The pedicled descending branch muscle-sparing latissimus dorsi flap for breast reconstruction.
The pedicled descending branch muscle-sparing latissimus dorsi flap with a transversely oriented skin paddle presents distinct advantages in breast reconstruction, including reduced donor-site morbidity and greater freedom of orientation of the skin paddle. This study reports the anatomical basis, surgical technique, complications, and aesthetic and functional outcomes following use of this flap for breast reconstruction. A retrospective study of 20 patients who underwent breast reconstruction with a pedicled muscle-sparing latissimus dorsi musculocutaneous flap was conducted. Indications for surgery included breast reconstruction following mastectomy, lumpectomy, and irradiation, and for correction of implant-related complications. Case-note review was performed, as was a functional evaluation consisting of a patient questionnaire, a Disabilities of the Arm, Shoulder, and Hand form, postoperative range-of-motion analysis, and instrumented strength testing comparing the operated and nonoperated sides. Aesthetic evaluation of the donor site was conducted by all patients. An anatomical study of 15 flaps harvested from fresh cadavers was performed to determine the location of the bifurcation of the thoracodorsal artery and the course of its descending branch. Twenty-four descending branch muscle-sparing latissimus dorsi flaps were harvested. All donor sites were closed primarily, with skin paddle sizes ranging up to 25 x 12 cm. There was one case of minor flap tip necrosis and no instances of seroma. There was no statistically significant difference in strength or range of motion of the shoulder joint when comparing the operated to the nonoperated side. Two patients reported minor functional impact following surgery. The pedicled descending branch muscle-sparing latissimus dorsi flap with a transversely orientated skin paddle results in minimal functional deficit of the donor site, absence of seroma, large freedom of orientation of the skin paddle, low rate of flap complications, and a cosmetically acceptable scar.


The UK postmortem organ retention crisis: a qualitative study of its impact on parents.
To explore the impact of postmortem organ retention on parents who made enquiries about their babies and children when the retention of hearts and other organs removed at postmortem and stored without explicit knowledge or consent of the next-of-kin came to public attention in the UK during 1999-2004. Qualitative study conducted 2003-2004. Data were collected via semi-structured, qualitative interviews and focus groups. 39 parents who had been affected by organ retention. Participants were recruited via three parental peer support groups and two NHS Hospital Trusts. Transcripts of the interviews and focus groups were analysed using a thematic approach that sought patterns within the data and highlighted important similarities and differences between participants' accounts. Participants reported the distressing impact organ retention had on their lives; their need for information about the retention of their babies' or children's organs; and the difficulties in their decision making about disposal of retained body parts and tissue blocks and slides. Analysis indicated that organ retention had evoked unresolved bereavement issues and a renewal of grief as well as an opportunity for some parents to resolve ongoing bereavement concerns. Parents in this study wanted NHS teams to appreciate the difficulties organ retention had caused them, deal with their enquiries proactively with openness and honesty, and facilitate an environment where they felt supported and could gain the answers to their questions and concerns that were provoked by postmortem organ retention. Such issues may also have implications for the care of other parents and relatives of deceased children.


BMI measurement in schools.
School-based BMI measurement has attracted attention across the nation as a potential approach to address obesity among youth. However, little is known about its impact or effectiveness in changing obesity rates or related physical activity and dietary behaviors that influence obesity. This article describes current BMI-measurement programs and practices, research, and expert recommendations and provides guidance on implementing such an approach. An extensive search for scientific articles, position statements, and current state legislation related to BMI-measurement programs was conducted. A literature and policy review was written and presented to a panel of experts. This panel, comprising experts in public health, education, school counseling, school medical care, and parenting, reviewed and provided expertise on this article. School-based BMI-measurement programs are conducted for surveillance or screening purposes. Thirteen states are implementing school-based BMI-measurement programs as required by legislation. Few studies exist that assess the utility of these programs in preventing increases in obesity or the effects these programs may have on weight-related knowledge, attitudes, and behaviors of youth and their families. Typically, expert organizations support school-based BMI surveillance; however, controversy exists over screening. BMI screening does not currently meet all of the American Academy of Pediatrics' criteria for determining whether screening for specific health conditions should be implemented in schools. Schools initiating BMI-measurement programs should adhere to safeguards to minimize potential harms and maximize benefits, establish a safe and supportive environment for students of all body sizes, and implement science-based strategies to promote physical activity and healthy eating.


Neighborhood and PA: neighborhood factors and physical activity in African American public housing residents.
In the US, public housing developments are typically located in lower socioeconomic status neighborhoods that may have poorer quality street level conditions, placing residents in neighborhoods that are less supportive for physical activity (PA). This study investigated the relationship of detailed, objectively assessed street-level pedestrian features with self-reported and measured PA in African American public housing residents. Every street segment (N = 2093) within an 800 m radius surrounding each housing development (N = 12) was systematically assessed using the Pedestrian Environment Data Scan (PEDS). Participants completed an interviewer administered International Physical Activity Questionnaire (IPAQ) Short Form and wore a pedometer for 1 week. Women reported significantly less vigorous (mean = 1955 vs. 2896 METs), moderate (mean = 733 vs. 1309 mets), walking (mean = 1080 vs. 1376 METs), and total (mean = 3768 vs. 5581 METs) PA on the IPAQ compared with men (all P <.05). Women took fewer pedometer steps per day (M = 3753 vs. 4589) compared with men, but this was not statistically significant. Regression analyses showed that for women, lower speed limits were associated with vigorous; higher street segment density was associated with more moderate PA; lower speed limits, fewer crossing aids, and more lanes were associated with more walking; and, fewer lanes was associated with more overall PA. For men, fewer sidewalk connections were associated with more moderate PA; lower speed limits were associated with more walking; and, lower speed limits was associated with more overall PA. Neighborhood factors influence physical activity; in particular, lower speed limits appear most commonly linked with increased physical activity in both men and women.


The effect of niacinamide on osteoarthritis: a pilot study.
To evaluate the effect of niacinamide, on selected parameters of osteoarthritis using a double-blind, placebo controlled study design. Seventy two patients with osteoarthritis were randomized for treatment with niacinamide or an identical placebo for 12 weeks. Outcome measures included global arthritis impact and pain, joint range of motion and flexibility, erythrocyte sedimentation rate, complete blood count, liver function tests, cholesterol, uric acid, and fasting blood sugar. Compliance was monitored with a pill record sheet and interview. Global arthritis impact improved by 29% (95% confidence interval [CI] 6, 46) in subjects on niacinamide and worsened by 10% in placebo subjects (p = 0.04). Pain levels did not change but those on niacinamide reduced their anti-inflammatory medications by 13% (95% CI 9, 94; p = 0.01). Niacinamide reduced erythrocyte sedimentation rate by 22% (95% CI 6, 51; p < 0.005) and increased joint mobility by 4.5 degrees over controls (8 degrees vs 3.5 degrees; p = 0.04). Side effects were mild but higher in the niacinamide group (40% vs 27%, p = 0.003). This study indicates that niacinamide may have a role in the treatment of osteoarthritis. Niacinamide improved the global impact of osteoarthritis, improved joint flexibility, reduced inflammation, and allowed for reduction in standard anti-inflammatory medications when compared to placebo. More extensive evaluation of niacinamide in arthritis is warranted.


Genetic polymorphisms in glutathione S-transferase mu and theta, N-acetyltransferase, and CYP1A1 and risk of gliomas.
The role of genetic polymorphisms in modulating susceptibility to carcinogenic exposures has been well explored for tobacco-related neoplasms but not for other neoplasms including gliomas. It is relevant to explore these polymorphisms because certain carcinogenic exposures such as nitrosamines are implicated in the risk of gliomas. We therefore conducted a pilot case-control study to examine the role of polymorphisms in GSTM1, GSTT1, NAT2 (rapid, intermediate, and slow acetylation), and CYP1A1 and risk of glioma. Ninety patients diagnosed with glioma were ascertained as part of an ongoing genetic epidemiological study and were age, gender, and race matched with 90 healthy controls. We used PCR based methodology to determine the prevalence of the above genetic polymorphisms using sequences and PCR conditions directly adapted from studies reported previously. We calculated univariate odds ratios and performed multiple logistic regression to assess interactions between polymorphisms. We found no statistically significant associations between the null genotypes of GSTM1 and GSTT1, and CYP1A1 and risk of gliomas. However, there was an intriguing pattern with NAT2 acetylation status (odds ratios, 1.81, 1.34, and 0.61 for rapid, intermediate, and slow acetylation, respectively; P = 0.10 for trend). It is unlikely that any single polymorphism is sufficiently predictive of risk, and a panel of markers integrated with epidemiological data should be conducted on a large number of study subjects to fully understand the role of genetic polymorphisms and brain tumor risk.


Functional redundancy of class I phosphoinositide 3-kinase (PI3K) isoforms in signaling growth factor-mediated human neutrophil survival.
We have investigated the contribution of individual phosphoinositide 3-kinase (PI3K) Class I isoforms to the regulation of neutrophil survival using (i) a panel of commercially available small molecule isoform-selective PI3K Class I inhibitors, (ii) novel inhibitors, which target single or multiple Class I isoforms (PI3Kα, PI3Kβ, PI3Kδ, and PI3Kγ), and (iii) transgenic mice lacking functional PI3K isoforms (p110δ(KO)γ(KO) or p110γ(KO)). Our data suggest that there is considerable functional redundancy amongst Class I PI3Ks (both Class IA and Class IB) with regard to GM-CSF-mediated suppression of neutrophil apoptosis. Hence pharmacological inhibition of any 3 or more PI3K isoforms was required to block the GM-CSF survival response in human neutrophils, with inhibition of individual or any two isoforms having little or no effect. Likewise, isolated blood neutrophils derived from double knockout PI3K p110δ(KO)γ(KO) mice underwent normal time-dependent constitutive apoptosis and displayed identical GM-CSF mediated survival to wild type cells, but were sensitized to pharmacological inhibition of the remaining PI3K isoforms. Surprisingly, the pro-survival neutrophil phenotype observed in patients with an acute exacerbation of chronic obstructive pulmonary disease (COPD) was resilient to inactivation of the PI3K pathway.


Model transcriptional networks with continuously varying expression levels.
At a time when genomes are being sequenced by the hundreds, much attention has shifted from identifying genes and phenotypes to understanding the networks of interactions among genes. We developed a gene network developmental model expanding on previous models of transcription regulatory networks. In our model, each network is described by a matrix representing the interactions between transcription factors, and a vector of continuous values representing the transcription factor expression in an individual. In this work we used the gene network model to look at the impact of mating as well as insertions and deletions of genes in the evolution of complexity of these networks. We found that the natural process of diploid mating increases the likelihood of maintaining complexity, especially in higher order networks (more than 10 genes). We also show that gene insertion is a very efficient way to add more genes to a network as it provides a much higher chance of developmental stability. The continuous model affords a more complete view of the evolution of interacting genes. The notion of a continuous output vector also incorporates the reality of gene networks and graded concentrations of gene products.


Stereotactic radiosurgery in intraocular malignant melanoma--retrospective study.
One day session linear accelerator based stereotactic radiosurgery of intraocular malignant melanoma is a method of "conservative" attitude to treat posterior uveal melanoma. Retrospective clinic-based study of patients with posterior uveal melanoma in stage T2/T3 who underwent stereotactic radiosurgery at linear accelerator in period 2001-2011. Immobilization of the affected eye was achieved by mechanical fixation to the stereotactic Leibinger frame. The stereotactic treatment planning after fusion of computed tomography and magnetic resonance imaging was optimized according to the critical structures (lenses, optic nerves, chiasm). In group of 96 patients with posterior uveal melanoma treated with one day session stereotactic radiosurgery, patient age ranged from 25 to 80 years with a median of 54 years. Median tumor volume at baseline was 0.6 cm(3) (with range from 0.2 to 1.0 cm(3)). Median maximal dose applied was 49.0 Gy (range from 37.0 to 52.0 Gy). Secondary enucleation was necessary in 11 patients (11.5%) due to complications like irradiation neuropathy and secondary glaucoma. Tumor local control was successful in 95% of patients in 3 years interval after stereotactic radiosurgery and in 85% of patients in 5 years interval after stereotactic radiosurgery. One step LINAC based stereotactic radiosurgery with a single dose 35.0 Gy is one of treatment options to treat T2 or T3 stage posterior uveal melanoma.


Multiple Victims of Carbon Monoxide Poisoning in the Aftermath of a Wildfire: A Case Series.
Carbon monoxide poisoning may occur in several contexts. Retrospective of 37 carbon monoxide poisoning cases that underwent hyperbaric oxygen during wildfires in Funchal in August 2016. The studied sample included 37 patients, mean age of 38 years, 78% males. Ten were firefighters, four children and two pregnant victims. Neurological symptoms were the most reported. Median carboxyhemoglobin level was 3.7% (IQR 2.7). All received high-flow oxygen from admission to delivery of hyperbaric oxygen. Persistence of symptoms was the main indication for hyperbaric oxygen. Median time to hyperbaric oxygen was 4.8 hours (IQR 9.5), at 2.5 ATA for 90 minutes, without major complications. Discharge in less than 24 hours occurred in 92% of the cases. Thirty days follow-up: five patients presented clinical symptoms of late neurological syndrome; twelve patients were lost to follow-up. Carboxyhemoglobin levels on admission and mean time to hyperbaric oxygen were no different between those who did and did not develop the syndrome at 30 days (p = 0.44 and p = 0.58, respectively). Late neurological syndrome at 30 days occurred in 20% and no new cases were reported at 12 months. Use of hyperbaric oxygen appears to have reduced the incidence of the syndrome. This seems to be the first Portuguese series reporting use of hyperbaric oxygen in carbon monoxide poisoning due to wildfires. The authors intend to alert to the importance of referral of these patients because the indications and benefits of this treatment are well documented. This is especially important given the ever-growing issue of wildfires in Portugal.


Vascular Patterns in Iguanas and Other Squamates: Blood Vessels and Sites of Thermal Exchange.
Squamates use the circulatory system to regulate body and head temperatures during both heating and cooling. The flexibility of this system, which possibly exceeds that of endotherms, offers a number of physiological mechanisms to gain or retain heat (e.g., increase peripheral blood flow and heart rate, cooling the head to prolong basking time for the body) as well as to shed heat (modulate peripheral blood flow, expose sites of thermal exchange). Squamates also have the ability to establish and maintain the same head-to-body temperature differential that birds, crocodilians, and mammals demonstrate, but without a discrete rete or other vascular physiological device. Squamates offer important anatomical and phylogenetic evidence for the inference of the blood vessels of dinosaurs and other extinct archosaurs in that they shed light on the basal diapsid condition. Given this basal positioning, squamates likewise inform and constrain the range of physiological thermoregulatory mechanisms that may have been found in Dinosauria. Unfortunately, the literature on squamate vascular anatomy is limited. Cephalic vascular anatomy of green iguanas (Iguana iguana) was investigated using a differential-contrast, dual-vascular injection (DCDVI) technique and high-resolution X-ray microcomputed tomography (μCT). Blood vessels were digitally segmented to create a surface representation of vascular pathways. Known sites of thermal exchange, consisting of the oral, nasal, and orbital regions, were given special attention due to their role in brain and cephalic thermoregulation. Blood vessels to and from sites of thermal exchange were investigated to detect conserved vascular patterns and to assess their ability to deliver cooled blood to the dural venous sinuses. Arteries within sites of thermal exchange were found to deliver blood directly and through collateral pathways. The venous drainage was found to have multiple pathways that could influence neurosensory tissue temperature, as well as pathways that would bypass neurosensory tissues. The orbital region houses a large venous sinus that receives cooled blood from the nasal region. Blood vessels from the nasal region and orbital sinus show anastomotic connections to the dural sinus system, allowing for the direct modulation of brain temperatures. The generality of the vascular patterns discovered in iguanas were assessed by firsthand comparison with other squamates taxa (e.g., via dissection and osteological study) as well as the literature. Similar to extant archosaurs, iguanas and other squamates have highly vascularized sites of thermal exchange that likely support physiological thermoregulation that "fine tunes" temperatures attained through behavioral thermoregulation.


Delivery Mode and the Transition of Pioneering Gut-Microbiota Structure, Composition and Predicted Metabolic Function.
Cesarean (C-section) delivery, recently shown to cause excess weight gain in mice, perturbs human neonatal gut microbiota development due to the lack of natural mother-to-newborn transfer of microbes. Neonates excrete first the in-utero intestinal content (referred to as meconium) hours after birth, followed by intestinal contents reflective of extra-uterine exposure (referred to as transition stool) 2 to 3 days after birth. It is not clear when the effect of C-section on the neonatal gut microbiota emerges. We examined bacterial DNA in carefully-collected meconium, and the subsequent transitional stool, from 59 neonates [13 born by scheduled C-section and 46 born by vaginal delivery] in a private hospital in Brazil. Bacterial DNA was extracted, and the V4 region of the 16S rRNA gene was sequenced using the Illumina MiSeq (San Diego, CA, USA) platform. We found evidence of bacterial DNA in the majority of meconium samples in our study. The bacterial DNA structure (i.e., beta diversity) of meconium differed significantly from that of the transitional stool microbiota. There was a significant reduction in bacterial alpha diversity (e.g., number of observed bacterial species) and change in bacterial composition (e.g., reduced Proteobacteria) in the transition from meconium to stool. However, changes in predicted microbiota metabolic function from meconium to transitional stool were only observed in vaginally-delivered neonates. Within sample comparisons showed that delivery mode was significantly associated with bacterial structure, composition and predicted microbiota metabolic function in transitional-stool samples, but not in meconium samples. Specifically, compared to vaginally delivered neonates, the transitional stool of C-section delivered neonates had lower proportions of the genera Bacteroides, Parabacteroides and Clostridium. These differences led to C-section neonates having lower predicted abundance of microbial genes related to metabolism of amino and nucleotide sugars, and higher abundance of genes related to fatty-acid metabolism, amino-acid degradation and xenobiotics biodegradation. In summary, microbiota diversity was reduced in the transition from meconium to stool, and the association of delivery mode with microbiota structure, composition and predicted metabolic function was not observed until the passing of the transitional stool after meconium.


Identification of competence pheromone responsive genes in Streptococcus pneumoniae by use of DNA microarrays.
Natural genetic transformation in Streptococcus pneumoniae is controlled in part by a quorum-sensing system mediated by a peptide pheromone called competence-stimulating peptide (CSP), which acts to coordinate transient activation of genes required for competence. To characterize the transcriptional response and regulatory events occurring when cells are exposed to competence pheromone, we constructed DNA microarrays and analysed the temporal expression profiles of 1817 among the 2129 unique predicted open reading frames present in the S. pneumoniae TIGR4 genome (84%). After CSP stimulation, responsive genes exhibited four temporally distinct expression profiles: early, late and delayed gene induction, and gene repression. At least eight early genes participate in competence regulation including comX, which encodes an alternative sigma factor. Late genes were dependent on ComX for CSP-induced expression, many playing important roles in transformation. Genes in the delayed class (third temporal wave) appear to be stress related. Genes repressed during the CSP response include ribosomal protein loci and other genes involved in protein synthesis. This study increased the number of identified CSP-responsive genes from approximately 40 to 188. Given the relatively large number of induced genes (6% of the genome), it was of interest to determine which genes provide functions essential to transformation. Many of the induced loci were subjected to gene disruption mutagenesis, allowing us to establish that among 124 CSP-inducible genes, 67 were individually dispensable for transformation, whereas 23 were required for transformation.


Is salt reabsorption in the human sweat duct subject to control?
There is a time lag between the beginning of sweat secretion and fully effective production of fluid of minimum salt content. It is suggested that changes in permeability to water or electrolytes have to be effected and may account for the time lag. The composition of thermal and pilocarpine sweat indicates that pharmacological stimulation does not wholely reproduce the physiological mechanism: pilocarpine sweat contains more sodium and more cyclic AMP, irrespective of the secretory rate. The sweat obtained from patients with cystic fibrosis has been compared with that from normal children: the concentrations of cyclic AMP and cyclic GMP are the same. Defective sodium reabsorption in the patients is therefore unlikely to be due to inadequate or excessive synthesis of these cyclic nucleotides.


Evaluating Two Evidence-Based Intervention Strategies to Promote CRC Screening Among Latino Adults in a Primary Care Setting.
Regular use of colorectal cancer screening can reduce incidence and mortality, but participation rates remain low among low-income, Spanish-speaking Latino adults. We conducted two distinct pilot studies testing the implementation of evidence-based interventions to promote fecal immunochemical test (FIT) screening among Latinos aged 50-75 years who were not up-to-date with CRC screening (n = 200) at a large Federally Qualified Health Center (FQHC) in San Diego, CA. One pilot focused on an opportunistic clinic visit "in-reach" intervention including a 30-min session with a patient navigator, review of an educational "flip-chart," and a take-home FIT kit with instructions. The second pilot was a system-level "outreach" intervention consisting of mailed materials (i.e., FIT kit, culturally and linguistically tailored instructions, and a pre-paid return envelope). Both received follow-up calls to promote screening completion and referrals for additional screening and treatment if needed. The primary outcome was FIT kit completion and return within 3 months assessed through electronic medical records. The in-reach pilot consisted of mostly insured (85%), women (82%), and Spanish-speaking (88%) patients. The outreach pilot consisted of mostly of Spanish-speaking (73%) women (64%), half of which were insured (50%). At a 3-month follow-up, screening completion was 76% for in-reach and 19% for outreach. These data demonstrate that evidence-based strategies to promote CRC screening can be implemented successfully within FQHCs, but implementation (particularly of mailed outreach) may require setting and population-specific optimization. Patient, provider, and healthcare system related implementation approaches and lessons learned from this study may be implemented in other primary care settings.


Eating nanomaterials: cruelty-free and safe? the EFSA guidance on risk assessment of nanomaterials in food and feed.
Nanomaterials are increasingly being added to food handling and packaging materials, or directly, to human food and animal feed. To ensure the safety of such engineered nanomaterials (ENMs), in May 2011, the European Food Safety Authority (EFSA) published a guidance document on Risk assessment of the application of nanoscience and nanotechnologies in the food and feed chain. It states that risk assessment should be performed by following a step-wise procedure. Whenever human or animal exposure to nanomaterials is expected, the general hazard characterisation scheme requests information from in vitro genotoxicity, toxicokinetic and repeated dose 90-day oral toxicity studies in rodents. Numerous prevailing uncertainties with regard to nanomaterial characterisation and their hazard and risk assessment are addressed in the guidance document. This article discusses the impact of these knowledge gaps on meeting the goal of ensuring human safety. The EFSA's guidance on the risk assessment of ENMs in food and animal feed is taken as an example for discussion, from the point of view of animal welfare, on what level of uncertainty should be considered acceptable for human safety assessment of products with non-medical applications, and whether animal testing should be considered ethically acceptable for such products.


Reducing the Levels of Akt Activation by PDK1 Knock-in Mutation Protects Neuronal Cultures against Synthetic Amyloid-Beta Peptides.
The Akt kinase has been widely assumed for years as a key downstream effector of the PI3K signaling pathway in promoting neuronal survival. This notion was however challenged by the finding that neuronal survival responses were still preserved in mice with reduced Akt activity. Moreover, here we show that the Akt signaling is elevated in the aged brain of two different mice models of Alzheimer Disease. We manipulate the rate of Akt stimulation by employing knock-in mice expressing a mutant form of PDK1 (phosphoinositide-dependent protein kinase 1) with reduced, but not abolished, ability to activate Akt. We found increased membrane localization and activity of the TACE/ADAM17 α-secretase in the brain of the PDK1 mutant mice with concomitant TNFR1 processing, which provided neurons with resistance against TNFα-induced neurotoxicity. Opposite to the Alzheimer Disease transgenic mice, the PDK1 knock-in mice exhibited an age-dependent attenuation of the unfolding protein response, which protected the mutant neurons against endoplasmic reticulum stressors. Moreover, these two mechanisms cooperatively provide the mutant neurons with resistance against amyloid-beta oligomers, and might singularly also contribute to protect these mice against amyloid-beta pathology.


The interrelationship of estrogen receptor and GnRH in a Basal vertebrate, the sea lamprey.
The hypothalamic-pituitary system is considered to be a vertebrate innovation and seminal event that emerged prior to or during the differentiation of the ancestral agnathans. Lampreys are the earliest evolved vertebrates for which there is a demonstrated neuroendocrine system. Lampreys have three hypothalamic gonadotropin-releasing hormones (GnRHs; lGnRH-I, -II, and -III) and two and possibly three pituitary GnRH receptors involved in mediating reproductive processes. Estradiol is considered to be a major reproductive steroid in both male and female lampreys. The purpose of this study was to investigate estrogen receptor (ER) expression in the lamprey brain in adult sea lampreys. Expression of ER mRNA was confirmed in the adult lamprey brain using RT-PCR. Using digoxigenin (DIG)-labeled probes, ER expression was shown to yield moderate, but distinct reaction products in specific neuronal nuclei of the lamprey brain, including the olfactory lobe, hypothalamus, habenular area, and hindbrain. Expression of ER in the hypothalamic area of the brain provides evidence of potential interaction between estradiol and GnRH(s), and is consistent with previous evidence showing estrogen feedback on GnRH in adult lamprey brain. Earlier studies have reported that there is a close distribution of glutamic acid decarboxylase (GAD; GABA-synthesizing enzyme) and lamprey GnRH in the preoptic region in adult lampreys. The establishment of a direct estradiol-kisspeptin-GABA-GnRH interaction in lamprey has yet to be determined and will require future functional and co-localization studies. The phylogenetic position of lampreys as a basal vertebrate allows lampreys to be a basis for understanding the molecular evolution of the neuroendocrine system that arose in the vertebrates.


Human fetal iridocorneal angle: a light and scanning electron microscopic study.
The iridocorneal angle and inner layers of the trabecular meshwork in human fetal eyes were studied by scanning electron microscopy. Tissue from 32 eyes of 17 fetuses with a gestational age from 12 to 22 weeks were investigated in order to determine the morphological changes in the cellular lining of the anterior chamber angle recess during development. The findings indicate that, although hexagonal corneal endothelial profiles extend almost to the angle apex in a few of the younger eyes examined (12-14 weeks), the lining is always perforated by a few discrete intercellular gaps (2-6 microns diameter). As development progresses it becomes clearer that the maturing meshwork is lined by uveal trabecular endothelial cells which are morphologically distinguishable from corneal endothelium. The frequency and size of the gaps between the inner uveal trabecular endothelial cells increase and are well developed by 18-20 weeks, clearly providing a route of communication between the fetal anterior chamber and the developing intercellular spaces in the primitive trabecular tissue. The implications of these observations on the 'Barkan's membrane' theory of congenital glaucoma are discussed.


Increased expression of PELP1 in human sperm is correlated with decreased semen quality.
Proline-, glutamic acid-, and leucine-rich protein 1 (PELP1) is a scaffolding protein involved in both genomic and nongenomic estrogen signal transduction pathways. To date, the role of PELP1 protein has yet to be characterized in human sperm and has not been associated with sperm parameters. To confirm the presence of PELP1 in human sperm, fresh semen samples were obtained from 178 donors. The study was designed to establish both mRNA and protein presence, and protein cellular localization. Additionally, the number of PELP1-positive spermatozoa was analyzed in men with normal and abnormal semen parameters. Sperm parameters were assessed according to the World Health Organization (WHO) 2010 standards. The presence of PELP1 in spermatozoa was investigated using four precise, independent techniques. The qualitative presence of transcripts and protein was assessed using reverse transcription-polymerase chain reaction (RT-PCR) and western blot protocols, respectively. The cellular localization of PELP1 was investigated by immunocytochemistry. Quantitative analysis of PELP1-positive cells was done by flow cytometry. PELP1 mRNA and protein was confirmed in spermatozoa. Immunocytochemical analysis identified the presence of PELP1 in the midpieces of human sperm irrespective of sperm parameters. Becton Dickinson fluorescence-activated cell sorting (FACSCalibur™) analysis revealed a significantly lower number of PELP1-positive cells in males with normal semen parameters versus abnormal samples (42.78% ± 11.77% vs 61.05% ± 21.70%, respectively; P = 0.014). The assessment of PELP1 may be a time-saving method used to obtain information about sperm quality. The results of our study suggest that PEPL1 may be utilized as an indicator of sperm quality; thereby, PELP1 may be an additional biomarker useful in the evaluation of male infertility.


Para-hydrogen induced polarization of Si-29 NMR resonances as a potentially useful tool for analytical applications.
Para-hydrogen-induced polarization effects have been observed in the (29)Si NMR spectra of trimethylsilyl para-hydrogenated molecules. The high signal enhancements and the long T(1) values observed for the (29)Si hyperpolarized resonances point toward the possibility of using (29)Si for hyperpolarization applications. A method for the discrimination of multiple compounds and/or complex mixtures of hydroxylic compounds (such as steroids), consisting of the silylization of alcoholic functionalities with an unsaturated silylalkyl moiety and subsequent reaction with para-H(2), is proposed.


Regulatory mechanisms in cell-mediated immune responses. VIII. Differential expression of I-region determinants by suppressor cells and their targets in suppression of mixed leukocyte reactions.
The phenotypic expression of I-region determinants on cells producing and responding to MLR suppressor factor (MLR-TsF) was established in these studies. Alloantigen-activated MLR suppressor T cells (MLR-Ts), which produce MLR-TsF bearing gene products of the I-C subregion, were exposed to anti-I subregion sera and complement (C) before in vitro culture for MLR-TsF production. Suppressor activity was prevented by removal of cells bearing I-C determinants, whereas elimination of cells expressing I-A/B determinants had no effect. Interestingly, cytotoxic elimination of cells displaying I-J determinants also prevented MLR-TsF production. Admixture of anti-I-J and I-C antiserum-treated cells for MLR-TsF production failed to reconstitute suppressor activity, indicating that I-C and I-J gene products are expressed on a single population of cells critical to MLR suppression, rather than on distinct interacting subpopulations. Anti-I-C serum activity specific for I-C+ MLR-Ts was removed by adsorption with nylon wool-nonadherent splenic T cells and concanavalin A-activated thymocytes; adsorption with splenic B cells from anti-Thy-1,2 serum and C-treated spleen failed to remove relevant anti-I-C activity. These data suggest that regulatory I-C molecules, like I-J molecules, are preferentially expressed on T lymphocytes. Expression of I-C, or other I-region molecules on responder cell targets of MLR-TsF activity was also investigated. Responder cells were pretreated with anti-I subregion-specific sera in blocking or complement-dependent cytotoxic protocols before addition to MLR with MLR-TsF. Neither blocking nor the cytotoxic removal of cells bearing I-C or other I-region determinants from MLR responder populations interfered with MLR-TsF suppression. Because it has previously been demonstrated that MLR-TsF interacts optimally with activated, I-C syngeneic target cells, blocking and cytotoxic studies with anti-I subregion sera were also performed with responder cells activated by 24 h culture in MLR in the absence of MLR-TsF. Brief MLR-TsF pulse after antiserum treatment generated marked suppression regardless of blocking or absence of cells bearing serologically detected I-region determinants. I-C restricted suppression may thus be mediated not by interaction with I-C-bearing cells, but by target cells which exist in requisite association with populations of I-C+ cells.


Hypoxic conditions increase hypoxia-inducible transcription factor 2alpha and enhance chondrogenesis in stem cells from the infrapatellar fat pad of osteoarthritis patients.
Stem cells derived from the infrapatellar fat pad (IPFP) are a potential source of stem cells for the repair of articular cartilage defects. Hypoxia has been shown to improve chondrogenesis in adult stem cells. In this study we investigated the effects of hypoxia on gene expression changes and chondrogenesis in stem cells from the IPFP removed from elderly patients with osteoarthritis at total knee replacement. Adherent colony-forming cells were isolated and cultured from the IPFP from total knee replacement. The cells at passage 2 were characterised for stem cell surface epitopes, and then cultured for 14 days as cell aggregates in chondrogenic medium under normoxic (20% oxygen) or hypoxic (5% oxygen) conditions. Gene expression analysis, DNA and glycosoaminoglycan assays and immunohistochemical staining were determined to assess chondrogenesis. IPFP-derived adherent colony-forming cells stained strongly for markers of adult mesenchymal stem cells, including CD44, CD90 and CD105, and they were negative for the haematopoietic cell marker CD34 and for the neural and myogenic cell marker CD56. Cell aggregates of IPFP cells showed a chondrogenic response. In hypoxic conditions there was increased matrix accumulation of proteoglycan but less cell proliferation, which resulted in 3.5-fold more glycosoaminoglycan per DNA after 14 days of culture. In hypoxia there was increased expression of hypoxia-inducible transcription factor (HIF)2alpha and not HIF1alpha, and the expression of key transcription factors SOX5, SOX6 and SOX9, and that of aggrecan, versican and collagens II, IX, X and XI, was also increased. These results show that cells with stem cell characteristics were isolated from the IPFP of elderly patients with osteoarthritis and that their response to chondrogenic culture was enhanced by lowered oxygen tension, which upregulated HIF2alpha and increased the synthesis and assembly of matrix during chondrogenesis. This has important implications for tissue engineering applications of cells derived from the IPFP.


Intraosseous infusion in pediatric patients.
In traumatically injured or medically unstable pediatric patients requiring resuscitation, gaining intravenous access often is frustrating for the physician and agonizing for the patient. Even when cardiopulmonary resuscitation is performed by trained professionals, cardiac arrests in children in the prehospital setting have a mortality of 79% to 100%. Immediate vascular access such as that obtained by intraosseous infusion improves survival. The intraosseous infusion technique uses the medullary cavity in the tibia as a "noncollapsible vein" for parenteral infusion. It is indicated in a child in shock or cardiac arrest when two attempts to access peripheral vasculature have failed or when more than 2 minutes have elapsed in the attempt to gain access. Epinephrine, bicarbonate, calcium, lidocaine, and volume expanders can be infused via the intraosseous route. Complications rarely occur. The technique described here is gaining acceptance in both prehospital and emergency department settings.


Abeta protofibrils possess a stable core structure resistant to hydrogen exchange.
Protofibrils are transient structures observed during in vitro formation of mature amyloid fibrils and have been implicated as the toxic species responsible for cell dysfunction and neuronal loss in Alzheimer's disease (AD) and other protein aggregation diseases. To better understand the roles of protofibrils in amyloid assembly and Alzheimer's disease, we characterized secondary structural features of these heterogeneous and metastable assembly intermediates. We chromatographically isolated different size populations of protofibrils from amyloid assembly reactions of Abeta(1-40), both wild type and the Arctic variant associated with early onset familial AD, and exposed them to hydrogen-deuterium exchange analysis monitored by mass spectrometry (HX-MS). We show that HX-MS can distinguish among unstructured monomer, protofibrils, and fibrils by their different protection patterns. We find that about 40% of the backbone amide hydrogens of Abeta protofibrils are highly resistant to exchange with deuterium even after 2 days of incubation in aqueous deuterated buffer, implying a very stable, presumably H-bonded, core structure. This is in contrast to mature amyloid fibrils, whose equally stable structure protects about 60% of the backbone amide hydrogens over the same time frame. We also find a surprising degree of specificity in amyloid assembly, in that wild type Abeta is preferentially excluded from both protofibrils and fibrils grown from an equimolar mixture of wild type and Arctic mutant peptides. These and other data are interpreted and discussed in terms of the role of protofibrils in fibril assembly and in disease.


Investigating Priming Effects of Physical Practice on Motor Imagery-Induced Event-Related Desynchronization.
For motor imagery (MI) to be effective, an internal representation of the to-be-imagined movement may be required. A representation can be achieved through prior motor execution (ME), but the neural correlates of MI that are primed by ME practice are currently unknown. In this study, young healthy adults performed MI practice of a unimanual visuo-motor task (Group MI, n = 19) or ME practice combined with subsequent MI practice (Group ME&MI, n = 18) while electroencephalography (EEG) was recorded. Data analysis focused on the MI-induced event-related desynchronization (ERD). Specifically, changes in the ERD and movement times (MT) between a short familiarization block of ME (Block pre-ME), conducted before the MI or the ME combined with MI practice phase, and a short block of ME conducted after the practice phase (Block post-ME) were analyzed. Neither priming effects of ME practice on MI-induced ERD were found nor performance-enhancing effects of MI practice in general. We found enhancements of the ERD and MT in Block post-ME compared to Block pre-ME, but only for Group ME&MI. A comparison of ME performance measures before and after the MI phase indicated however that these changes could not be attributed to the combination of ME and MI practice. The mixed results of this study may be a consequence of the considerable intra- and inter-individual differences in the ERD, introduced by specifics of the experimental setup, in particular the individual and variable task duration, and suggest that task and experimental setup can affect the interplay of ME and MI.


Shear Modulus of the Lower Leg Muscles in Patients with Medial Tibial Stress Syndrome.
This study aimed to investigate the in vivo kinematics of shear modulus of the lower leg muscles in patients with medial tibial stress syndrome (MTSS). The study population included 46 limbs with MTSS and 40 healthy limbs. The shear modulus of the medial head of the gastrocnemius, lateral head of the gastrocnemius, soleus, peroneus longus and tibialis anterior muscles were measured using shear wave ultrasound elastography. As a result, the shear modulus of the lower leg muscles was significantly greater in patients with MTSS than in healthy patients (p < 0.01). Based on the differences in shear modulus of lower leg muscles between the patients with MTSS and healthy patients, the measurements obtained via shear wave ultrasound elastography could be used to evaluate risk factors of MTSS.


Long distance communication in the human brain: timing constraints for inter-hemispheric synchrony and the origin of brain lateralization.
Analysis of corpus callosum fiber composition reveals that inter-hemispheric transmission time may put constraints on the development of inter-hemispheric synchronic ensembles, especially in species with large brains like humans. In order to overcome this limitation, a subset of large-diameter callosal fibers are specialized for fast inter-hemispheric transmission, particularly in large-brained species. Nevertheless, the constraints on fast inter-hemispheric communication in large-brained species can somehow contribute to the development of ipsilateral, intrahemispheric networks, which might promote the development of brain lateralization.


Telenephrology: current perspectives and future directions.
There is increasing interest in telemedicine among physicians and patients; however, the evidence regarding the quality of care delivered by telemedicine, and telenephrology in particular, compared with in-person care is limited. In this review, different electronic modalities used to deliver nephrology care are reviewed and critiqued, with a focused analysis from the Australian and United States perspectives. Both countries are geographically expansive with significant rural populations where access to nephrology care is limited. However, their health care systems are organized differently. The Australian health care system is a mostly nonprofit, single-payer system, whereas the United States system is more fractured with a greater proportion of patients covered by for-profit private insurance or no insurance coverage. Videoconferencing is widely used in Australia to manage kidney disease including chronic kidney disease, dialysis, pediatric nephrology, and post-kidney transplantation care. In contrast, the United States telenephrology experience is limited, with most reports originating from the Veterans Health Administration, a single-payer system providing care for nearly 9 million veterans, ∼3 million of whom reside in rural communities. Preliminary reports from the Veterans Health Administration suggest that that delivery of nephrology care via videoconferencing results in clinical outcomes that are at least equivalent to in-person care and improved patient adherence to scheduled appointments. Nevertheless, large, adequately controlled studies are needed to identify patient populations that are most likely to benefit from telenephrology and to determine the optimal systems for the delivery of telenephrology care.


Melatonin inhibits angiogenesis in SH-SY5Y human neuroblastoma cells by downregulation of VEGF.
Vascular endothelial growth factor (VEGF) produced from tumor cells plays a crucial role in the pathogenesis and neovascularization of neuroblastoma. Inhibition of VEGF secretion by tumor cells, as well as VEGF-regulated signaling in endothelial cells, are important to reduce the angiogenesis and growth of neuroblastoma. Since melatonin has anti-angiogenic effects in tumor cell lines, the aim of the present study was to study melatonin modulation of the pro-angiogenic effects of VEGF in neuroblastoma cells (SH-SY5Y). We used co-cultures of SH-SY5Y and endothelial cells. VEGF expression and protein levels were analyzed by quantitative RT-PCR and ELISA, respectively. Endothelial cell migration was assessed by wound-healing assay and endothelial angiogenesis by a tube formation assay. Melatonin inhibited the pro-angiogenic effects of SH-SY5Y cells. The conditioned medium collected from the neuroblastoma cells was angiogenically active and stimulated proliferation, migration and tube formation in endothelial cells. This effect was significantly counteracted by the addition of either anti-VEGF or melatonin. Melatonin inhibited VEGF expression and secretion in SH-SY5Y cells, decreasing the levels of VEGF available for endothelial cells. Melatonin has anti-angiogenic effects at different steps of the angiogenic process in SH-SY5Y neuroblastoma cells, through the downregulation of VEGF.


Can Special Light Glasses Reduce Sleepiness and Improve Sleep of Nightshift Workers? A Placebo-Controlled Explorative Field Study.
Nightshift workers go against the natural sleep-wake rhythm. Light can shift the circadian clock but can also induce acute alertness. This placebo-controlled exploratory field study examined the effectiveness of light glasses to improve alertness while reducing the sleep complaints of hospital nurses working nightshifts. In a crossover within-subjects design, 23 nurses participated, using treatment glasses and placebo glasses. Sleepiness and sleep parameters were measured. A linear mixed model analysis on sleepiness revealed no significant main effect of the light intervention. An interaction effect was found indicating that under the placebo condition, sleepiness was significantly higher on the first nightshift than on the last night, while under the treatment condition, sleepiness remained stable across nightshift sessions. Sleepiness during the commute home also showed a significant interaction effect, demonstrating that after the first nightshift, driver sleepiness was higher for placebo than for treatment. Subjective sleep quality showed a negative main effect of treatment vs. placebo, particularly after the first nightshift. In retrospect, both types of light glasses were self-rated as effective. The use of light glasses during the nightshift may help to reduce driver sleepiness during the commute home, which is relevant, as all participants drove home by car or (motor) bike.


The microfluidic multitrap nanophysiometer for hematologic cancer cell characterization reveals temporal sensitivity of the calcein-AM efflux assay.
Cytometric studies utilizing flow cytometry or multi-well culture plate fluorometry are often limited by a deficit in temporal resolution and a lack of single cell consideration. Unfortunately, many cellular processes, including signaling, motility, and molecular transport, occur transiently over relatively short periods of time and at different magnitudes between cells. Here we demonstrate the multitrap nanophysiometer (MTNP), a low-volume microfluidic platform housing an array of cell traps, as an effective tool that can be used to study individual unattached cells over time with precise control over the intercellular microenvironment. We show how the MTNP platform can be used for hematologic cancer cell characterization by measuring single T cell levels of CRAC channel modulation, non-translational motility, and ABC-transporter inhibition via a calcein-AM efflux assay. The transporter data indicate that Jurkat T cells exposed to indomethacin continue to accumulate fluorescent calcein for over 60 minutes after calcein-AM is removed from the extracellular space.


A30P α-Synuclein interferes with the stable integration of adult-born neurons into the olfactory network.
Impaired olfaction is an early symptom in Parkinson disease (PD), although the exact cause is as yet unknown. Here, we investigated the link between PD-related mutant α-Synuclein (α-SYN) pathology and olfactory deficit, by examining the integration of adult-born neurons in the olfactory bulb (OB) of A30P α-SYN overexpressing mice. To this end, we chose to label one well-known vulnerable subpopulation of adult-born cells, the dopaminergic neurons. Using in vivo two-photon imaging, we followed the dynamic process of neuronal turnover in transgenic A30P α-SYN and wild-type mice over a period of 2.5 months. Our results reveal no difference in the number of cells that reach, and possibly integrate into, the glomerular layer in the OB. However, in mutant transgenic mice these new neurons have a significantly shortened survival, resulting in an overall reduction in the addition of neurons to the glomerular layer over time. We therefore propose unstable integration and impaired homeostasis of functional new neurons as a likely contributor to odour discrimination deficits in mutant α-SYN mice.


Identification of viral structural polypeptides of Thogoto virus (a tick-borne orthomyxo-like virus) and functions associated with the glycoprotein.
Thogoto (THO) virus is a tick-borne virus which shares morphological and genetic features with members of the Orthomyxoviridae family although the viral glycoprotein appears to be related to gp64 of baculoviruses. Characterization of THO virus was undertaken to clarify its taxonomic position. Purified virus preparations contained at least six virus-encoded polypeptides with apparent M(r) values ranging from 29K to 92K. A 75K polypeptide was identified as an envelope-associated glycoprotein by Triton X-100 and salt dissociation studies, and by proteolytic degradation of the exposed proteins of the virion. By the same criteria, the nucleoprotein and the matrix protein were identified as the 52K and 29K polypeptides, respectively. Immunofluorescence studies using monoclonal antibodies (MAbs) located the glycoprotein on the external cell membrane and the nucleoprotein in the nucleus of infected cells indicating that virus replication involved a nuclear phase. In addition, the virus displayed haemagglutination and haemolytic activities with an optimum at pH 6. These activities are functions of the viral glycoprotein since they were inhibited by anti-glycoprotein MAbs. The data reported here support the notion that THO virus is a member of the Orthomyxoviridae family but that it should be classified in a group distinct from the other influenza viruses.


The influence of income on morbidity, mortality and dependency in elderly Hong Kong Chinese.
The association between income and mortality, morbidity and dependency is examined in a 3-year prospective follow-up study of 2032 subjects aged 70 years and above in the Hong Kong Special Administrative Region, China. Subjects were recruited using stratified disproportional random sampling of the Old Age and Disability Allowance Schemes, covering over 90% of the population. Subjects were interviewed at baseline and after 36 months. Presence or absence of disease was based on self-report of doctor diagnosis together with a check of medication taken. Functional status was measured using the Barthel Index. For the disease analysis, subjects with the disease being analyzed at baseline were excluded; similarly for the dependency analysis, subjects who were dependent at baseline were excluded. Chi-square test, univariate and multiple logistic regression were used to examine the association between income and mortality, development of new disease, and dependency. There was no association between income and mortality, or with development of new disease. Development of dependency was associated with lower income at baseline. An income of less than 1000 HK dollars per month increased the risk of dependency by 1.8-fold (95%CI 1.1-2.9). However, this association disappeared after adjustment for age and sex. Absolute income is not an important factor contributing to mortality, morbidity and dependency in elderly Chinese aged 70 years and above. A freely accessible health and social service at low or no cost, the survivor effect, or other factors may account for the lack of association with income, contrary to findings from studies of whole populations worldwide. Therefore manipulating income alone is unlikely to affect these outcomes in the elderly.


Decontamination of a hospital room using gaseous chlorine dioxide: Bacillus anthracis, Francisella tularensis, and Yersinia pestis.
This study assessed the efficacy of gaseous chlorine dioxide for inactivation of Bacillus anthracis, Francisella tularensis, and Yersinia pestis in a hospital patient care suite. Spore and vegetative cells of Bacillus anthracis Sterne 34F2, spores of Bacillus atrophaeus ATCC 9372 and vegetative cells of both Francisella tularensis ATCC 6223 and Yersinia pestis A1122 were exposed to gaseous chlorine dioxide in a patient care suite. Organism inactivation was then assessed by log reduction in viable organisms postexposure to chlorine dioxide gas compared to non-exposed control organism. Hospital room decontamination protocols utilizing chlorine dioxide gas concentrations of 377 to 385 ppm maintained to exposures of 767 ppm-hours with 65% relative humidity consistently achieved complete inactivation of B. anthracis and B. atrophaeus spores, as well as vegetative cells of B. anthracis, F. tularensis, and Y. pestis. Decrease in exposure (ppm-hours) and relative humidity (<65%) or restricting airflow reduced inactivation but achieved >8 log reductions in organisms. Up to 10-log reductions were achieved in a hospital room with limited impact on adjacent areas, indicating chlorine dioxide concentrations needed for decontamination of highly concentrated (>6 logs) organisms can be achieved throughout a hospital room. This study translates laboratory chlorine dioxide fumigation studies applied in a complex clinical environment.


Spallanzani's mouse: a model of restoration and regeneration.
The ability to regenerate is thought to be a lost phenotype in mammals, though there are certainly sporadic examples of mammalian regeneration. Our laboratory has identified a strain of mouse, the MRL mouse, which has a unique capacity to heal complex tissue in an epimorphic fashion, i.e., to restore a damaged limb or organ to its normal structure and function. Initial studies using through-and-through ear punches showed rapid full closure of the ear holes with cartilage growth, new hair follicles, and normal tissue architecture reminiscent of regeneration seen in amphibians as opposed to the scarring usually seen in mammals. Since the ear hole closure phenotype is a quantitative trait, this has been used to show-through extensive breeding and backcrossing--that the trait is heritable. Such analysis reveals that there is a complex genetic basis for this trait with multiple loci. One of the major phenotypes of the MRL mouse is a potent remodeling response with the absence or a reduced level of scarring. MRL healing is associated with the upregulation of the metalloproteinases MMP-2 and MMP-9 and the downregulation of their inhibitors TIMP-2 and TIMP-3, both present in inflammatory cells such as neutrophils and macrophages. This model has more recently been extended to the heart. In this case, a cryoinjury to the right ventricle leads to near complete scarless healing in the MRL mouse whereas scarring is seen in the control mouse. In the MRL heart, bromodeoxyuridine uptake by cardiomyocytes filling the wound site can be seen 60 days after injury. This does not occur in the control mouse. Function in the MRL heart, as measured by echocardiography, returns to normal.


Obstetric and perinatal outcomes from the australian and new zealand twin-twin transfusion syndrome registry.
Our purpose was to investigate the antepartum characteristics and perinatal outcomes of twin-twin transfusion syndrome cases from a multicenter national registry. Perinatal centers in Australia and New Zealand voluntarily notified a central evaluation registry with information on identified pregnancies with twin-twin transfusion syndrome during 1995 through 1998. One hundred twelve cases of twin-twin transfusion syndrome were registered. The median gestation at diagnosis was 21.5 weeks (range, 14.4-34.6 weeks). Oligohydramnios-polyhydramnios sequence was the most common presentation, with 84% of cases involving "stuck" twinning. Therapeutic amnioreduction was used in 92 cases (82.1%), with the median number of procedures per case being 2 (range, 1-23). The median gestation at delivery was 29 weeks (range, 18-38 weeks). The overall perinatal survival rate was 62.5%. Abnormal findings on cranial ultrasonography were present in 27.3% of live neonates, and periventricular leukomalacia was reported in 10.8%. Increased gestational age at delivery, the presence of umbilical artery diastolic flow, and a prolonged interval from final amnioreduction to delivery were positively associated with the delivery of live fetuses without complications. The majority of antenatally identified cases of twin-twin transfusion syndrome are managed with serial amnioreduction. Despite contemporary obstetric and neonatal management strategies, perinatal mortality and morbidity rates are high.


Reliability and Validity of a Brief Tool to Measure Children's Physical Activity.
We assessed the validity and reliability of a modified Godin-Leisure-Time Exercise Questionnaire in youth in grades 6 through 8. The questionnaire was completed by 250 children twice at a 1 wk interval to assess reliability. After the second questionnaire administration the children wore an accelerometer for 7 d (criterion measure). Pearson correlations between the first and second reports of frequency of participation in strenuous and moderate physical activity were 0.68 and 0.51, respectively. Self-reported participation in strenuous activity was weakly correlated with strenuous activity as measured by accelerometer (r = 0.23, P = 0.01). A weak non-significant correlation was found between reported versus measured engagement in moderate activity (r = 0.13, P = 0.07). Findings suggest the questionnaire evaluated in this study may be of very limited use for assessing children's physical activity.


Transient receptor potential vanilloid 4-expressing macrophages and keratinocytes contribute differentially to allergic and nonallergic chronic itch.
Chronic itch is a highly debilitating symptom that underlies many medical disorders with no universally effective treatments. Although unique neuronal signaling cascades in the sensory ganglia and spinal cord have been shown to critically promote the pathogenesis of chronic itch, the role of skin-associated cells remains poorly understood. We sought to examine the cutaneous mechanisms underlying transient receptor potential vanilloid 4 (TRPV4)-mediated allergic and nonallergic chronic itch. Expression of TRPV4 in chronic itch and healthy control skin preparations was examined by using real-time RT-PCR. Trpv4eGFP mice were used to study the expression and function of TRPV4 in the skin by means of immunofluorescence staining, flow cytometry, calcium imaging, and patch-clamp recordings. Genetic and pharmacologic approaches were used to examine the role and underlying mechanisms of TRPV4 in mouse models of dry skin-associated chronic itch and spontaneous scratching associated with squaric acid dibutylester-induced allergic contact dermatitis. TRPV4 is selectively expressed by dermal macrophages and epidermal keratinocytes in mice. Lineage-specific deletion of TRPV4 in macrophages and keratinocytes reduces allergic and nonallergic chronic itch in mice, respectively. Importantly, TRPV4 expression is significantly increased in skin biopsy specimens from patients with chronic idiopathic pruritus in comparison with skin from healthy control subjects. Moreover, TRPV4-dependent chronic itch requires 5-hydroxytryptamine (5-HT) signaling secondary to activation of distinct 5-HT receptors in mice with allergic and those with nonallergic chronic itch conditions. Our study reveals previously unrecognized mechanisms by which TRPV4-expressing epithelial and immune cells in the skin critically and dynamically mediate chronic itch and unravels novel targets for therapeutics in the setting of chronic itch.


Finite element analysis of the performance of additively manufactured scaffolds for scapholunate ligament reconstruction.
Rupture of the scapholunate interosseous ligament can cause the dissociation of scaphoid and lunate bones, resulting in impaired wrist function. Current treatments (e.g., tendon-based surgical reconstruction, screw-based fixation, fusion, or carpectomy) may restore wrist stability, but do not address regeneration of the ruptured ligament, and may result in wrist functional limitations and osteoarthritis. Recently a novel multiphasic bone-ligament-bone scaffold was proposed, which aims to reconstruct the ruptured ligament, and which can be 3D-printed using medical-grade polycaprolactone. This scaffold is composed of a central ligament-scaffold section and features a bone attachment terminal at either end. Since the ligament-scaffold is the primary load bearing structure during physiological wrist motion, its geometry, mechanical properties, and the surgical placement of the scaffold are critical for performance optimisation. This study presents a patient-specific computational biomechanical evaluation of the effect of scaffold length, and positioning of the bone attachment sites. Through segmentation and image processing of medical image data for natural wrist motion, detailed 3D geometries as well as patient-specific physiological wrist motion could be derived. This data formed the input for detailed finite element analysis, enabling computational of scaffold stress and strain distributions, which are key predictors of scaffold structural integrity. The computational analysis demonstrated that longer scaffolds present reduced peak scaffold stresses and a more homogeneous stress state compared to shorter scaffolds. Furthermore, it was found that scaffolds attached at proximal sites experience lower stresses than those attached at distal sites. However, scaffold length, rather than bone terminal location, most strongly influences peak stress. For each scaffold terminal placement configuration, a basic metric was computed indicative of bone fracture risk. This metric was the minimum distance from the bone surface to the internal scaffold bone terminal. Analysis of this minimum bone thickness data confirmed further optimisation of terminal locations is warranted.


Subcutaneous adipose tissue releases interleukin-6, but not tumor necrosis factor-alpha, in vivo.
We measured arterio-venous differences in concentrations of tumor necrosis factor-alpha (TNF alpha) and interleukin-6 (IL-6) across a sc adipose tissue bed in the postabsorptive state in 39 subjects [22 women and 17 men; median age, 36 yr (interquartile range, 26-48 yr); body mass index, 31.8 kg/m2 (range, 22.3- 38.7 kg/m2); percent body fat, 28.7% (range, 17.6-50.7%)]. A subgroup of 8 subjects had arteriovenous differences measured across forearm muscle. Thirty subjects were studied from late morning to early evening; 19 ate a high carbohydrate meal around 1300 h, and 11 continued to fast. We found a greater than 2-fold increase in IL-6 concentrations across the adipose tissue bed [arterial, 2.27 pg/mL (range, 1.42-3.53 pg/mL); venous, 6.71 pg/mL (range, 3.36-9.62 pg/mL); P < 0.001], but not across forearm muscle. Arterial plasma concentrations of IL-6 correlated significantly with body mass index (Spearman's r = 0.48; P < 0.01) and percent body fat (Spearman's r = 0.49; P < 0.01). Subcutaneous adipose tissue IL-6 production increased by the early evening (1800-1900 h) in both subjects who had extended their fasting and those who had eaten. Neither deep forearm nor sc adipose tissue consistently released TNF alpha [across adipose tissue: arterial, 1.83 pg/mL (range, 1.36-2.34 pg/mL); venous, 1.85 pg/mL (range, 1.44-2.53 pg/mL); P = NS: across forearm muscle: arterial, 1.22 pg/mL (range, 0.74-2.76 pg/mL); venous, 0.99 pg/mL (range, 0.69-1.70 pg/mL); P = NS]. Although both IL-6 and TNF alpha are expressed by adipose tissue, our results show that there are important differences in their systemic release. TNF alpha is not released by this sc depot. In contrast, IL-6 is released from the depot and is thereby able to signal systemically.


Random sampling of the Central European bat fauna reveals the existence of numerous hitherto unknown adenoviruses.
From over 1250 extant species of the order Chiroptera, 25 and 28 are known to occur in Germany and Hungary, respectively. Close to 350 samples originating from 28 bat species (17 from Germany, 27 from Hungary) were screened for the presence of adenoviruses (AdVs) using a nested PCR that targets the DNA polymerase gene of AdVs. An additional PCR was designed and applied to amplify a fragment from the gene encoding the IVa2 protein of mastadenoviruses. All German samples originated from organs of bats found moribund or dead. The Hungarian samples were excrements collected from colonies of known bat species, throat or rectal swab samples, taken from live individuals that had been captured for faunistic surveys and migration studies, as well as internal organs of dead specimens. Overall, 51 samples (14.73%) were found positive. We detected 28 seemingly novel and six previously described bat AdVs by sequencing the PCR products. The positivity rate was the highest among the guano samples of bat colonies. In phylogeny reconstructions, the AdVs detected in bats clustered roughly, but not perfectly, according to the hosts' families (Vespertilionidae, Rhinolophidae, Hipposideridae, Phyllostomidae and Pteropodidae). In a few cases, identical sequences were derived from animals of closely related species. On the other hand, some bat species proved to harbour more than one type of AdV. The high prevalence of infection and the large number of chiropteran species worldwide make us hypothesise that hundreds of different yet unknown AdV types might circulate in bats.


Transcriptomic responses to ocean acidification in larval sea urchins from a naturally variable pH environment.
Some marine ecosystems already experience natural declines in pH approximating those predicted with future anthropogenic ocean acidification (OA), the decline in seawater pH caused by the absorption of atmospheric CO2 . The molecular mechanisms that allow organisms to inhabit these low pH environments, particularly those building calcium carbonate skeletons, are unknown. Also uncertain is whether an enhanced capacity to cope with present day pH variation will confer resistance to future OA. To address these issues, we monitored natural pH dynamics within an intertidal habitat in the Northeast Pacific, demonstrating that upwelling exposes resident species to pH regimes not predicted to occur elsewhere until 2100. Next, we cultured the progeny of adult purple sea urchins (Strongylocentrotus purpuratus) collected from this region in CO2 -acidified seawater representing present day and near future ocean scenarios and monitored gene expression using transcriptomics. We hypothesized that persistent exposure to upwelling during evolutionary history will have selected for increased pH tolerance in this population and that their transcriptomic response to low pH seawater would provide insight into mechanisms underlying pH tolerance in a calcifying species. Resulting expression patterns revealed two important trends. Firstly, S. purpuratus larvae may alter the bioavailability of calcium and adjust skeletogenic pathways to sustain calcification in a low pH ocean. Secondly, larvae use different strategies for coping with different magnitudes of pH stress: initiating a robust transcriptional response to present day pH regimes but a muted response to near future conditions. Thus, an enhanced capacity to cope with present day pH variation may not translate into success in future oceans.


[Metoprolol CR/XL: advanced formulation of a classical beta-blocker].
Metoprolol is a selective beta(1)-adrenergic antagonist extensively used in major fields of cardiology since 1975. Metoprolol has proven its efficacy in reducing cardiovascular events and mortality in patients with hypertension and coronary heart disease in large clinical trials. Recently developed controlled release/extended release (CR/XL) formulation of metoprolol succinate was designed to provide relatively constant metoprolol plasma concentrations and beta(1)-blockade while retaining the convenience of once daily administration. The avoidance of high peak plasma concentrations with metoprolol succinate is associated with lesser degree of adverse effects and may improve patients compliance. This formulation of metoprolol has demonstrated efficacy in reducing cardiovascular events and mortality in patients with heart failure. More recently evidence for antiatherogenic activity of metoprolol succinate has been also obtained.


Outcomes of hydralazine induced renal vasculitis.
Hydralazine has been implicated as an etiologic agent for lupus-like syndrome and vasculitis. Hydralazine-induced vasculitis frequently affects the kidney, but the long-term renal outcomes in these patients have not yet been studied. Patients who had a diagnosis of ANCA-associated vasculitis (AAV) and were on hydralazine at the time of AAV diagnosis were included in this retrospective cohort study. Clinical and laboratory data were obtained from the review of medical records. Seven patients met the criteria for hydralazine-induced AAV. Five patients (71%) were African-American and four (57%) were female. The median age was 69 years at the time of diagnosis. All patients had renal involvement with two of them showing lung involvement as well. All patients had positive MPO antibody and one patient had positive PR3 antibody. ANA was positive in all patients, and three of seven patients had positive anti-histone antibody. All of them were treated with immunosuppression and withdrawal of hydralazine. Three patients reached end-stage renal disease. The median follow-up time was 13 months. Renal involvement in hydralazine-induced AAV was universal and can be associated with a poor renal outcome despite immunosuppressive therapy.


Identification of a resin-dentin hybrid layer in vital human dentin created in vivo: durable bonding to vital dentin.
The present study investigated the bond of 5% 4-methacryloxyethyl trimellitate anhydride in methyl methacrylate, initiated by partially oxidized tri-n-butyl borane in the presence of poly(methyl methacrylate) powder, to vital human dentin. In vivo dentinal substrates were pretreated for 10 or 30 seconds with an aqueous solution of 10% citric acid and 3% ferric chloride. Transmission electron microscopic examination of the bonded cross sections revealed the formation of a transitional, or "hybrid," layer of resin-reinforced dentin created by the impregnation, co-mingling and envelopment of collagen bundles, and encapsulation of hydroxylapatite crystals. The in vivo adhesion was assumed to be durable, because results of microscopic examinations were comparable to those of durable bonding of the same resin to extracted bovine dentin. Vital dentin exhibited greater resistance to demineralization by the acid solution than do extracted teeth. Carious extracted teeth were more easily dissolved in acid than were noncarious extracted teeth.


Psychiatric symptoms and histories among people detained in police cells.
This study examined the psychiatric symptoms, mental health histories and psychiatric medication use in a sample of people detained in police cells. Offences that led to the detention episode were compared between those with and without psychiatric symptoms. Detainees were interviewed by nurses who completed a clinical interview and the Brief Psychiatric Rating Scale. Full histories of contact data for participants were then drawn from the public mental health services database and the police database, and from their general practitioners. One-third of the 614 detainees exhibited psychiatric symptoms in police custody; and 42% received medical treatment after arrest. Over half (55%) of the detainees had previous contact with the public mental health system. Having a history of contact with mental health services was found to contribute significantly to psychiatric symptoms in police cells. Offences committed by detainees did not differ between those presenting with and without psychiatric symptoms. Many detainees in police cells experience psychiatric symptoms. This creates a significant clinical need necessitating timely access to health care and a continuity of care with health service providers beyond the initial police cell contact. Such a service model will require the development of functional interagency partnerships between the police and health services.


Streptavidin functionalized polymer nanodots fabricated by visible light lithography.
Two-photon polymerization, optionally combined with stimulated emission depletion (STED) lithography, allows two and three dimensional polymer fabrication with structure sizes and resolution below the diffraction limit. Structuring of polymers with photons, whose wavelength is within the visible range of the electromagnetic spectrum, gives new opportunities to a large field of applications e.g. in the field of biotechnology and tissue engineering. In order to create new biotechnological applications, versatile methods are needed to functionalize the polymeric structures. Here we report the creation of polymer-nanodots with high streptavidin (SA) affinity via two-photon polymerization (TPP). Controlling the size of the polymer dots allows for limiting the number of the SA molecules. TPP dots with a diameter of a few 100 nm show up to 100% streptavidin loading. We can show that most of the dots are loaded by one to two streptavidins on average. Attached streptavidin molecules remain functional and are capable to bind 0.7 biotin molecules on average. The presented functionalized nanostructures may be used as platforms for a multitude of biological experimental setups. Nanoscopic well defined structures, capable of selective binding of streptavin proteins, used as linkers for other biotinylated biomolecules, may also find application in in-vitro sensing, like for example lab on chip devices with limited surface area.


Unifying theoretical framework for deciphering the oxygen reduction reaction on platinum.
Rapid conversion of oxygen into water is crucial to the operation of polymer electrolyte fuel cells and other emerging electrochemical energy technologies. Chemisorbed oxygen species play double-edged roles in this reaction, acting as vital intermediates on one hand and site-blockers on the other. Any attempt to decipher the oxygen reduction reaction (ORR) must first relate the formation of oxygen intermediates to basic electronic and electrostatic properties of the catalytic surface, and then link it to parameters of catalyst activity. An approach that accomplishes this feat will be of great utility for catalyst materials development and predictive model formulation of electrode operation. Here, we present a theoretical framework for the multiple interrelated surface phenomena and processes involved, particularly, by incorporating the double-layer effects. It sheds light on the roles of oxygen intermediates and gives out the Tafel slope and exchange current density as continuous functions of electrode potential. Moreover, it develops the concept of a rate determining term, which should replace the concept of a rate determining step for multielectron reactions, and offers a new perspective on the volcano relation of the ORR.


Preclinical Pharmacokinetics Study of R- and S-Enantiomers of the Histone Deacetylase Inhibitor, AR-42 (NSC 731438), in Rodents.
AR-42, a new orally bioavailable, potent, hydroxamate-tethered phenylbutyrate class I/IIB histone deacetylase inhibitor currently is under evaluation in phase 1 and 2 clinical trials and has demonstrated activity in both hematologic and solid tumor malignancies. This report focuses on the preclinical characterization of the pharmacokinetics of AR-42 in mice and rats. A high-performance liquid chromatography-tandem mass spectrometry assay has been developed and applied to the pharmacokinetic study of the more active stereoisomer, S-AR-42, when administered via intravenous and oral routes in rodents, including plasma, bone marrow, and spleen pharmacokinetics (PK) in CD2F1 mice and plasma PK in F344 rats. Oral bioavailability was estimated to be 26 and 100% in mice and rats, respectively. R-AR-42 was also evaluated intravenously in rats and was shown to display different pharmacokinetics with a much shorter terminal half-life compared to that of S-AR-42. Renal clearance was a minor elimination pathway for parental S-AR-42. Oral administration of S-AR-42 to tumor-bearing mice demonstrated high uptake and exposure of the parent drug in the lymphoid tissues, spleen, and bone marrow. This is the first report of the pharmacokinetics of this novel agent, which is now in early phase clinical trials.


Single photon emission tomography with 99mTc-exametazime in major depression and the pattern of brain activity underlying the psychotic/neurotic continuum.
Forty patients with a major depressive episode were investigated at rest using Single Photon Emission Tomography (SPET or SPECT) with 99mTc-exametazime, an intravenous ligand taken into brain in proportion to regional cerebral blood flow, thereby providing an estimate of regional metabolism. All patients were unipolar and were rated on the Newcastle scale and with the 17-item Hamilton scale. They also completed a range of neuropsychological tests. They were compared with 20 control subjects matched for age, gender, premorbid intelligence and education. The uptake of 99mTc-exametazime was expressed for a range of anatomically defined regions of interest relative to calcarine/occipital cortex. The depressed group showed reduced uptake in the majority of cortical and sub-cortical regions examined, most significantly in temporal, inferior frontal and parietal areas. Unexpectedly, there was a strong positive association between uptake and scores on the Newcastle scale, especially in cingulate areas and frontal cortex. After removing the variance attributable to the Newcastle ratings, however, there emerged the expected negative association between Hamilton scores and anterior tracer uptake. The associations between neuropsychological impairment and regional brain uptake of tracer in part reflected the pattern seen with the Newcastle scale: for example, impairment of memory function correlated with higher uptake into posterior cingulate areas. We propose that depressive illness may be characterised by two processes. One leads to an overall reduction in anterior neocortical function, perhaps related to symptom severity. The other mechanism is manifest as relatively increased function, most notably within cingulate and frontal areas of the cerebral cortex in association with psychotic symptoms. The findings offer new understanding of the brain states underlying depressive illness and a potential focus to subsequent neuropharmacological analysis.


Bestrophin-1 encodes for the Ca2+-activated anion channel in hippocampal astrocytes.
In mammalian brain, neurons and astrocytes are reported to express various chloride and anion channels, but the evidence for functional expression of Ca(2+)-activated anion channel (CAAC) and its molecular identity have been lacking. Here we report electrophysiological evidence for the CAAC expression and its molecular identity by mouse Bestrophin 1 (mBest1) in astrocytes of the mouse brain. Using Ca(2+) imaging and perforated-patch-clamp analysis, we demonstrate that astrocytes displayed an inward current at holding potential of -70 mV that was dependent on an increase in intracellular Ca(2+) after G(alphaq)-coupled receptor activation. This current was mediated mostly by anions and was sensitive to well known anion channel blockers such as niflumic acid, 5-nitro-2(3-phenylpropylamino)-benzoic acid, and flufenamic acid. To find the molecular identity of the anion channel responsible for the CAAC current, we analyzed the expression of candidate genes and found that the mRNA for mouse mBest1 is predominantly expressed in acutely dissociated or cultured astrocytes. Whole-cell patch-clamp analysis using HEK293T cells heterologously expressing full-length mBest1 showed a Ca(2+)-dependent current mediated by mBest1, with a complete impairment of the current by a putative pore mutation, W93C. Furthermore, mBest1-mediated CAAC from cultured astrocytes was significantly reduced by expression of mBest1-specific short hairpin RNA (shRNA), suggesting that the CAAC is mediated by a channel encoded by mBest1. Finally, hippocampal CA1 astrocytes in hippocampal slice also showed mBest1-mediated CAAC because it was inhibited by mBest1-specific shRNA. Collectively, these data provide molecular evidence that the mBest1 channel is responsible for CAAC function in astrocytes.


After rehabilitation: an 18-month follow-up of elderly inner-city women.
Elderly inner-city women (n = 125) greater than the age of 60 and living alone and who were consecutively admitted to a large, urban, university-based rehabilitation hospital were followed to (a) examine the power of standardized clinical measures to predict who was living alone 18 months after discharge, (b) determine whether live-alone women at 18 months' follow-up were more independent in instrumental activities of daily living (IADL) than women who were not living alone, and (c) investigate whether women who return home to live alone and have low or declining physical function are at risk for subsequent relocation or death. Data from four standardized assessments (physical function, cognition, comorbidity, and depression) and demographic information were gathered during in-patient rehabilitation. Self-report IADL data were collected via telephone interviews at 3, 6, and 18 months' follow-up. Statistical analysis of results showed that physical function, cognition, and comorbidity were significant and independent predictors of living alone at 18 months' follow-up. Women living alone at 18 months reported significantly greater IADL independence than women who were not living alone. Path analysis confirmed that the relationship between the clinical measures and living situation at 18 months was mediated by self-reported IADL functioning. Standard clinical data obtained at discharge are useful to identify who can return home to live alone after rehabilitation, but in-home assessment of IADL remains key to understanding the complex skills required to live alone.


Extensive linkage disequilibrium in the achaete-scute complex of Drosophila melanogaster.
We have analyzed the level of gametic association between restriction map variants in a sample of 44 X chromosomes from a natural population of Drosophila melanogaster. Of 21 pairwise tests involving 7 restriction map polymorphisms in the yellow-achaete-scute complex, 17 were found to be significant, including some between restriction sites over 80 kb apart. Three-way linkage disequilibria and their variances were also estimated for all 35 three-way comparisons between these loci. Twelve such tests were found to be significant, again spanning distances of up to 80 kb on the restriction map. Only 9 of a possible 128 haplotypes were represented in the sample and 8 of these could be linked together by changes at a single site. The strength of these associations at y-ac-sc is unusual by comparison with studies on other regions of the genome of D. melanogaster, and is consistent with the very low level of recombination which has been reported for the complex. However, our estimate of nucleotide diversity in the region is not significantly different from those made for some other loci in this species.


Cytochemical localization of Na+/K+-ATPase activity in cochlear strial marginal cells after various catecholamine administrations.
Sodium/potassium-activated adenosine triphosphatase (Na+/K+-ATPase) activity in the kidney and brain is high, and is regulated by catecholamines. Na+/K+-ATPase activity is also high in the basolateral infoldings of the strial marginal cells, where it aids in maintaining the characteristic electrolyte composition of the endolymph. To clarify the involvement of humoral control in strial function, particularly the role of catecholamines, the K+-dependent p-nitrophenylphosphatase (K+-NPPase) activity of strial marginal cells was investigated in guinea pigs using a cerium-based cytochemical method. The effects of reserpine, serotonin (5-HT), norepinephrine (NE), epinephrine (EP), both alone and in combination, were studied. High doses of reserpine cause depletion of sympathetic substances. Strial K+-NPPase activity was decreased after reserpine or dopamine treatment, and was increased after 5-HT, NE, and EP treatment. After reserpinization, repeated treatment with 5-HT, NE, or EP led to detectable strial enzyme activity. Thus, exogenous 5-HT, NE, and EP were able to restore strial K+-NPPase activity in the reserpine-treated animals. These results suggested that biogenic amines regulate strial K+-NPPase activity. Thus, the function of the stria vascularis may be regulated by the opposing actions of these catecholamines, and 5-HT.


Eradication of hepatitis C virus infection and the development of hepatocellular carcinoma: a meta-analysis of observational studies.
Hepatitis C virus (HCV) is a leading cause of hepatocellular carcinoma (HCC). In the United States, this form of cancer occurs in approximately 15 000 persons annually. A systematic review of the evidence is needed to assess the benefits of treatment of HCV-infected persons on development of HCC. To systematically review observational studies to determine the association between response to HCV therapy and development of HCC among persons at any stage of fibrosis and those with advanced liver disease. MEDLINE, EMBASE, CINAHL, the Cochrane Library, Web of Science, and the Database of Abstracts of Reviews and Effectiveness from inception through February 2012. English-language observational studies that compared therapy-derived sustained virologic response (SVR) with no response to therapy among HCV-infected persons, targeted an adult population, and had an average follow-up of at least 2 years. Two investigators independently extracted data into uniform relative risk measures. The Grading of Recommendations Assessment, Development and Evaluation framework was used to determine the quality of the evidence. Thirty studies fulfilled the inclusion criteria, and 18 provided adjusted effect estimates that were used to calculate pooled relative risks. Among HCV-infected persons, SVR was associated with reduced risk for HCC (relative risk for all persons, 0.24 [95% CI, 0.18 to 0.31], moderate-quality evidence; advanced liver disease hazard ratio, 0.23 [CI, 0.16 to 0.35], moderate-quality evidence). In the meta-analyses, some variables could not be controlled for because of the observational design of the included studies. Sustained virologic response after treatment among HCV-infected persons at any stage of fibrosis is associated with reduced HCC. The evidence was determined to be of moderate quality.


Online management of text production from pictures: a comparison between fifth graders and undergraduate students.
This study was designed to enhance our understanding of the online management of writing processes by two groups of writers with a different level of expertise, and to explore the impact of this online management on text quality. To this aim, fifth graders (mean age 10.5 years) and undergraduate students (mean age 22.6 years) were asked to compose a narrative from a visual source of images, while their handwriting activity and eye movements were recorded by means of Eye & Pen software and a digitizing tablet. Results showed that fifth graders and undergraduate students used different strategies to engage in high-level source-based text elaboration processes throughout their writing. The main differences concerned the density of source consultation during prewriting, on the one hand, and during pauses, on the other hand. Relationships between these characteristics of online management and text quality were minimal in fifth graders, while in undergraduate students they were more substantial as in the case of syntactic complexity. These findings suggest that with age, the online management of writing becomes more closely related to text quality. In line with a capacity view of writing, it is also concluded that the online management of writing processes of fifth graders is highly constrained by a lack of fluent text production skills which ultimately affects their text quality.


Evolution of Dermatofibrosarcoma Protuberans to DFSP-Derived Fibrosarcoma: An Event Marked by Epithelial-Mesenchymal Transition-like Process and 22q Loss.
Dermatofibrosarcoma protuberans (DFSP) is a rare and indolent cutaneous sarcoma. At times, a fibrosarcomatous transformation marked by a more aggressive clinical behavior may be present. We investigated the natural history and the molecular bases of progression from classic DFSP to the fibrosarcomatous form (FS-DFSP), looking, retrospectively, at the outcome of all patients affected by primary DFSP treated at our institution from 1993 to 2012 and analyzing the molecular profile of 5 DFSPs and 5 FS-DFSPs by an integrated genomics approach (whole transcriptome sequencing, copy number analysis, FISH, qRT-PCR, IHC). The presence of fibrosarcomatous features was identified in 20 (7.6%) patients out of 263 DFSP. All cases were treated with macroscopic complete surgery. A local relapse occurred in 4 of 23 patients who received a microscopic marginal surgery (2 classic DFSP, 2 FS-DFSP), while metastasis affected 2 patients, both FS-DFSP (10% of FS-DFSP), being the first event. DFSP evolution to FS-DFSP was paralleled by a transcriptional reprogramming. The recurrent loss of chromosome 22q appeared to contribute to this phenomenon by promoting the expression of epigenetic regulators, such as EZH2. Loss of the p16/CDKN2A/INK4A locus at 9p was also observed in two FS-DFSP metastatic cases. FS-DFSP is a rare subgroup among DFSP, with a 10% metastatic risk, that was independent from local recurrence and that was not observed in DFSP, that were all cured by wide surgery. Chromosome 22q deletion might play a role in FS-DFSP, and p16 loss may convey a poor outcome. EZH2 dysregulation was also found and represents a druggable target. Mol Cancer Res; 14(9); 820-9. ©2016 AACR.


Optimal search filters for detecting quality improvement studies in Medline.
As the knowledge translation and comparative effectiveness research agendas gain momentum, we can expect more evidence on which to base quality improvement (QI) programmes. Unaided searches for such content in the literature, however, are likely to be daunting, with searches missing key articles while mainly retrieving articles that are irrelevant to the question being asked. The objective of this study was to develop and validate optimal Medline search filters for retrieving original and review articles about clinical QI. Analytical survey in the McMaster Clinical Hedges database and Health Knowledge Refinery (HKR) of 161 clinical journals to determine the operating characteristics of QI search filters developed by computerised combinations of terms selected to detect original QI studies and systematic reviews meeting basic methodological criteria for scientific merit. Results from a derivation random subset of articles were tested in a validation random subset. The Clinical Hedges QI database contained 49,233 citations of which 471 (0.96%) were original or review QI studies; of those, 282 (60%) were methodologically sound. Combinations of search terms reached peak sensitivities of 100% at a specificity of 89.3% for detecting methodologically sound original and review QI studies, and sensitivities of 97.6% at a specificity of 53.0% for detecting all original and review QI studies independent of rigour. Operating characteristics of the search filters derived in the development database worked similarly in the validation database, without statistical differences. New empirically derived Medline search filters have been validated to optimise retrieval of original and review QI articles.


[An evaluation of efficacy of minocycline as an anti-rheumatic drug in patients with active and refractory rheumatoid arthritis].
The efficacy and safety of minocycline was investigated in Japanese patients with rheumatoid arthritis (RA) who had already received more than three disease modifying anti-rheumatic drugs (DMARDs). Minocycline was administered at 100 mg twice a day to fifteen patients with active RA. The drug efficacy was evaluated by the clinical variables including the number of painful and/or swollen joints, the duration of morning stiffness, grip strength, the erythrocyte sedimentation rate, serum concentrations of C-reactive protein, and the titer of rheumatoid factor. Three patients experienced adverse effects such as dizziness and abdominal pain or discomfort, but only one patient with abdominal pain and dizziness was discontinued. Fourteen RA patients, who had taken minocycline for at least 6 months, were subjected to the clinical evaluation. Among them, 8 patients (54%) showed a significant improvement of clinical valuables for disease activity, beginning even at 4 weeks of the therapy. The continued effects were observed in 8 patients with over 1 year-minocycline therapy. Intriguingly, an active patient with a history of multiple DMARDs-resistancy showed a marked favorable response to this drug. The present study indicates that minocycline may be an effective DMARD with highly safe performance for patients with active and refractory RA. This is the first demonstration of the benefit of minocycline in the Japanese patients.