complex. Glu131 is specifically suggested to function as a general base during catalysis by promoting the nucleophilic attack of the zinc-bound water/hydroxide on the substrate carbonyl carbon. The structures of the three SGAP complexes are compared with recent structures of three related aminopeptidases: Aeromonas proteolytica aminopeptidase (AAP), leucine aminopeptidase (LAP), and methionine aminopeptidase (MAP) and their complexes with corresponding inhibitors and analogs. These structural results have been used for the simulation of several species along the reaction coordinate and for the suggestion of a general scheme for the proteolytic reaction catalyzed by SGAP.


Ecological significance of residual exposures and effects from the Exxon Valdez oil spill.
An ecological significance framework is used to assess the ecological condition of Prince William Sound (PWS), Alaska, USA, in order to address the current management question: 17 y following the Exxon Valdez oil spill (EVOS), are there any remaining and continuing ecologically significant exposures or effects on the PWS ecosystem caused by EVOS? We examined the extensive scientific literature funded by the Exxon Valdez Trustees or by ExxonMobil to assess exposures and effects from EVOS. Criteria to assess ecological significance include whether a change in a valued ecosystem component (VEC) is sufficient to affect the structure, function, and/or health of the system and whether such a change exceeds natural variability. The EVOS occurred on 24 March 1989, releasing over 250,000 barrels of crude oil into PWS. Because PWS is highly dynamic, the residual oil was largely eliminated in the first few years, and now only widely dispersed, highly weathered, or isolated small pockets of residual contamination remain. Many other sources of polycyclic aromatic hydrocarbons (PAHs) exist in PWS from past or present human activities or natural oil seeps. Multiple-lines-of-evidence analyses indicate that residual PAHs from EVOS no longer represent an ecologically significant exposure risk to PWS. To assess the ecological significance of any residual effects from EVOS, we examined the literature on more than 20 VECs, including primary producers, filter feeders, fish and bird primary consumers, fish and bird top predators, a bird scavenger, mammalian primary consumers and top predators, biotic communities, ecosystem-level properties of trophodynamics and biogeochemical processes, and landscape-level properties of habitat mosaic and wilderness quality. None of these has any ecologically significant effects that are detectable at present, with the exception of 1 pod of orcas and possibly 1 subpopulation of sea otters; however, in both those cases, PWS-wide populations appear to have fully recovered. Many other stressors continue to affect PWS adversely, including climate and oceanographic variability, increased tourism and shipping, invasive species, the 1964 earthquake, and overexploitation of marine resources, with associated cascading effects on populations of PWS fish and predators. We conclude that the PWS ecosystem has now effectively recovered from EVOS.


Iron status predicts treatment failure and mortality in tuberculosis patients: a prospective cohort study from Dar es Salaam, Tanzania.
Experimental data suggest a role for iron in the course of tuberculosis (TB) infection, but there is limited evidence on the potential effects of iron deficiency or iron overload on the progression of TB disease in humans. The aim of the present analysis was to examine the association of iron status with the risk of TB progression and death. We analyzed plasma samples and data collected as part a randomized micronutrient supplementation trial (not including iron) among HIV-infected and HIV-uninfected TB patients in Dar es Salaam, Tanzania. We prospectively related baseline plasma ferritin concentrations from 705 subjects (362 HIV-infected and 343 HIV-uninfected) to the risk of treatment failure at one month after initiation, TB recurrence and death using binomial and Cox regression analyses. Overall, low (plasma ferritin<30 µg/L) and high (plasma ferritin>150 µg/L for women and>200 µg/L for men) iron status were seen in 9% and 48% of patients, respectively. Compared with normal levels, low plasma ferritin predicted an independent increased risk of treatment failure overall (adjusted RR = 1.95, 95% CI: 1.07 to 3.52) and of TB recurrence among HIV-infected patients (adjusted RR = 4.21, 95% CI: 1.22 to 14.55). High plasma ferritin, independent of C-reactive protein concentrations, was associated with an increased risk of overall mortality (adjusted RR = 3.02, 95% CI: 1.95 to 4.67). Both iron deficiency and overload exist in TB patients and may contribute to disease progression and poor clinical outcomes. Strategies to maintain normal iron status in TB patients could be helpful to reduce TB morbidity and mortality.


Sensitivity of optical sensors based on laser-excited surface-plasmon waves.
We investigate the effect of the divergence of a Gaussian laser beam on the resonance curve and the sensitivity of optical sensors based on surface-plasmon resonance (SPR). For He-Ne laser beams it is found that, for beams with a waist radius of less than 300 microm, the SPR-curve characteristics differ appreciably from the case in which a plane wave is considered. Simple expressions for the sensitivity of (bio)chemical sensors are given. A simple Lorentzian model is used to estimate the maximum possible sensitivity when a multilayer system is used to enhance the resonance peak. It was found that the sensitivity can reach its highest value when the width of the SPR curve is equal to the laser-beam divergence. The results could be particularly important when a SPR curve is used to measure the absolute value of the refractive index of a sample or the dielectric constant and the thickness of a metal layer.


Eclipse instrumentation for the solar corona.
The expedition of the Harvard College Observatory, the Smithsonian Astrophysical Observatory, and the National Geographic Society to Miahuatlán, Mexico, to observe the total solar eclipse of 7 March 1970, is described. Instrumentation included a coronal spectrograph, television cameras recording on videotape, telescopes for photography of coronal polarization, and cameras for direct photography. Photographs and preliminary microphotometer tracings are included.


Sialic acids in human gastric aspirates: detection of 9-O-lactyl- and 9-O-acetyl-N-acetylneuraminic acids and a decrease in total sialic acid concentration with age.
1. The total sialic acid content of human gastric aspirates was measured using a colorimetric assay. Care was taken to optimize the assay and to eliminate interference. 2. The sialic acid content of gastric aspirates collected under resting conditions from 77 patients with non-ulcer dyspepsia was found to decrease with age from > 100 micrograms/ml at 25 years and younger to < 20 micrograms/ml above 70 years of age. 3. Analysis of the sialic acids by gas chromatography, mass spectrometry and thin-layer chromatography showed the presence of N-acetylneuraminic acid and two O-acylated derivatives, 9-O-acetyl- and 9-O-lactyl-N-acetylneuraminic acids. These forms were predominantly glycosidically bound. 4. Thin-layer chromatographic analysis of individual aspirate samples showed that the O-acetylated sialic acids were present in all samples, with a maximum of 25% and a minimum of 5% of the total sialic acids.


Modal content in hypocycloid Kagomé hollow core photonic crystal fibers.
The modal content of 7 and 19 cell Kagomé anti resonant hollow core fibers (K-ARF) with hypocycloid core surrounds is experimentally investigated through the spectral and spatial (S2) imaging technique. It is observed that the 7 and 19 cell K-ARF reported here, support 4 and 7 LP mode groups respectively, however the observation that K-ARF support few mode groups is likely to be ubiquitous to 7 and 19 cell K-ARFs. The transmission loss of the higher order modes (HOMs) was measured via S2 and a cutback method. In the 7 cell K-ARF it is found that the LP11 and LP21 modes have approximately 3.6 and 5.7 times the loss of the fundamental mode (FM), respectively. In the 19 cell it is found that the LP11 mode has approximately 2.57 times the loss of the FM, while the LP02 mode has approximately 2.62 times the loss of the FM. Additionally, bend loss in these fibers is studied for the first time using S2 to reveal the effect of bend on modal content. Our measurements demonstrate that K-ARFs support a few mode groups and indicate that the differential loss of the HOMs is not substantially higher than that of the FM, and that bending the fiber does not induce significant inter modal coupling. A study of three different input beam coupling configurations demonstrates increased HOM excitation at output and a non-Gaussian profile of the output beam if poor mode field matching is achieved.


Effects of oral environment stabilization procedures on counts of Candida spp. in children.
The effects of oral environment stabilization procedures on counts of Candida spp. have rarely been discussed, and no conclusive results are found in the literature. The aim of this study was thus to ascertain the effects of oral environment stabilization procedures with glass ionomer and zinc oxide-eugenol cements on counts of Candida spp. in the oral cavity of children. For this purpose, oral rinses of sterile phosphate-buffered saline were initially collected from 30 boys and 30 girls, positive for Candida in the saliva and aged from 4 to 10 years. Data on the initial quantity of CFU/ml of Candida were obtained. Then, the children were randomly divided into two groups and oral environment stabilization procedures were performed using zinc oxide-eugenol cement or glass ionomer cement. One week after the procedures were performed, oral rinses were collected again and final Candida counts were obtained. An expressive reduction in Candida counts was observed in both groups. The zinc oxide-eugenol and glass ionomer cements were efficient in the reduction of Candida counts and statistically significant differences were observed between initial and final counts in both groups. Considering the percentage of reduction, the zinc oxide-eugenol cement presented more favorable results, with a reduction of 70%. A reduction of 46% was observed with the use of the glass ionomer cement. According to the obtained results, we concluded that oral environment stabilization procedures were efficient in reducing Candida spp. counts, especially when the zinc oxide-eugenol cement was employed.


Systemic vascular inflammation in abdominal aortic aneurysm patients: a contrast-enhanced PET/CT study.
The aim of this paper was to investigate the presence of systemic vascular inflammation and its relationship with risk factors and biomarkers of systemic inflammation related to atherosclerosis in asymptomatic abdominal aortic aneurysm (AAA) patients. Thirty AAA patients and 30 age-matched controls underwent contrast-enhanced 2-deoxy-2-[18F]fluoro-D-glucose (FDG) PET/CT. C-reactive protein, erythrocyte sedimentation rate, white blood cell count and differential, serum fibrinogen, D-dimer and full lipid panel were also evaluated. Region of interest analyses were performed to obtain target-to-background (TBR) metabolism of aorta, subclavian, carotid, iliac arteries and AAA. CT-based arterial calcium load (CL) was evaluated. Arterial Metabolism and CL intergroup differences were tested (unpaired t-test). Linear regression analysis was performed only between blood biomarkers on one side and both TBR and ACL of the arterial districts that resulted significantly different between patients and controls on the other. In all the analyses P values <0.05 were considered significant. FDG-uptake was higher with respect to controls in aorta, carotid and iliac arteries (P<0.01, P<0.007, P<0.04 respectively). AAA and aorta metabolism showed an inverse correlation with HDL-chol (P<0.02 and P<0.01, respectively) while only aorta showed a direct correlation with lymphocytes' count (P<0.02). Carotid metabolism was directly correlated with monocytes' count and C-reactive protein concentration (P<0.02 and P<0.004, respectively). The present findings support the relevance of systemic vascular inflammation in all phases of atherosclerosis-related disorders. Moreover they confirm the concept that acute ischemic syndromes might represent the local result of a systemic inflammation rather than the focal involvement of a single arterial lesion.


Collaboration between developing and developed countries and between developing countries in occupational health research and surveillance.
Collaborative occupational health and safety studies between counterparts in developing and developed countries and between developing countries have demonstrated their potential for improving occupational health and safety. Such collaboration in occupational health and safety is encouraged in the development of infrastructure in research empowerment and capacity building. This action includes the setting of priorities, the identification and documentation of problems, sponsorship, data bases and surveillance systems, technical support, methodology, publishing, research and training programs, controlled intervention, information exchange, and networking. Examples of priorities in occupational health and safety in the developing world include the informal sector (informally hired and independent workers), temporary work, pesticides, accidents, dusts, carcinogens, solvents, ergonomics, women and child labor, human immunodeficiency virus/acquired immunodeficiencey syndrome (HIV/AIDS), and transfer of hazardous materials and technologies. The sustainability of occupational health and safety structures and functions in the developing countries is a primary concern. Socioethical principles emphasize local, national, mutual and global gains. Examples of collaboration are given. Pervasive problems and strategies toward their solution are highlighted.


Usefulness of core needle biopsy for thyroid nodules with macrocalcifications: comparison with fine-needle aspiration.
This study was performed to determine the benefits of core needle biopsy (CNB), as compared with fine-needle aspiration (FNA), for the diagnosis of thyroid nodules with macrocalcifications. The institutional review board approved this retrospective study, and informed consent was waived. From February 2010 to March 2012, the study included 147 thyroid nodules with macrocalcification of 145 consecutive patients who underwent simultaneous FNA and CNB for each nodule. Diagnostic accuracy and inconclusive diagnoses, including nondiagnostic reading and atypia of undetermined significance or follicular lesion of undetermined significance reading were compared among FNA, CNB, and a combination of FNA and CNB (FNA/CNB) using McNemar's test; the benefits of CNB were calculated. Compared to FNA, CNB and FNA/CNB showed fewer inconclusive diagnoses (FNA vs. CNB: 62/147 [42.2%] vs. 14/147 [9.5%], p<0.001; FNA vs. 62/147 [42.2%] vs. 14/147 [9.5%], p<0.001), resulting in the avoidance of repeat FNA or diagnostic surgery in 48 of 62 patients (77.4%, respectively in CNB and FNA/CNB) who would have undergone these procedures if only FNA was performed. Compared to FNA, FNA/CNB showed higher sensitivity and accuracy (sensitivity: 23/32 [71.9%] vs. 31/32 [96.9%], p=0.008; accuracy: 77/86 [89.5%] vs. 85/86 [98.8%], p=0.008), resulting in avoidance of delayed surgery in eight of nine patients (88.9%) with thyroid cancer in whom the surgery would have been missed if FNA only had been performed. In the workup of thyroid nodules with macrocalcification, compared with FNA alone, FNA/CNB decreases inconclusive diagnoses and increases sensitivity, thereby reducing repeated FNA procedures, diagnostic surgeries, and delayed therapeutic surgeries.


Kinesin-1 Proteins KIF5A, -5B, and -5C Promote Anterograde Transport of Herpes Simplex Virus Enveloped Virions in Axons.
Herpes simplex virus (HSV) and other alphaherpesviruses must spread from sites of viral latency in sensory ganglia to peripheral tissues, where the viruses can replicate to higher titers before spreading to other hosts. These viruses move in neuronal axons from ganglia to the periphery propelled by kinesin motors moving along microtubules. Two forms of HSV particles undergo this anterograde transport in axons: (i) unenveloped capsids that become enveloped after reaching axon tips and (ii) enveloped virions that are transported within membrane vesicles in axons. Fundamental to understanding this axonal transport is the question of which of many different axonal kinesins convey HSV particles. Knowing which kinesins promote axonal transport would provide clues to the identity of HSV proteins that tether onto kinesins. Prominent among axonal kinesins are the kinesin-1 (KIF5A, -5B, and -5C) and kinesin-3 (e.g., KIF1A and -1B) families. We characterized fluorescent forms of cellular cargo molecules to determine if enveloped HSV particles were present in the vesicles containing these cargos. Kinesin-1 cargo proteins were present in vesicles containing HSV particles, but not kinesin-3 cargos. Fluorescent kinesin-1 protein KIF5C extensively colocalized with HSV particles, while fluorescent kinesin-1 KIF1A did not. Silencing of kinesin-1 proteins KIF5A, -5B, and -5C or light chains KLC1 and KLC2 inhibited the majority of HSV anterograde transport, while silencing of KIF1A had little effect on HSV transport in axons. We concluded that kinesin-1 proteins are important in the anterograde transport of the majority of HSV enveloped virions in neuronal axons and kinesin-3 proteins are less important.IMPORTANCE Herpes simplex virus (HSV) and other alphaherpesviruses, such as varicella-zoster virus, depend upon the capacity to navigate in neuronal axons. To do this, virus particles tether onto dyneins and kinesins that motor along microtubules from axon tips to neuronal cell bodies (retrograde) or from cell bodies to axon tips (anterograde). Following reactivation from latency, alphaherpesviruses absolutely depend upon anterograde transport of virus particles in axons in order to reinfect peripheral tissues and spread to other hosts. Which of the many axonal kinesins transport HSV in axons is not clear. We characterized fluorescent cellular cargo molecules and kinesins to provide evidence that HSV enveloped particles are ferried by kinesin-1 proteins KIF5A, -5B, and -5C and their light chains, KLC1 and KLC2, in axons. Moreover, we obtained evidence that kinesin-1 proteins are functionally important in anterograde transport of HSV virions by silencing these proteins.


Antitumor activity of capsaicin on human colon cancer cells in vitro and colo 205 tumor xenografts in vivo.
Capsaicin was reported to inhibit cancer cell growth. The aim of this study was to evaluate the antitumor potential of capsaicin by studying antitumor activity in vitro as well as in vivo. The in vitro studies are to examine the effects of capsaicin on human colon cancer colo 205 cells after exposure to capsaicin. The results showed that capsaicin induced cytotoxic effects in a time- and dose-dependent manner and increased reactive oxygen species (ROS) and Ca(2+) but decreased the level of mitochondrial membrane potential (ΔΨ(m)) in colo 205 cells. Data from Western blotting analysis indicated that the levels of Fas, cytochrome c, and caspases were increased, leading to cell apoptosis. Capsaicin decreased the levels of anti-apoptotic proteins such as Bcl-2 and increased the levels of pro-apoptotic proteins such as Bax. Capsaicin-induced apoptosis in colo 205 cells was also done through the activations of caspase-8, -9 and -3. In vivo studies in immunodeficient nu/nu mice bearing colo 205 tumor xenografts showed that capsaicin effectively inhibited tumor growth. The potent in vitro and in vivo antitumor activities of capsaicin suggest that capsaicin might be developed for the treatment of human colon cancer.


Characterization of an essential Orc2p-associated factor that plays a role in DNA replication.
The Saccharomyces cerevisiae Orc2 protein is a subunit of the origin recognition complex, ORC, which binds in a sequence-specific manner to yeast origins of DNA replication. With screens for orc2-1 synthetic lethal mutations and Orc2p two-hybrid interactors, a novel Orc2p-associated factor (Oaf1p) was identified. OAF1 is essential, its gene product is localized to the nucleus, and an oaf1 temperature-sensitive mutant arrests as large budded cells with a single nucleus. The mutant oaf1-2, isolated in the synthetic lethal screen, loses plasmids containing a single origin of DNA replication at a high rate, but it maintains plasmids carrying multiple potential origins of DNA replication. In addition, the OAF1 gene product tagged with the hemagglutinin antigen epitope binds to a DNA affinity column containing covalently linked tandem repeats of an essential origin element. These results suggest a role for OAFI in the initiation of DNA replication. Mutant alleles of cdc7 and cdc14 were also isolated in the orc2-1 synthetic lethal screen. Cdc7p, like Oaf1p, also interacts with Orc2p in two-hybrid assays.


Evaluation of a non-parametric modelling for meropenem in critically ill patients using Monte Carlo simulation.
In critically ill patients treated with meropenem, the proposed pharmacokinetics/pharmacodynamics (PK/PD) efficacy index is to keep the free drug concentration 4-5 times above the minimum inhibitory concentration (MIC) of the germ isolated, for 100% of the interval regimen. The objectives were to design a population pharmacokinetics model for meropenem in critically ill patients and to evaluate different dosage schemes that achieve the optimal PK/PD objectives. This retrospective, observational, single-centre study included 80 critically ill patients (154 samples) treated with meropenem between May 2011 and December 2017. Patient data, concentrations, treatment and bacteriological variables were collected from electronic medical records. Total and free concentrations of meropenem were modelled in Pmetrics. Monte Carlo simulations were performed to assess the probability of achieving the PK/PD target for different dosage regimens. For patients with available data, the number of patients with a free concentration 4 times higher or lower than the observed MIC for the P. aeruginosa and E. coli was investigated. A one-compartment model with first-order elimination adequately described serum total and free meropenem concentrations. The only variable that significantly influenced the elimination constant of meropenem was the creatinine clearance (CLcr) calculated using the CKD-EPI formula. The highest probability of achieving the pharmacodynamic objective was with 3-h infusion dosage regimens. Sixty percent and 89% of patients attained a free drug concentration 4 times above the MIC for P. aeruginosa and E. coli respectively. This study proposed different dosing regimens depending on renal clearance strata and the MIC of the germ targeted.


Coffee consumption and urologic cancer risk: a meta-analysis of cohort studies.
Controversial results were reported among several epidemiologic studies on the relationship between coffee consumption and urologic cancer risk. We, therefore, conducted this meta-analysis to clarify these associations. Electronic databases including Pubmed, Embase and Cochrane library were searched between January 1966 and August 2013 for eligible studies. Pooled relative risk (RR) and its 95 % confidence interval (CI) were calculated. All P values are two tailed. Thirteen cohorts were eligible for inclusion. As to prostate cancer (PCa), significant reverse association was found among highest versus none/lowest analysis with acceptable heterogeneity (RR 0.86, 95 % CI 0.79-0.95; I(2) 25 %, P value for heterogeneity: 0.221). A pooled RR which assessed advanced PCa was 0.73 (with 95 % CI 0.50-1.07), and a slight stronger reverse association was found in fatal PCa. However, a slight insignificant reverse association, basing on 8 studies with 9 outcomes, was found in dose-response analysis (RR 0.98, 95 % CI 0.93-1.03). For kidney and bladder cancer, insignificant associations were found in both highest versus none/lowest analyses and dose-response analyses. Our findings suggest that coffee consumption may reduce the risk of PCa. No associations were found with both bladder and kidney cancer. Further well-designed large-scaled cohort studies are warranted to provide more definitive conclusions.


Wheat streak mosaic virus alters the transcriptome of its vector, wheat curl mite (Aceria tosichella Keifer), to enhance mite development and population expansion.
Wheat streak mosaic virus (WSMV; genus Tritimovirus; family Potyviridae) is an economically important wheat virus that is transmitted by the wheat curl mite (WCM; Aceria tosichella Keifer) in a persistent manner. Virus-vector coevolution may potentially influence vector gene expression to prolong viral association and thus increase virus transmission efficiency and spread. To understand the transcriptomic responses of WCM to WSMV, RNA sequencing was performed to assemble and analyse transcriptomes of WSMV viruliferous and aviruliferous mites. Among 7291 de novo-assembled unigenes, 1020 were differentially expressed between viruliferous and aviruliferous WCMs using edgeR at a false discovery rate ≤0.05. Differentially expressed unigenes were enriched for 108 gene ontology terms, with the majority of the unigenes showing downregulation in viruliferous mites in comparison to only a few unigenes that were upregulated. Protein family and metabolic pathway enrichment analyses revealed that most downregulated unigenes encoded enzymes and proteins linked to stress response, immunity and development. Mechanistically, these predicted changes in mite physiology induced by viral association could be suggestive of pathways needed for promoting virus-vector interactions. Overall, our data suggest that transcriptional changes in viruliferous mites facilitate prolonged viral association and alter WCM development to expedite population expansion, both of which could enhance viral transmission.


Assessing youth policies. A system of indicators for local government.
In the current European climate of economic, financial and political crisis and the questioning of the welfare state, assessing public policies assume a primary and strategic relevance in clarifying the results and contributions of policy actions. In this article, we aim to present the current situation in relation to youth policy assessment so as to formulate a system of assessment indicators in the sphere of Spanish local government youth policy. A review is conducted of some of the principal contributions in the field of constructing indicators for evaluating youth policies. We have found that most of these evaluation tools exist on a national or state level and that there is a dearth of local or municipal tools. The article concludes with a concrete proposal for an assessment tool: the SIAPJove (Sistema d'Indicadors d'Avaluació per a les Polítiques Municipals de Joventut or System of Assessment Indicators for Local Government Youth Policies) (web page: http://siapjove.udg.edu/). It provides both quantitative and qualitative indicators for local youth policy managers to obtain assessment reports with relative ease in 12 possible areas for assessment within youth policy.


Transfusion interventions in critical bleeding requiring massive transfusion: a systematic review.
Critical bleeding (CB) requiring massive transfusion (MT) can occur in a variety of clinical contexts and is associated with substantial mortality and morbidity. In 2011, the Australian National Blood Authority (NBA) published patient blood management guidelines for CB and MT, which found limited high-quality evidence from which only 2 recommendations could be made. The aim of this systematic review (SR) was to update these guidelines and identify evidence gaps still to be addressed. A comprehensive search was performed for randomized controlled trials (RCTs) and SRs using MeSH index and free text terms in MEDLINE, the Cochrane Library (Issue 11, 2012), EMBASE, CINHAL, PUBMED, and the Transfusion Evidence Library up to July 15, 2014. The evidence was grouped according to 4 questions based on the original guideline relating to transfusion interventions: (1) effect of dose, timing, and ratio of red blood cells (RBCs) to component therapy on patient outcomes; (2) effect of RBC transfusion on patient outcomes; (3) effect of fresh frozen plasma, platelet, cryoprecipitate, fibrinogen concentrate, and prothrombin complex concentrate on patient outcomes; and (4) effect of recombinant activated factor VII (rFVIIa) on patient outcomes. From this search, 19 studies were identified: 6 RCTs and 13 SRs. Two of the RCTs were pilot/feasibility studies, 3 were investigating rFVIIa, and 1 compared restrictive versus liberal RBC transfusion in upper gastrointestinal hemorrhage. Overall, limited new evidence was identified and substantial evidence gaps remain, particularly with regard to the effect of component therapies, including ratio of RBC to component therapies, on patient outcomes. Clinical trials to address these questions are required.


Interleukins, from 1 to 37, and interferon-γ: receptors, functions, and roles in diseases.
Advancing our understanding of mechanisms of immune regulation in allergy, asthma, autoimmune diseases, tumor development, organ transplantation, and chronic infections could lead to effective and targeted therapies. Subsets of immune and inflammatory cells interact via ILs and IFNs; reciprocal regulation and counter balance among T(h) and regulatory T cells, as well as subsets of B cells, offer opportunities for immune interventions. Here, we review current knowledge about ILs 1 to 37 and IFN-γ. Our understanding of the effects of ILs has greatly increased since the discoveries of monocyte IL (called IL-1) and lymphocyte IL (called IL-2); more than 40 cytokines are now designated as ILs. Studies of transgenic or knockout mice with altered expression of these cytokines or their receptors and analyses of mutations and polymorphisms in human genes that encode these products have provided important information about IL and IFN functions. We discuss their signaling pathways, cellular sources, targets, roles in immune regulation and cellular networks, roles in allergy and asthma, and roles in defense against infections.


The relationship between form and space perception, constructional abilities, and clumsiness in children.
The Sensory Integration and Praxis Tests (SIPT) (Ayres, 1989) were administered to 21 children with learning disabilities and 18 children without learning disabilities, aged 5 to 8 years. The children with learning disabilities were divided into two groups, clumsy and nonclumsy, on the basis of their scores on the Test of Motor Impairment (Stott, Moyes, & Henderson, 1984). It was hypothesized that the learning-disabled children in the clumsy group would score significantly lower than the learning-disabled children in the nonclumsy group on the six SIPT subtests that measure form and space perception and visual construction and that the nonclumsy learning-disabled children, in turn, would score significantly lower than the non-learning-disabled children. It was further hypothesized that there would be a significant correlation between the degree of clumsiness and the degree of visual-perceptual and constructional deficits. An analysis of the data indicated that both groups of learning-disabled children scored lower than the non-learning-disabled children on four of the six SIPT subtests. The clumsy and nonclumsy children with learning disabilities, however, differed from each other on only two subtests. The degree of clumsiness correlated significantly with three of the six subtests. The results are discussed in terms of variations in perceptual and motor skills related to subtypes of learning disabilities.


Completion and toxicity of induction chemotherapy for metastatic testicular cancer: an updated evaluation of Japanese patients.
Combination of bleomycin, etoposide and cisplatin (BEP) remains the standard chemotherapy for testicular cancer. Since the development of BEP in the 1980s, there has been a considerable advance in supportive therapies, such as granulocyte colony-stimulating-factor and 5-HT3 antagonists. Therefore, we re-evaluated the completion and toxicity of BEP combined with modern supportive care. The medical records of all 42 testicular cancer patients who received induction chemotherapy at Tsukuba University Hospital were reviewed. Toxicities during the induction chemotherapy were graded according to the Japanese CTCAE v3.0. Dose reduction was needed in only three patients. The subsequent chemotherapy was started at the planned 3 week interval or within 3 days of postponement in 89% of the treatment cycles. The average relative dose intensity (RDI) of bleomycin was 0.95, while that for etoposide and cisplatin was 0.97. There was no death due to toxicity. The most frequent toxicity was leukopenia (grade 3 in 44% and grade 4 in 55%). Post-chemotherapy diffusion capacity was significantly decreased in 30% of patients. Two patients developed bleomycin-induced pneumonitis, but recovered successfully. Sixteen patients received second line or salvage chemotherapy after BEP, subsequently. The overall 5 year cause-specific survival rate was 85%. BEP with high RDIs is acceptable if combined with modern supportive care, with acceptable toxicity profile in most patients.


Task-shifting: experiences and opinions of health workers in Mozambique and Zambia.
This paper describes the task-shifting taking place in health centres and district hospitals in Mozambique and Zambia. The objectives of this study were to identify the perceived causes and factors facilitating or impeding task-shifting, and to determine both the positive and negative consequences of task-shifting for the service users, for the services and for health workers. Data collection involved individual and group interviews and focus group discussions with health workers from the civil service. In both the Republic of Mozambique and the Republic of Zambia, health workers have to practice beyond the traditional scope of their professional practice to cope with their daily tasks. They do so to ensure that their patients receive the level of care that they, the health workers, deem due to them, even in the absence of written instructions.The "out of professional scope" activities consume a significant amount of working time. On occasions, health workers are given on-the-job training to assume new roles, but job titles and rewards do not change, and career progression is unheard of. Ancillary staff and nurses are the two cadres assuming a greater diversity of functions as a result of improvised task-shifting. Our observations show that the consequences of staff deficits and poor conditions of work include heavier workloads for those on duty, the closure of some services, the inability to release staff for continuing education, loss of quality, conflicts with patients, risks for patients, unsatisfied staff (with the exception of ancillary staff) and hazards for health workers and managers. Task-shifting is openly acknowledged and widespread, informal and carries risks for patients, staff and management.


Targeting Ultrasmall Gold Nanoparticles with cRGD Peptide Increases the Uptake and Efficacy of Cytotoxic Payload.
Cyclic arginyl-glycyl-aspartic acid peptide (cRGD) peptides show a high affinity towards αVβ3 integrin, a receptor overexpressed in many cancers. We aimed to combine the versatility of ultrasmall gold nanoparticles (usGNP) with the target selectivity of cRGD peptide for the directed delivery of a cytotoxic payload in a novel design. usGNPs were synthesized with a modified Brust-Schiffrin method and functionalized via amide coupling and ligand exchange and their uptake, intracellular trafficking, and toxicity were characterized. Our cRGD functionalized usGNPs demonstrated increased cellular uptake by αVβ3 integrin expressing cells, are internalized via clathrin-dependent endocytosis, accumulated in the lysosomes, and when loaded with mertansine led to increased cytotoxicity. Targeting via cRGD functionalization provides a mechanism to improve the efficacy, tolerability, and retention of therapeutic GNPs.