Transgenic mice expressing different levels of soluble platelet/endothelial cell adhesion molecule-IgG display distinct inflammatory phenotypes.
Platelet/endothelial cell adhesion molecule-1 (PECAM-1, CD31), expressed on the surfaces of leukocytes and concentrated in the junctions between endothelial cells plays an important role in transendothelial migration of neutrophils and monocytes. Soluble recombinant PECAM-IgG injected i.v. into mice blocks acute leukocyte emigration by 80%. To study the role of PECAM in models of chronic inflammation, we generated transgenic mice constitutively expressing soluble full-length murine PECAM as an IgG chimera. Three founder lines expressed this transgene and constitutively secreted murine PECAM-IgG into the plasma where it was maintained at characteristic concentrations for each line. All mice had similar hematologic profiles to wild-type littermates and were healthy when maintained in the standard laboratory animal facility. Both the leukocytes and the endothelium of mice of all transgenic lines expressed the same levels of endogenous PECAM-1 as wild-type littermates. Similarly, there were no detectable differences in the expression of several other common leukocyte and endothelial cell adhesion molecules. Mice that produced moderate (10-20 microg/ml) concentrations of PECAM-IgG demonstrated a severely blunted acute inflammatory response, despite mobilizing appropriate numbers of circulating leukocytes. Surprisingly, mice that constitutively produced high (400-1,000 microg/ml) concentrations of PECAM-IgG were unresponsive to its anti-inflammatory effects. This is the first demonstration that a soluble form of a cell adhesion molecule can be stably expressed and retain efficacy in vivo over prolonged periods. This approach is applicable to many other extracellular molecules. However, the plasma concentrations of such constitutively produced inhibitors may greatly influence the resulting phenotype.


The influence of central corneal thickness on intraocular pressure measured by goldmann applanation tonometry among selected Ethiopian communities.
Estimates of intraocular pressure (IOP) are influenced directly by the central corneal thickness (CCT). We assume and apply a single value for CCT (520 μm) in applanation tonometry estimates, although there is compelling evidence that CCT varies between individuals. To determine the influence of CCT and other factors on IOP among Ethiopians. A cross sectional study was conducted among 300 sampled individuals from June to July 2006. The CCT was measured using OcuScan® R×P Ophthalmic Ultrasound and readings of IOP were made with Goldmann applanation tonometer. The data was analyzed using SPSS version 12 and S-Plus 2000 of statistical packages. Out of 300 individuals, 184 (61.3%) were males. The mean age was 42.57 years (SD±16.71), mean IOP 13.39 mm Hg (SD±2.81), and mean CCT 518.68 μm (SD±32.92). There was statistically significant relationship between CCT and IOP (r=0.199, P<0.001) and a borderline statistically significant detectable change of CCT with age (r=0.012, P=0.057) with a downward trend of at least 0.001 mm decrease in CCT/decade starting from age 30 years but with pronounced change from 50 years onward. For every 30 μm difference in CCT from the mean in either way, there was an approximately 1.1 mm Hg difference in the estimated IOP from the mean IOP (13.40 mm Hg). No significant relationship was found between IOP and age, sex or ethnicity (P>0.05). The CCT of Ethiopians is thin and hence can result in underestimation of IOP measured by GAT.


Transcutaneous spinal direct current stimulation increases corticospinal transmission and enhances voluntary motor output in humans.
Optimization of motor performance is of importance in daily life, in relation to recovery following injury as well as for elite sports performance. The present study investigated whether transcutaneous spinal direct current stimulation (tsDCS) may enhance voluntary ballistic activation of ankle muscles and descending activation of spinal motor neurons in able-bodied adults. Forty-one adults (21 men; 24.0 ± 3.2 years) participated in the study. The effect of tsDCS on ballistic motor performance and plantar flexor muscle activation was assessed in a double-blinded sham-controlled cross-over experiment. In separate experiments, the underlying changes in excitability of corticospinal and spinal pathways were probed by evaluating soleus (SOL) motor evoked potentials (MEPs) following single-pulse transcranial magnetic stimulation (TMS) over the primary motor cortex, SOL H-reflexes elicited by tibial nerve stimulation and TMS-conditioning of SOL H-reflexes. Measures were obtained before and after cathodal tsDCS over the thoracic spine (T11-T12) for 10 min at 2.5 mA. We found that cathodal tsDCS transiently facilitated peak acceleration in the ballistic motor task compared to sham tsDCS. Following tsDCS, SOL MEPs were increased without changes in H-reflex amplitudes. The short-latency facilitation of the H-reflex by subthreshold TMS, which is assumed to be mediated by the fast conducting monosynaptic corticomotoneuronal pathway, was also enhanced by tsDCS. We argue that tsDCS briefly facilitates voluntary motor output by increasing descending drive from corticospinal neurones to spinal plantar flexor motor neurons. tsDCS can thus transiently promote within-session CNS function and voluntary motor output and holds potential as a technique in the rehabilitation of motor function following central nervous lesions.


[The selection of the composition of the medium for optimizing the amine-synthetic activity of aerobic bacilli].
Nutrient medium chosen as a basic one after preliminary test of several media known from literature has been optimized to intensify biosynthesis and amine nitrogen production by three strains of aerobic sporulating bacteria to culture liquid. The method of mathematical planning used in the experiments has permitted obtaining the components ratio for the medium on which production of amine nitrogen to the environment increased 2.3-3.2 times. The best variants of the optimized medium promoted an increase of the aminosynthetic activity of the studied bacteria by more than 320%. The obtained nutrient medium is appropriate for a wide screening of aerobic bacilli for their ability to synthesize amino compounds.


Reactions between nitric oxide and haemoglobin under physiological conditions.
The tenet of high-affinity nitric oxide (NO) binding to a haemoglobin (Hb) has shaped our view of haem proteins and of small diffusible signaling molecules. Specifically, NO binds rapidly to haem iron in Hb (k approximately 10[7] M[-1] s[-1]) and once bound, the NO activity is largely irretrievable (Kd approximately 10[-5] s[-1]); the binding is purportedly so tight as to be unaffected by O2 or CO. However, these general principles do not consider the allosteric state of Hb or the nature of the allosteric effector, and they mostly derive from the functional behaviour of fully nitrosylated Hb, whereas Hb is only partially nitrosylated in vivo. Here we show that oxygen drives the conversion of nitrosylhaemoglobin in the 'tense' T (or partially nitrosylated, deoxy) structure to S-nitrosohaemoglobin in the 'relaxed' R (or ligand-bound, oxy) structure. In the absence of oxygen, nitroxyl anion (NO-) is liberated in a reaction producing methaemoglobin. The yields of both S-nitrosohaemoglobin and methaemoglobin are dependent on the NO/Hb ratio. These newly discovered reactions elucidate mechanisms underlying NO function in the respiratory cycle, and provide insight into the aetiology of S-nitrosothiols, methaemoglobin and its related valency hybrids. Mechanistic reexamination of NO interactions with other haem proteins containing allosteric-site thiols may be warranted.


Professionalism and the know-do gap: exploring intrinsic motivation among health workers in Tanzania.
Professionalism can be defined generally as adhering to the accepted standards of a profession and placing the interests of the public above the individual professional's immediate interests. In the field of medicine, professionalism should lead at least some practitioners in developing countries to effectively care for their patients despite the absence of extrinsic incentives to do so. In this study we examine the behavior of 80 practitioners from the Arusha region of Tanzania for evidence of professionalism. We show that about 20% of these practitioners behave professionally, and almost half of those who do so practice in the public sector. These professional health care workers provide high quality care even when they work in an environment that does not reward this effort, a finding that has important implications for the use of performance-based incentives.


Hematopoietic transcription factor mutations: important players in inherited platelet defects.
Transcription factors (TFs) are proteins that bind to specific DNA sequences and regulate expression of genes. The molecular and genetic mechanisms in most patients with inherited platelet defects are unknown. There is now increasing evidence that mutations in hematopoietic TFs are an important underlying cause for defects in platelet production, morphology, and function. The hematopoietic TFs implicated in patients with impaired platelet function and number include runt-related transcription factor 1, Fli-1 proto-oncogene, E-twenty-six (ETS) transcription factor (friend leukemia integration 1), GATA-binding protein 1, growth factor independent 1B transcriptional repressor, ETS variant 6, ecotropic viral integration site 1, and homeobox A11. These TFs act in a combinatorial manner to bind sequence-specific DNA within promoter regions to regulate lineage-specific gene expression, either as activators or repressors. TF mutations induce rippling downstream effects by simultaneously altering the expression of multiple genes. Mutations involving these TFs affect diverse aspects of megakaryocyte biology, and platelet production and function, culminating in thrombocytopenia and platelet dysfunction. Some are associated with predisposition to hematologic malignancies. These TF variants may occur more frequently in patients with inherited platelet defects than generally appreciated. This review focuses on alterations in hematopoietic TFs in the pathobiology of inherited platelet defects.


Lipid metabolism in inflammation-related diseases.
There are thousands of lipid species existing in cells, which belong to eight different categories. Lipids are the essential building blocks of cells. Recent studies have started to unveil the important functions of lipids in regulating cell metabolism. However, we are still at a very early stage in fully understanding the physiological and pathological functions of lipids. The application of lipidomics for studying lipid metabolism can provide a direct readout of the cellular status and broadens our understanding of the mechanisms that underpin metabolic disease states. This review provides an introduction to lipid metabolism and its role in modulating homeostasis and immunity. We also describe representative applications of lipidomics for studying lipid metabolism in inflammation-related diseases.


Evaluation of the craniofacial and oral characteristics of individuals with Down syndrome: A review of the literature.
The aim of this investigation was to describe the craniofacial and oral characteristics of children and/or adolescents with and without Down syndrome (DS). A bibliographic search of the Medline database (via PubMed), Scopus and SCIELO was performed using the keywords "craniofacial characteristics", "dental characteristics" and "Down syndrome". Systematic reviews, observational cross-sectional and longitudinal studies were included. On the contrary, case reports, letters to the editor, editorials and opinion articles were excluded. 251 articles were recovered, and only 30 fulfilled the selection criteria. DS patients were characterized by reduced dimensions of the maxillary bone, mandible, and skull base, compared to normal patients. Likewise, some of these abnormalities influenced more frequent presentation of a class III malocclusion in these patients. On the other hand, this population group showed a higher prevalence of periodontal diseases, less risk of dental caries, and the presence of alterations in the tongue, lips, dental development and palate morphology. The quality of life of these individuals is affected by difficulties in swallowing, talking, eating or breathing through the nose. In conclusion, the craniofacial and oral characteristics of DS patients present various alterations compared to healthy patients, and these alterations have a negative impact on their quality of life.


Combined posterior flap and anterior suspended flap dacryocystorhinostomy: A modification of external dacryocystorhinostomy.
External dacryocystorhinostomy (DCR) remains a reliable surgical technique for the treatment of obstruction of lacrimal drainage system beyond the common canalicular opening. To describe a simple modified double flap external DCR technique. Ninety six consecutive cases of chronic dacryocystitis with or without mucocele were selected irrespective of age and sex. In a modification to routine external DCR, a modified technique was followed, where both anterior and posterior flaps of lacrimal sac and nasal mucosa are created and sutured. Two double armed sutures were used to join the edges of anterior flaps, and elevate them anteriorly to avoid adhesion or apposition with underlying sutured posterior flaps, and to approximate the deep plane of the wound. At the end of average follow-up period of 13 months, we observed 98.9% objective and 96.8% subjective success rates. The average operation time was 45 minutes. No significant intraoperative or postoperative complications were noticed. We believe that combined posterior flap and anterior suspended flap DCR technique is simple to perform and has the advantage of both double flap DCR and anterior suspension of anterior flaps. The results of the study showed the efficacy of this simple modification.


Mechanical and structural adaptations to migration in the flight feathers of a Palaearctic passerine.
Current avian migration patterns in temperate regions have been developed during the glacial retreat and subsequent colonization of the ice-free areas during the Holocene. This process resulted in a geographic gradient of greater seasonality as latitude increased that favoured migration-related morphological and physiological (co)adaptations. Most evidence of avian morphological adaptations to migration comes from the analysis of variation in the length and shape of the wings, but the existence of intra-feather structural adjustments has been greatly overlooked despite their potential to be under natural selection. To shed some light on this question, we used data from European robins Erithacus rubecula overwintering in Campo de Gibraltar (Southern Iberia), where sedentary robins coexist during winter with conspecifics showing a broad range of breeding origins and, hence, migration distances. We explicitly explored how wing length and shape, as well as several functional (bending stiffness), developmental (feather growth rate) and structural (size and complexity of feather components) characteristics of flight feathers, varied in relation to migration distance, which was estimated from the hydrogen stable isotope ratios of the summer-produced tail feathers. Our results revealed that migration distance not only favoured longer and more concave wings, but also promoted primaries with a thicker dorsoventral rachis and shorter barb lengths, which, in turn, conferred more bending stiffness to these feathers. We suggest that these intra-feather structural adjustments could be an additional, largely unnoticed, adaptation within the avian migratory syndrome that might have the potential to evolve relatively quickly to facilitate the occupation of seasonal environments.


EDC: a microcomputer program to record and calculate expected date of confinement.
A microcomputer program was developed to compute the expected date of confinement (EDC) and to record the clinical parameters used in its calculation. In obstetrical care, it is important to establish the EDC. However, the last menstrual period on which the EDC is usually determined may be unknown, inaccurate or disagree with other clinical estimators of the gestational age. Useful predictions of the EDC can be derived from a number of clinical examinations. The program can be used to maintain a register from which the EDC is calculated by averaging the EDCs estimated from up to 19 parameters. The result is also displayed as the gestation age in number of weeks. The register containing information on a large number of pregnancies can be used to calculate the dispersion of estimated EDCs from the various clinical methods.


Single session high definition transcranial direct current stimulation to the cerebellum does not impact higher cognitive function.
The prefrontal cortex is central to higher order cognitive function. However, the cerebellum, generally thought to be involved in motor control and learning, has also been implicated in higher order cognition. Recent work using transcranial direct current stimulation (tDCS) provides some support for right cerebellar involvement in higher order cognition, though the results are mixed, and often contradictory. Here, we used cathodal high definition tDCS (HD-tDCS) over the right cerebellum to assess the impact of HD-tDCS on modulating cognitive performance. We predicted that stimulation would result in performance decreases, which would suggest that optimal cerebellar function is necessary for cognitive performance, much like the prefrontal cortex. That is, it is not simply a structure that lends support to complete difficult tasks. While the expected cognitive behavioral effects were present, we did not find effects of stimulation. This has broad implications for cerebellar tDCS research, particularly for those who are interested in using HD-tDCS as a way of examining cerebellar function. Further implications, limitations, and future directions are discussed with particular emphasis on why null findings might be critical in developing a clear picture of the effects of tDCS on the cerebellum.


Limited inner ear morphogenesis and neurosensory development are possible in the absence of GATA3.
Haploinsufficiency of Gata3 causes hypoparathyroidism, deafness and renal dysplasia (HDR) syndrome in mice and humans. Gata3 null mutation leads to early lethality around embryonic day (E)11.5, but catecholamine precursor administration can rescue Gata3 null mutants to E16.5. At E11.5, GATA3 deficiency results in the development of an empty otocyst with an endolymphatic duct. However, using rescued mice we found that some morphogenesis and neurosensory development is possible in the ear without Gata3. Extending previous studies, we find that at E16.5, Gata3 mutant inner ears can undergo partial morphogenesis and develop an endolymphatic duct, a utricular and saccular recess, and a shortened cochlear duct. In addition to the obvious morphogenic aberrations, these studies demonstrate that a subset of neurons develop and connect a fragmented sensory patch of MYO7A-positive hair cells to the vestibular nuclei of the brainstem. In situ hybridization studies reveal altered expression of several transcription factors relevant to ear development and we hypothesize that this may relate to the observed dysmorphia and restricted neurosensory development. While a cochlear duct can form, there is no concurrent cochlear neurosensory development, observations consistent with specific hearing defects encountered by HDR patients and mice with Gata3-associated expression alterations. Gata3 null mutant phenocopies the otic maldevelopment (cochlear duct formation in the absence of neurosensory development) seen in Foxg1cre mediated conditional deletion of microRNA processing enzyme, Dicer1. Finally, while GATA3 is expressed in the developing vestibulo-cochlear efferent (VCE) neurons, and its absence in the null mutants disrupts VCE projections to the ear, loss of GATA3 does not affect VCE progenitor cell migration.


Polyetherimide-grafted Fe₃O₄@SiO2₂ nanoparticles as theranostic agents for simultaneous VEGF siRNA delivery and magnetic resonance cell imaging.
Engineering a safe and high-efficiency delivery system for efficient RNA interference is critical for successful gene therapy. In this study, we designed a novel nanocarrier system of polyethyleneimine (PEI)-modified Fe3O4@SiO2, which allows high efficient loading of VEGF small hairpin (sh)RNA to form Fe3O4@SiO2/PEI/VEGF shRNA nanocomposites for VEGF gene silencing as well as magnetic resonance (MR) imaging. The size, morphology, particle stability, magnetic properties, and gene-binding capacity and protection were determined. Low cytotoxicity and hemolyticity against human red blood cells showed the excellent biocompatibility of the multifunctional nanocomposites, and also no significant coagulation was observed. The nanocomposites maintain their superparamagnetic property at room temperature and no appreciable change in magnetism, even after PEI modification. The qualitative and quantitative analysis of cellular internalization into MCF-7 human breast cancer cells by Prussian blue staining and inductively coupled plasma atomic emission spectroscopy analysis, respectively, demonstrated that the Fe3O4@SiO2/PEI/VEGF shRNA nanocomposites could be easily internalized by MCF-7 cells, and they exhibited significant inhibition of VEGF gene expression. Furthermore, the MR cellular images showed that the superparamagnetic iron oxide core of our Fe3O4@SiO2/PEI/VEGF shRNA nanocomposites could also act as a T2-weighted contrast agent for cancer MR imaging. Our data highlight multifunctional Fe3O4@SiO2/PEI/VEGF shRNA nanocomposites as a potential platform for simultaneous gene delivery and MR cell imaging, which are promising as theranostic agents for cancer treatment and diagnosis in the future.


Incidence of Hyperpronation in the ACL Injured Knee: A Clinical Perspective.
Assessing abnormal biomechanics when treating various lower extremity pathologies provides the athlete with comprehensive management and promotes injury prevention. However, there have been few previous investigations of abnormal biomechanical forces on ligamentous pathologies of the knee. During this clinical study we investigated the incidence of hyperpronation in subjects who have had an anterior cruciate ligament (ACL) injury. Fifty subjects with a past medical history of ACL rupture and 50 subjects without a history of lower extremity pathology participated in our study. Hyperpronation of the foot and ankle complex was measured with the navicular drop test. The ACL injured subjects had greater navicular drop test scores than noninjured subjects. This suggests that hyperpronation of the foot and ankle complex may increase the risk of injury to the ACL. There is a need for further investigation into possible pre-loading stresses on knee ligaments.


Y-STR Haplogroup Diversity in the Jat Population Reveals Several Different Ancient Origins.
The Jats represent a large ethnic community that has inhabited the northwest region of India and Pakistan for several thousand years. It is estimated the community has a population of over 123 million people. Many historians and academics have asserted that the Jats are descendants of Aryans, Scythians, or other ancient people that arrived and lived in northern India at one time. Essentially, the specific origin of these people has remained a matter of contention for a long time. This study demonstrated that the origins of Jats can be clarified by identifying their Y-chromosome haplogroups and tracing their genetic markers on the Y-DNA haplogroup tree. A sample of 302 Y-chromosome haplotypes of Jats in India and Pakistan was analyzed. The results showed that the sample population had several different lines of ancestry and emerged from at least nine different geographical regions of the world. It also became evident that the Jats did not have a unique set of genes, but shared an underlying genetic unity with several other ethnic communities in the Indian subcontinent. A startling new assessment of the genetic ancient origins of these people was revealed with DNA science.


The accessory optic system and the retino-hypothalamic system. A review.
The introduction of new techniques in neuroanatomy has helped to clarify a number of important issues on the nature of the accessory optic and retino-hypothalamic system. In this study, an effort was made, to collect all data obtainable, and to arrange them on the basis of some common parameter, so that the various results may be directly compared. These data were then interpreted on specific issues, although only limited coverage has been given to functional aspects, as described in older publications. The absence of a universally accepted concept of the function of both systems to date suggests the need for a thorough analysis of both contemporary and older literature dealing with a characterization of the structural components of the accessory optic and the retino-hypothalamic systems. On the basis of these anatomical studies it is concluded that the accessory optic system (AOS) is much more complex than formerly believed. Its development in various vertebrae classes is quite different. Among the mammals, the AOS is very well established in rodents but in primates and man its anatomical and functional role seems markedly reduced. In the rodents it consists of both superficially and deeply arranged axons which are in close topical relation to the cerebral peduncles. The axons not only supply the classic accessory otpic terminal nuclei but also the subthalamic nucleus and the substantia nigra. The secondary projections have not yet been established. The retino-hypothalamic system (RHS) mainly but not exclusively supplies the suprachismatic nucleus (sc). Crossed as well as uncrossed retinal fibres project to the ventro-lateral and to the posterior part of this nucleus. The cells within the sc combine both secretory and neuronal properties. The possible functions exerted are discussed. Both, the AOS and the RHS, are so closely related within the suprachiasmatic area that most methods fail in correlating experimental results with either system. The numerous problems which still remain to be clarified are also discussed.


Crystallographic, kinetic, and spectroscopic study of the first ligninolytic peroxidase presenting a catalytic tyrosine.
Trametes cervina lignin peroxidase (LiP) is a unique enzyme lacking the catalytic tryptophan strictly conserved in all other LiPs and versatile peroxidases (more than 30 sequences available). Recombinant T. cervina LiP and site-directed variants were investigated by crystallographic, kinetic, and spectroscopic techniques. The crystal structure shows three substrate oxidation site candidates involving His-170, Asp-146, and Tyr-181. Steady-state kinetics for oxidation of veratryl alcohol (the typical LiP substrate) by variants at the above three residues reveals a crucial role of Tyr-181 in LiP activity. Moreover, assays with ferrocytochrome c show that its ability to oxidize large molecules (a requisite property for oxidation of the lignin polymer) originates in Tyr-181. This residue is also involved in the oxidation of 1,4-dimethoxybenzene, a reaction initiated by the one-electron abstraction with formation of substrate cation radical, as described for the well known Phanerochaete chrysosporium LiP. Detailed spectroscopic and kinetic investigations, including low temperature EPR, show that the porphyrin radical in the two-electron activated T. cervina LiP is unstable and rapidly receives one electron from Tyr-181, forming a catalytic protein radical, which is identified as an H-bonded neutral tyrosyl radical. The crystal structure reveals a partially exposed location of Tyr-181, compatible with its catalytic role, and several neighbor residues probably contributing to catalysis: (i) by enabling substrate recognition by aromatic interactions; (ii) by acting as proton acceptor/donor from Tyr-181 or H-bonding the radical form; and (iii) by providing the acidic environment that would facilitate oxidation. This is the first structure-function study of the only ligninolytic peroxidase described to date that has a catalytic tyrosine.


Entire ABL1 Gene Deletion Without BCR/ABL1 Rearrangement in a Female Patient with B-Cell Precursor Acute Lymphoblastic Leukemia.
Acute lymphoblastic leukemia (ALL) is a malignant disease characterized by lymphocytic B-line or T-line cells abnormally proliferating in the bone marrow or extramedullary sites. BCR/ABL1 fusion protein in patients with ALL accounts for acts in 15-30% of B-lineage ALL cases, usually in adolescence. However, entire ABL1 gene deletion without BCR/ABL1 rearrangement is a rare phenomenon in ALL patients. Here we describe the first case of entire ABL1 gene deletion without BCR/ABL1 rearrangement in a female B-ALL patient. Relevant literature is reviewed to explain the association between ABL1 deletion and the pathogenesis/prognosis of this disease. ABL gene deletion can repress the activation of p53 and p73, and disrupt TGF-β signaling pathway to allow malignant cells to invade the normal tissue. The clinical significance of ABL gene deletion needs to be further explored.


Rosai-Dorfman disease: A pathological experience from 2 tertiary care hospitals in Western Saudi Arabia.
To document the clinicopathological features of Rosai-Dorfman disease (RDD) at 2 tertiary hospitals in the western region of Saudi Arabia. We retrieved all cases diagnosed as RDD at King Abdulaziz University Hospital and King Faisal Specialist Hospital and Research Center, Jeddah, Saudi Arabia, diagnosed between January 2001 until June 2021. A total of 13 new RDD cases were reported, including 7 nodal and 6 extranodal type. The extranodal sites included larynx, optic chiasm, dura and brain, lumbar vertebrae, and left arm soft tissue.There were 6 males and 7 females. Ages averaged 34 years and ranged from 4-56 years. A total of 2 cases were associated with Hodgkin's lymphoma, and 2 cases have been initially misdiagnosed as other entities. All patients were treated with surgical excision, and steroid was added in 3 cases. Over 2-60 months of follow-up, recurrence occurred in 2 cases. Awareness of this entity is important for pathologists to avoid misdiagnosis. While the optimal treatment remains controversial, surgical resection is generally curative. The prognosis is good with rare recurrence. Multicenteer prospective studies are probably the best to evaluate treatment options and improve outcomes.


Examining the effects of a weighted pack on functional movements in smokejumpers.
Smokejumpers are required to parachute from planes, carry gear weighing more than 50 kg, and hike on steep terrain. With a majority of injuries sustained to the lower extremity, it is imperative to understand the influence a weighted pack may have on functional performance. To examine the effects of external load on functional movements in Smokejumpers. Using repeated measures design, ten Smokejumpers completed two trials consisting of 3 movements in weighted (50 kg) and unweighted conditions. Nine males and one female (age of 40.1±8.4 years, mass 81.1±8.3 kg) performed overhead squat, hurdle step and anterior reach. Movements were scored based on established guidelines. The mean of three trials was recorded for anterior reach on both limbs. Differences between weighted and unweighted scores in the overhead squat (p = 0.001), ND hurdle step (p = 0.005), D hurdle step (p = 0.000) and overall composite scores (p = 0.006) were found to be significantly different. Differences were also noted in D (p = 0.035) and ND (p = 0.045) anterior reach. The addition of a weighted pack negatively influences functional movements in Smokejumpers, which may lead to greater injury risk. Implementation of injury prevention strategies to reduce occupational injury risk should be explored.


Cost-Effectiveness of Caries Prevention in Practice: A Randomized Controlled Trial.
A 2-arm parallel-group randomized controlled trial measured the cost-effectiveness of caries prevention in caries-free children aged 2 to 3 y attending general practice. The setting was 22 dental practices in Northern Ireland. Participants were centrally randomized into intervention (22,600 ppm fluoride varnish, toothbrush, a 50-mL tube of 1,450 ppm fluoride toothpaste, and standardized prevention advice) and control (advice only), both provided at 6-monthly intervals during a 3-y follow-up. The primary outcome measure was conversion from caries-free to caries-active states assessed by calibrated and blinded examiners; secondary outcome measures included decayed, missing, or filled teeth surfaces (dmfs); pain; and extraction. Cumulative costs were related to each of the trial's outcomes in a series of incremental cost effectiveness ratios (ICERs). Sensitivity analyses examined the impact of using dentist's time as measured by observation rather than that reported by the dentist. The costs of applying topical fluoride were also estimated assuming the work was undertaken by dental nurses or hygienists rather than dentists. A total of 1,248 children (624 randomized to each group) were recruited, and 1,096 (549 in the intervention group and 547 in the control group) were included in the final analyses. The mean difference in direct health care costs between groups was £107.53 (£155.74 intervention, £48.21 control, P < 0.05) per child. When all health care costs were compared, the intervention group's mean cost was £212.56 more than the control group (£987.53 intervention, £774.97 control, P < 0.05). Statistically significant differences in outcomes were only detected with respect to carious surfaces. The mean cost per carious surface avoided was estimated at £251 (95% confidence interval, £454.39-£79.52). Sensitivity analyses did not materially affect the study's findings. This trial raises concerns about the cost-effectiveness of a fluoride-based intervention delivered at the practice level in the context of a state-funded dental service (EudraCT No: 2009-010725-39; ISRCTN: ISRCTN36180119).


[Intratumor chemotherapy of patients with cancer of the ovaries].
The paper presents the results of intratumoral chemotherapy of 32 cases of single metastases of stage III-IV ovarian cancer into the Douglas pouch. The metastases were detected at different stages after primary treatment. Thiotepa, cyclophosphamide, sarcolysin and methotrexate were administered in 81.2, 9.4, 6.2 and 3.1% of cases, respectively. A clinically-significant effect was recorded in 14 out of 32 cases (43.7%); tumor process was arrested in 15 cases (46.9%); treatment failed in 3 cases (9.4%). Toxic side-effects were less frequent and pronounced than in patients given standard systemic monochemotherapy.


In our own voice-family companion: reducing self-stigma of family members of persons with serious mental illness.
This article reports preliminary findings from a novel, family peer-based intervention designed to reduce self-stigma among family members of people with serious mental illness. A total of 158 primary caregivers of patients with schizophrenia were recruited from a large urban mental health facility (93 caregivers) or from a family and consumer advocacy organization (65 caregivers). Caregivers (N=122) who reported they perceived at least a moderate level of mental illness-related stigma were evaluated on measures of self-stigma, withdrawal, secrecy, anxiety, and social comparison and randomly assigned to receive one of two, one-session group interventions: a peer-led intervention (In Our Own Voice-Family Companion [IOOV-FC]) designed to stimulate group discussion or a clinician-led family education session, which delivered information about mental illness in a structured, didactic format. IOOV-FC consisted of playing a videotape of family members who describe their experiences coping with stigma, which was followed by a discussion led by two family peers who modeled sharing their own experiences and facilitated group sharing. Of 24 family members and ten consumers, 96% rated the videotape above a predetermined acceptability threshold on a 19-item scale assessing cultural sensitivity, respect for different stakeholders, relevance of content, and technical quality (α=.92). Caregivers receiving IOOV-FC with low to moderate pretreatment anxiety reported a substantial reduction in self-stigma (effect size=.50) relative to those receiving clinician-led family education (p=.017) as well as significant reductions in secrecy (p=.031). Peer-led group interventions may be more effective in reducing family self-stigma than clinician-led education, at least for persons reporting experiencing low to moderate anxiety levels on a standard questionnaire


An evaluation of a noninvasive method of assessing alveolar bone levels in an experimental model of cleft lip and palate.
The purpose of this study was to evaluate an ultrasound mucous-membrane-thickness-measuring device as a noninvasive, nonionizing alternative to radiography in the assessment of alveolar bone grafting. This was a prospective experimental study on porcine cadaver models. An ultrasound technique (Krupp SDM) was assessed ex vivo on three specially developed porcine cadaver models in comparison to radiography and ridge-mapping. Direct measurement of the mucosal thickness provided a standard for comparison. In each model, 30 measurement sites were identified for comparison of the techniques. All measurement techniques demonstrated clinically acceptable reproducibility. Of the clinical measurement techniques, radiography proved to be the most reliable, showing a small, nonsignificant statistical difference from direct measurement. Both the ultrasound technique and ridge-mapping showed significant tendencies to underestimate mucosal thickness that became greater with increasing mucosal thickness. At sites where mucosal thickness was less than 6 mm, the ultrasound technique underestimated mucosal thickness by 0.6 mm on average. At sites where mucosal thickness exceeded 6 mm, ultrasonic artifacts rendered the ultrasound technique unreliable. The ultrasound technique could prove to be a useful clinical adjunct to radiography in the assessment of alveolar bone grafts, but in this particular application, care should be taken when using it to assess deeper alveolar defects.


Intragastric bile acids and histological changes in gastric mucosa.
Multiple gastric biopsies and gastric juice aspirates were taken in 108 patients undergoing routine or review gastroscopy for a variety of upper gastrointestinal disorders. The gastric juice was measured for free and total bile acids and the biopsies examined for premalignant mucosal changes. Total bile acid levels were significantly higher in patients with atrophic gastritis, intestinal metaplasia and dysplasia but not chronic gastritis. There was no correlation between the severity of the dysplasia and total bile acid levels. Free bile acid levels were significantly higher in patients with atrophic gastritis but not in patients with chronic gastritis, intestinal metaplasia or dysplasia. These results suggest that intragastric bile acids may be implicated in premalignant histological changes of gastric mucosa and thus play a part in gastric carcinogenesis.


Fishy tales of prolactin-releasing peptide.
Prolactin (PRL) is an important regulator of multiple biological functions, but a specific PRL-releasing factor, PRL-releasing peptide (PrRP), was isolated only recently from mammals and teleosts. Although this peptide seems to be a strong candidate for being a physiologically relevant stimulator of PRL expression and secretion in teleost pituitary and peripheral organs, it may not be a typical or classic hypothalamic releasing factor in rats. We now know that its biological actions are not limited solely to PRL stimulation, because it is also a neuromodulator of several hypothalamus-pituitary axes and is involved in some brain circuits with the regulation of food intake and cardiovascular functions. Moreover, it plays a direct role in hypertension and retinal information processing. It is the purpose of this review to provide a comprehensive survey of our current knowledge of PrRP and to provide a comparative point of view.


Clinical measurement of walking balance in people post stroke: a systematic review.
To identify walking balance measures which have been established for use with ambulatory people post stroke and reflect the balance requirements of community walking. MEDLINE, Embase, AMED. Measures reflecting walking balance, with tasks that include a stepping action in standing, used with people post stroke were reviewed. Measures with clinical utility were evaluated for psychometric properties, including reliability, validity and clinical interpretation. Nine measures (24 papers) were identified that met the requirement of measuring walking balance in people post stroke with demonstrated clinical utility. Outcome measures with multiple tasks (Brunel Balance Assessment, Modified Emory Functional Ambulation Profile, Dynamic Gait Index, Community Balance and Mobility Scale, and mini-Balance Evaluation Systems Test) as opposed to single task measures (Step Test, Side Step Test and Four Square Step Test, Timed Up and Go), reflect a broader range of walking balance required to accommodate the variable challenges which may be expected at the community level of walking. Most tools report excellent reliability when used by physiotherapists. Validity remains far more challenging to establish. Evaluation of clinical interpretation is limited for all measures. The multiple-task outcome measures reviewed reflected walking balance activities often undertaken during community mobility. Single-task measures may be useful as screening measures, identifying walking balance deficits associated with basic/lower levels of walking balance. Construct validity and clinical interpretability of each measure in ambulatory people post stroke requires further research to identify the level of community mobility represented by each measure of walking balance.


Clinical challenges in patients with cancer-associated thrombosis: Canadian expert consensus recommendations.
Venous thromboembolism is a common complication in cancer patients, and thromboembolism is the second most common cause of death after cancer progression. A number of clinical practice guidelines provide recommendations for the management of cancer-associated thrombosis. However, the guidelines lack recommendations covering commonly encountered clinical challenges (for example, thrombocytopenia, recurrent venous thromboembolism, etc.) for which little or no evidence exists. Accordingly, recommendations were developed to provide expert guidance to medical oncologists and other health care professionals caring for patients with cancer-associated thrombosis. The current expert consensus was developed by a team of 21 clinical experts. For each identified clinical challenge, the literature in medline, embase, and Evidence Based Medicine Reviews was systematically reviewed. The quality of the evidence was assessed, summarized, and graded. Consensus statements were generated, and the experts voted anonymously using a modified Delphi process on their level of agreement with the various statements. Statements were progressively revised through separate voting iterations and were then finalized. Clinicians using these recommendations and suggestions should tailor patient management according to the risks and benefits of the treatment options, patient values and preferences, and local cost and resource allocations.


Traumatic brain injury detection using electrophysiological methods.
Measuring neuronal activity with electrophysiological methods may be useful in detecting neurological dysfunctions, such as mild traumatic brain injury (mTBI). This approach may be particularly valuable for rapid detection in at-risk populations including military service members and athletes. Electrophysiological methods, such as quantitative electroencephalography (qEEG) and recording event-related potentials (ERPs) may be promising; however, the field is nascent and significant controversy exists on the efficacy and accuracy of the approaches as diagnostic tools. For example, the specific measures derived from an electroencephalogram (EEG) that are most suitable as markers of dysfunction have not been clearly established. A study was conducted to summarize and evaluate the statistical rigor of evidence on the overall utility of qEEG as an mTBI detection tool. The analysis evaluated qEEG measures/parameters that may be most suitable as fieldable diagnostic tools, identified other types of EEG measures and analysis methods of promise, recommended specific measures and analysis methods for further development as mTBI detection tools, identified research gaps in the field, and recommended future research and development thrust areas. The qEEG study group formed the following conclusions: (1) Individual qEEG measures provide limited diagnostic utility for mTBI. However, many measures can be important features of qEEG discriminant functions, which do show significant promise as mTBI detection tools. (2) ERPs offer utility in mTBI detection. In fact, evidence indicates that ERPs can identify abnormalities in cases where EEGs alone are non-disclosing. (3) The standard mathematical procedures used in the characterization of mTBI EEGs should be expanded to incorporate newer methods of analysis including non-linear dynamical analysis, complexity measures, analysis of causal interactions, graph theory, and information dynamics. (4) Reports of high specificity in qEEG evaluations of TBI must be interpreted with care. High specificities have been reported in carefully constructed clinical studies in which healthy controls were compared against a carefully selected TBI population. The published literature indicates, however, that similar abnormalities in qEEG measures are observed in other neuropsychiatric disorders. While it may be possible to distinguish a clinical patient from a healthy control participant with this technology, these measures are unlikely to discriminate between, for example, major depressive disorder, bipolar disorder, or TBI. The specificities observed in these clinical studies may well be lost in real world clinical practice. (5) The absence of specificity does not preclude clinical utility. The possibility of use as a longitudinal measure of treatment response remains. However, efficacy as a longitudinal clinical measure does require acceptable test-retest reliability. To date, very few test-retest reliability studies have been published with qEEG data obtained from TBI patients or from healthy controls. This is a particular concern because high variability is a known characteristic of the injured central nervous system.


Improvement of insulin signalling rescues inflammatory cardiac dysfunction.
Inflammation resulting from virus infection is the cause of myocarditis; however, the precise mechanism by which inflammation induces cardiac dysfunction is still unclear. In this study, we investigated the contribution of insulin signalling to inflammatory cardiac dysfunction induced by the activation of signalling by NF-κB, a major transcriptional factor regulating inflammation. We generated mice constitutively overexpressing kinase-active IKK-β, an essential kinase for NF-κB activation, in cardiomyocytes (KA mice). KA mice demonstrated poor survival and significant cardiac dysfunction with remarkable dilation. Histologically, KA hearts revealed increased cardiac apoptosis and fibrosis and the enhanced recruitment of immune cells. By molecular analysis, we observed the increased phosphorylation of IRS-1, indicating the suppression of insulin signalling in KA hearts. To evaluate the contribution of insulin signalling to cardiac dysfunction in KA hearts, we generated mice with cardiac-specific suppression of phosphatase and tensin homologue 10 (PTEN), a negative regulator of insulin signalling, in the KA mouse background (KA-PTEN). The suppression of PTEN successfully improved insulin signalling in KA-PTEN hearts, and interestingly, KA-PTEN mice showed significantly improved cardiac function and survival. These results indicated that impaired insulin signalling underlies the mechanism involved in inflammation-induced cardiac dysfunction, which suggests that it may be a target for the treatment of myocarditis.


Transient accumulation and bidirectional movement of KIF13B in primary cilia.
Primary cilia are microtubule-based sensory organelles whose assembly and function rely on the conserved bidirectional intraflagellar transport (IFT) system, which is powered by anterograde kinesin-2 and retrograde cytoplasmic dynein-2 motors. Nematodes additionally employ a cell-type-specific kinesin-3 motor, KLP-6, which moves within cilia independently of IFT and regulates ciliary content and function. Here, we provide evidence that a KLP-6 homolog, KIF13B, undergoes bursts of bidirectional movement within primary cilia of cultured immortalized human retinal pigment epithelial (hTERT-RPE1) cells. Anterograde and retrograde intraciliary velocities of KIF13B were similar to those of IFT (as assayed using IFT172-eGFP), but intraciliary movement of KIF13B required its own motor domain and appeared to be cell-type specific. Our work provides the first demonstration of motor-driven, intraciliary movement by a vertebrate kinesin other than kinesin-2 motors.


Genetic and Functional Profiling of CD16-Dependent Natural Killer Activation Identifies Patients at Higher Risk of Cardiac Allograft Vasculopathy.
Cardiac transplantation is an effective therapy for end-stage heart failure. Because cardiac allograft vasculopathy (CAV) is the major cause of late mortality after heart transplant (HT), there is a need to identify markers that reflect inflammatory or cytotoxic immune mechanisms contributing to its onset. Noninvasive and early stratification of patients at risk remains a challenge for adapting individualized therapy. The CD16 (Fc-gamma receptor 3A [FCGR3A]) receptor was recently identified as a major determinant of antibody-mediated natural killer (NK) cell activation in HT biopsies; however, little is known about the role of CD16 in promoting allograft vasculopathy. This study aimed to investigate whether markers that reflect CD16-dependent circulating NK cell activation may identify patients at higher risk of developing CAV after HT. Blood samples were collected from 103 patients undergoing routine coronarography angiography for CAV diagnosis (median 5 years since HT). Genomic and phenotypic analyses of FCGR3A/CD16 Fc-receptor profiles were compared in CAV-positive (n=52) and CAV-free patients (n=51). The levels of CD16 expression and rituximab-dependent cell cytotoxic activity of peripheral NK cells in HT recipients were evaluated using a noninvasive NK-cellular humoral activation test. Enhanced levels of CD16 expression and antibody-dependent NK cell cytotoxic function of HT recipients were associated with the FCGR3A-VV genotype. The frequency of the FCGR3A-VV genotype was significantly higher in the CAV+ group (odds ratio, 3.9; P=0.0317) than in the CAV- group. The FCGR3A-VV genotype was identified as an independent marker correlated with the presence of CAV at the time of coronary angiography by using multivariate logistic regression models. The FCGR3A-VV genotype was also identified as a baseline-independent predictor of CAV risk (odds ratio, 4.7; P=0.023). This study unravels a prominent role for the CD16-dependent NK cell activation pathway in the complex array of factors that favor the progression of transplant arteriosclerosis. It highlights the clinical potential of a noninvasive evaluation of FCGR3A/CD16 in the early stratification of CAV risk. The recognition of CD16 as a major checkpoint that controls immune surveillance may promote the design of individualized NK cell-targeted therapies to limit vascular damage in highly responsive sensitized patients. URL: https://www.clinicaltrials.gov. Unique identifier: NCT01569334.


Monte carlo analysis of two-photon fluorescence imaging through a scattering medium.
The behavior of two-photon fluorescence imaging through a scattering medium is analyzed by use of the Monte Carlo technique. The axial and transverse distributions of the excitation photons in the focused Gaussian beam are derived for both isotropic and anisotropic scatterers at different numerical apertures and at various ratios of the scattering depth with the mean free path. The two-photon fluorescence profiles of the sample are determined from the square of the normalized excitation intensity distributions. For the same lens aperture and scattering medium, two-photon fluorescence imaging offers a sharper and less aberrated axial response than that of single-photon confocal fluorescence imaging. The contrast in the corresponding transverse fluorescence profile is also significantly higher. Also presented are results comparing the effects of isotropic and anisotropic scattering media in confocal reflection imaging. The convergence properties of the Monte Carlo simulation are also discussed.


LncRNA pathway involved in premature preterm rupture of membrane (PPROM): an epigenomic approach to study the pathogenesis of reproductive disorders.
Preterm birth (PTB) is a live birth delivered before 37 weeks of gestation (GW). About one-third of PTBs result from the preterm premature rupture of membranes (PPROM). Up to the present, the pathogenic mechanisms underlying PPROM are not clearly understood. Here, we investigated the differential expression of long chain non-coding RNAs (lncRNAs) in placentas of PTBs with PPROM, and their possible involvement in the pathogenic pathways leading to PPROM. A total number of 1954, 776, and 1050 lncRNAs were identified with a microarray from placentas of PPROM (group A), which were compared to full-term birth (FTB) (group B), PTB (group C), and premature rupture of membrane (PROM) (group D) at full-term, respectively. Instead of investigating the individual pathogenic role of each lncRNA involved in the molecular mechanism underlying PPROM, we have focused on investigating the metabolic pathways and their functions to explore what is the likely association and how they are possibly involved in the development of PPROM. Six groups, including up-regulation and down-regulation in the comparisons of A vs. B, A vs. C, and A vs. D, of pathways were analyzed. Our results showed that 22 pathways were characterized as up-regulated 7 down-regulated in A vs. C, 18 up-regulated and 15 down-regulated in A vs. D, and 33 up-regulated and 7 down-regulated in A vs. B. Functional analysis showed pathways of infection and inflammatory response, ECM-receptor interactions, apoptosis, actin cytoskeleton, and smooth muscle contraction are the major pathogenic mechanisms involved in the development of PPROM. Characterization of these pathways through identification of lncRNAs opened new avenues for further investigating the epigenomic mechanisms of lncRNAs in PPROM as well as PTB.


Testing alternative cascades from internalizing and externalizing symptoms to adolescent alcohol use and alcohol use disorder through co-occurring symptoms and peer delinquency.
Given the equivocal literature on the relationship between internalizing symptoms and early adolescent alcohol use (AU) and AU disorder (AUD), the present study took a developmental perspective to understand how internalizing and externalizing symptoms may operate together in the etiology of AU and AUD. We pit the delayed onset and rapid escalation hypothesis (Hussong et al., 2011) against a synthesis of the dual failure model and the stable co-occurring hypothesis (Capaldi, 1992; Colder et al., 2013, 2018) to test competing developmental pathways to adolescent AU and AUD involving problem behavior, peer delinquency, and early initiation of AU. A latent transactional and mediational framework was used to test pathways to AUD spanning developmental periods before AU initiation (Mage = 11) to early and high risk for AUD (Mage = 14-15 and Mage = 17-18). The results supported three pathways to AUD. The first started with "pure" externalizing symptoms in early childhood and involved multiple mediators, including the subsequent development of co-occurring symptoms and peer delinquency. The second pathway involved stable co-occurring symptoms. Interestingly, chronically elevated pure internalizing symptoms did not figure prominently in pathways to AUD. Selection and socialization effects between early AU and peer delinquency constituted a third pathway.


Autologous serum eye drops for the treatment of dry eye diseases.
Conventional treatment of dry eye mainly consists of the use of preservative-free artificial eye drops and punctal occlusion. None of the commercially available artificial tear preparations include essential tear components such as epidermal growth factor, hepatocyte growth factor, fibronectin, neurotrophic growth factor, and vitamin A-all of which have been shown to play important roles in the maintenance of a healthy ocular surface epithelial milieu. We reported previously that autologous serum (AS) eye drops contain these essential factors and that AS eye drops are beneficial in the treatment of ocular surface diseases such as persistent epithelial defects, superior limbic keratoconjunctivitis, keratoconjunctivitis sicca, and neurotrophic keratopathy. However, there is some controversy regarding the efficacy of AS treatment. We demonstrated that this modality is more effective than artificial tears in a randomized control study. In in vivo and in vitro experiments, AS eye drops showed marked suppression of apoptosis in the conjunctival and corneal epithelium. Albumin, the major protein in serum, improved ocular surface damage in vivo and rescued apoptosis after serum deprivation in vitro. The biological background of AS eye drops and previous clinical studies of these medications for the treatment of dry eye are discussed.


Biological Parts for Plant Biodesign to Enhance Land-Based Carbon Dioxide Removal.
A grand challenge facing society is climate change caused mainly by rising CO2 concentration in Earth's atmosphere. Terrestrial plants are linchpins in global carbon cycling, with a unique capability of capturing CO2 via photosynthesis and translocating captured carbon to stems, roots, and soils for long-term storage. However, many researchers postulate that existing land plants cannot meet the ambitious requirement for CO2 removal to mitigate climate change in the future due to low photosynthetic efficiency, limited carbon allocation for long-term storage, and low suitability for the bioeconomy. To address these limitations, there is an urgent need for genetic improvement of existing plants or construction of novel plant systems through biosystems design (or biodesign). Here, we summarize validated biological parts (e.g., protein-encoding genes and noncoding RNAs) for biological engineering of carbon dioxide removal (CDR) traits in terrestrial plants to accelerate land-based decarbonization in bioenergy plantations and agricultural settings and promote a vibrant bioeconomy. Specifically, we first summarize the framework of plant-based CDR (e.g., CO2 capture, translocation, storage, and conversion to value-added products). Then, we highlight some representative biological parts, with experimental evidence, in this framework. Finally, we discuss challenges and strategies for the identification and curation of biological parts for CDR engineering in plants.


Potential Benefits of Combined Statin and Metformin Therapy on Resistance Training Response in Older Individuals.
Metformin and statins are currently the focus of large clinical trials testing their ability to counter age-associated declines in health, but recent reports suggest that both may negatively affect skeletal muscle response to exercise. However, it has also been suggested that metformin may act as a possible protectant of statin-related muscle symptoms. The potential impact of combined drug use on the hypertrophic response to resistance exercise in healthy older adults has not been described. We present secondary statin analyses of data from the MASTERS trial where metformin blunted the hypertrophy response in healthy participants (>65 years) following 14 weeks of progressive resistance training (PRT) when compared to identical placebo treatment (n = 94). Approximately one-third of MASTERS participants were taking prescribed statins. Combined metformin and statin resulted in rescue of the metformin-mediated impaired growth response to PRT but did not significantly affect strength. Improved muscle fiber growth may be associated with medication-induced increased abundance of CD11b+/CD206+ M2-like macrophages. Sarcopenia is a significant problem with aging and this study identifies a potential interaction between these commonly used drugs which may help prevent metformin-related blunting of the beneficial effects of PRT. Trial Registration: ClinicalTrials.gov, NCT02308228, Registered on 25 November 2014.


Treating sleep and circadian problems to promote mental health: perspectives on comorbidity, implementation science and behavior change.
Insufficient sleep and mistimed sleep are prominent, yet under-appreciated and understudied, contributors to poor mental health and to mental disorders. The evidence that improving sleep and circadian functioning is an important pathway to mental health continues to mount. The goal of this paper is to highlight three major challenges ahead. Challenge 1 points to the possibility that comorbidity is the norm not the exception for the sleep and circadian disorders that are associated with mental disorders. Hence, the sleep and circadian problems experienced by people diagnosed with a mental disorder may not fit into the neat diagnostic categories of existing nosologies nor be adequately treated with single disorder approaches. The Sleep Health Framework and the Transdiagnostic Intervention for Sleep and Circadian Dysfunction (TranS-C) are discussed as alternative approaches. Challenge 2 points to the large time lag between the development of a treatment and the availability of that treatment in routine clinical practice. This is a key reason for the emergence of implementation science, which is a flourishing, well-developed, and quickly moving field. There is an urgent need for more applications of implementation science within sleep and circadian science. Challenge 3 describes one of the greatest puzzles of our time-the need to unlock the fundamental elements of behavior change. There is potential to harness the science of behavior change to encourage widespread engagement in sleep health behavior and thereby reduce the staggering burden of sleep and circadian problems and the associated mental health problems.


Effect of implementing a heart failure admission care bundle on hospital readmission and mortality rates: interrupted time series study.
This study aimed to evaluate the impact of developing and implementing a care bundle intervention to improve care for patients with acute heart failure admitted to a large London hospital. The intervention comprised three elements, targeted within 24 hours of admission: N-terminal pro-B-type natriuretic peptide (NT-proBNP) test, transthoracic Doppler two-dimensional echocardiography and specialist review by cardiology team. The SHIFT-Evidence approach to quality improvement was used. During implementation, July 2015-July 2017, 1169 patients received the intervention. An interrupted time series design was used to evaluate impact on patient outcomes, including 15 618 admissions for 8951 patients. Mixed-effects multiple Poisson and log-linear regression models were fitted for count and continuous outcomes, respectively. Effect sizes are slope change ratios pre-intervention and post-intervention. The intervention was associated with reductions in emergency readmissions between 7 and 90 days (0.98, 95% CI 0.97 to 1.00), although not readmissions between 0 and 7 days post-discharge. Improvements were seen in in-hospital mortality (0.96, 95% CI 0.95 to 0.98), and there was no change in trend for hospital length of stay. Care process changes were also evaluated. Compliance with NT-proBNP testing was already high in 2014/2015 (162 of 163, 99.4%) and decreased slightly, with increased numbers audited, to 2016/2017 (1082 of 1101, 98.2%). Over this period, rates of echocardiography (84.7-98.9%) and specialist input (51.6-90.4%) improved. Care quality and outcomes can be improved for patients with acute heart failure using a care bundle approach. A systematic approach to quality improvement, and robust evaluation design, can be beneficial in supporting successful improvement and learning.


Impact of testicular cancer on sperm small non-coding RNA signature: a pilot study.
Testicular germ cell tumours (TGCTs) are the most common tumours in young adults of European ancestry. The high heritability and the constantly increased incidence, which has doubled over the last 20 years, strongly suggest that both genetic and environmental factors are likely to shape the TGCT susceptibility. While genome-wide association studies have identified loci associated with TGCT susceptibility, the role played by environmental molecular vectors in TGCT susceptibility remains unclear. Evidence shows that sperm non-coding RNAs provide a good vision of the environmental stresses experienced by men. Here, to determine whether TGCT impacts the abundance of specific non-coding RNAs in sperm, small RNA deep sequencing analysis of sperm of 25 men aged between 19 and 42 years, diagnosed with (n = 16) or without (n = 9) TGCT was performed. The primary analysis showed no statistical significance in the sncRNA population between the TGCT and non-TGCT groups. However, when sperm physiological parameters were considered to look for differentially expressed sncRNA, we evidenced 11 differentially expressed sncRNA between patients and control which allow a clear discrimination between control and TGCT samples after Hierarchical Clustering analysis. Together, these findings indicate that sperm small non-coding RNAs abundance may have the potential for diagnosing men with TGCT. However, specific care should be taken regarding sperm physiological parameters of the TGCT patients. Hence, larger studies are needed to confirm our findings and to determine whether such a signature associates with the risks to develop TGCT.


Speech and language results in children with a cochlear implant.
At the House Ear Institute, speech and language assessments are a regular part of the evaluation protocol for the cochlear implant clinical trials in children. The assessments are conducted preimplant and at specific postimplant intervals. Paired comparisons of the children's performance at pre- and post-implant intervals reveal significant improvements in both imitative and spontaneous speech production abilities. However, some differences between groups are noted. Children implanted at an early age demonstrate a greater number of significant improvements in speech production, while children using oral communication have better skills at all test intervals. In addition, significant improvements on three of the four receptive language measures and one of the four expressive language measures are demonstrated at the 6-mo postimplant test interval. A significant decrease in performance is noted for one receptive language measure. In a second study, the speech scores of control groups and postimplant groups of the same age (3, 4, or 5 yr) are compared. Implanted children score higher in all but one of 24 contrasts, and these differences are statistically significant in five of the comparisons.


Is poor nutrition masking the effects of depomedroxyprogesterone acetate on bones in adolescent users?
Research in the developed countries has documented bone loss in adolescents who use depomedroxyprogesterone acetate (DMPA) as a contraceptive for less than two years. DMPA use often begins during adolescence in Bangladesh, a South Asian developing country, where more than 50% of women are undernourished. Poor nutrition is also associated with low bone mineral density (BMD) in South Asian women. We investigated the effects of long-term (two or more years) DMPA use on BMD in Bangladeshi women who started its use in their adolescence. Lumbar spine and femur neck BMD were acquired using dual energy X-ray absorptiometry for 100 adolescents (50 DMPA users and 50 non-users) in a cross-sectional study in Dhaka, Bangladesh. Multivariate analysis was used to determine the associations between BMD and DMPA use. Stratified analysis of DMPA use investigated the determinants of BMD in both groups. The participants (mean age 18 +/- 2 years) were generally below their ideal body weight. No significant differences in BMD were found between the two groups. Weight (odds ratio [OR] 0.96, 95 percent confidence interval [CI], 0.92-1.00) and height (OR 0.68, 95 percent CI 0.49-0.94) were independent determinants (p-value is less than 0.05) of lumbar and femur neck BMD, respectively. Poor nutritional status, indicated by a less-than-ideal body weight, may be masking the effects of DMPA on bone loss among adolescent users. Our findings suggest that nutritional supplementation may be required with DMPA prescription to promote bone health in adolescent users who are approaching peak bone mass.


The impact of gout guidelines.
This review discusses the impact of recent treatment guidelines for the management of gout and the barriers to treating gout patients. Multiple guidelines for both the treatment and prevention of gout have been put forth in the last decade including those from the British Rheumatism Society; the European League Against Rheumatism; the Multinational Evidence, Expertise, Exchange Initiative; the Japanese Society of Gout and Nucleic Acid Metabolism; the American College of Rheumatology. These guidelines are designed to facilitate the management of gout by providers with key recommendations for the management of hyperuricemia, which is the greatest risk factor for developing gout. However, despite the extant guidelines, overall adherence to recommendations and uptake have been slow and initiation of urate-lowering therapy, titration of dosing, and monitoring of serum urate is infrequent. Greater education in proper management as well as increased awareness of new treatment strategies appear to be the primary reasons for this gap and offer avenues for improvement in management as well as areas for further research. Gout remains a treatment challenge for both acute and chronic disease. Despite the availability of management guidelines, primary care providers are struggling with appropriate management of the disease. More research tools and strategies are needed to improve overall outcomes and quality of care.


How embodied is perceptual decision making? Evidence for separate processing of perceptual and motor decisions.
The extent to which different cognitive processes are "embodied" is widely debated. Previous studies have implicated sensorimotor regions such as lateral intraparietal (LIP) area in perceptual decision making. This has led to the view that perceptual decisions are embodied in the same sensorimotor networks that guide body movements. We use event-related fMRI and effective connectivity analysis to investigate whether the human sensorimotor system implements perceptual decisions. We show that when eye and hand motor preparation is disentangled from perceptual decisions, sensorimotor areas are not involved in accumulating sensory evidence toward a perceptual decision. Instead, inferior frontal cortex increases its effective connectivity with sensory regions representing the evidence, is modulated by the amount of evidence, and shows greater task-positive BOLD responses during the perceptual decision stage. Once eye movement planning can begin, however, an intraparietal sulcus (IPS) area, putative LIP, participates in motor decisions. Moreover, sensory evidence levels modulate decision and motor preparation stages differently in different IPS regions, suggesting functional heterogeneity of the IPS. This suggests that different systems implement perceptual versus motor decisions, using different neural signatures.


The K domain mediates heterodimerization of the Arabidopsis floral organ identity proteins, APETALA3 and PISTILLATA.
MADS genes in plants encode key developmental regulators of vegetative and reproductive development. The majority of well-characterized plant MADS proteins contain two conserved domains, the DNA-binding MADS domain and the K domain. The K domain is predicted to form three amphipathic alpha-helices referred to as K1, K2, and K3. In this report, we define amino acids and subdomains important for heterodimerization between the two Arabidopsis floral organ identity MADS proteins APETALA3 (AP3) and PISTILLATA (PI). Analysis of mutants defective in dimerization demonstrates that K1, K2 and the region between K1 and K2 are critical for the strength of AP3/PI dimerization. The majority of the critical amino acids are hydrophobic indicating that the K domain mediates AP3/PI interaction primarily through hydrophobic interactions. Specially, K1 of AP3 and PI resembles a leucine zipper motif. Most mutants defective in AP3/PI heterodimerization in yeast exhibit partial floral organ identity function in transgenic Arabidopsis. Our results also indicate that the motif containing Asn-98 and specific charged residues in K1 (Glu-97 in PI and Arg-102 in AP3) are important for both the strength and specificity of AP3/PI heterodimer formation.


Therapeutic epitopes of Leptospira LipL32 protein and their characteristics.
Two LipL32-specific mouse monoclonal antibodies (mAbLPF1 and mAbLPF2) which neutralized Leptospira-mediated hemolysis in vitro and rescued hamsters from lethal Leptospira infection were produced. In this communication, locations and characteristics of the protective epitopes of the mAbs were studied by using a truncated LipL32 recombinant protein based-immunoassay and phage consensus mimotope identification and multiple alignments. The mAbLPF1 epitope consisted of P243, L244, I245, H246, L252 and Q253 on the LipL32 protein; it is mapped on the surface-exposed region of non-continuous β13-turn and C-terminal amphipathic α6 helix with hydrophobic patch, contributing to phospholipid/host cell adhesion and membrane insertion on one side, and hydrophilic, acidic and basic amino acid residues on another side. The epitope peptide of the mAbLPF2 is linear 122PEEKSMPHW130 and located on surface-exposed α1 and α2 between β7 and β8 that bound to several host constituents. Both epitopes are highly conserved among the pathogenic and intermediately pathogenic Leptospira spp. and are absent from the LipL32 superfamily proteins of other microorganisms. This study not only enlightens the molecular mechanisms of the therapeutic mAbLPF1 and mAbLPF2, but also elaborates the potential of the two LipL32 regions as diagnostic and vaccine targets for leptospirosis.


Modulations in the abundance of salt clusters in electrosprays
The abundance of tetraheptylammonium bromide clusters produced from formamide solutions by electrospray ionization (ESI) is investigated. It exhibits a wavy pattern when plotted as a function of cluster size, successive waves being ordered according to the initial cluster charge z. This structure confirms the ion evaporation mechanism of Iribarne and Thomson and simplifies drastically the determination of the distribution of cluster charge z and radius R, from which the kinetics of ion evaporation from charged drops can be inferred.


Revisiting Proton Pump Inhibitors as Chemoprophylaxis Against the Progression of Barrett's Esophagus.
Barrett's esophagus (BE) is associated with chronic gastroesophageal reflux disease and is a known precursor to esophageal adenocarcinoma. While endoscopic surveillance strategies and the role for endoscopic eradication therapy have been well established, there has been much interest in identifying chemopreventive agents to disrupt or halt the metaplasia-dysplasia-carcinoma sequence in patients with BE. No pharmacological agent has held more hope in reducing the risk of neoplastic progression in BE than proton pump inhibitors (PPIs). However, data supporting PPIs for chemoprevention have largely been from observational cohort and case-control studies with mixed results. In this review, we revisit the literature and highlight the role of PPIs in patients with BE as it pertains to chemoprophylaxis against the progression of BE to dysplasia and esophageal adenocarcinoma.


Health-information needs of HIV-positive adults in Latin America and the Caribbean: an integrative review of the literature.
An assessment of information needs is essential for care planning for patients living with chronic diseases such as human immunodeficiency virus (HIV). The extent to which these assessments have been conducted in Latin America and the Caribbean (LAC) is unknown. The purpose of this study was, therefore, to identify, evaluate, and summarize what research has been conducted to examine patient perceptions of their health-information needs among adults living with HIV in LAC. Using an integrative review methodology, a literature search of six databases was conducted in April and May 2015. Inclusion criteria were peer-reviewed articles published in English or Spanish that assessed the information needs of HIV-positive patients living in LAC. The quality of included articles was assessed and relevant characteristics of each article were extracted, compared, and presented. Searches returned 1885 citations, 11 of which met inclusion criteria. Studies included were conducted in 8 of 33 countries, used multiple research designs, demonstrated varying needs between populations, and found numerous unmet information needs. Information about HIV in general, methods of infection transmission, antiretroviral medications, other sexually transmitted diseases, and effective coping mechanisms were the most commonly mentioned needs. Healthcare providers were the largest and most reliable source of health information for many participants and it was emphasized that in order for health education to be effective, programs should include both individual and group components. Patients indicated that they may have difficulty processing and using information through an incorrect understanding of medications, not changing risk behaviors, and by stating that information can be overwhelming or poorly communicated. Further research on information needs is warranted so that healthcare providers and organizations may provide the information patients need to appropriately manage their health.


Simulated effects of sulfur deposition on nutrient cycling in class I wilderness areas.
We predicted the effects of sulfate (SO(4)) deposition on wilderness areas designated as Class I air quality areas in western North Carolina using a nutrient cycling model (NuCM). We used three S deposition simulations: current, 50% decrease, and 100% increase. We measured vegetation, forest floor, and root biomass and collected soil, soil solution, and stream water samples for chemical analyses. We used the closest climate stations and atmospheric deposition stations to parameterize NuCM. The areas were: Joyce Kilmer (JK), Shining Rock (SR), and Linville Gorge (LG). They differ in soil acidity and nutrients, and soil solution and stream chemistry. Shining Rock and LG have lower soil solution base cation and higher acidic ion concentrations than JK. For SR and LG, the soil solution Ca/Al molar ratios are currently 0.3 in the rooting zone (A horizon), indicating Al toxicity. At SR, the simulated Ca/Al ratio increased to slightly above 1.5 after the 30-yr simulation regardless of S deposition reduction. At LG, Ca/Al ratios ranged from 1.6 to 2.4 toward the end of the simulation period, the 100% increase scenario had the lower value. Low Ca/Al ratios suggest that forests at SR and LG are significantly stressed under current conditions. Our results also suggest that SO(4) retention is low, perhaps contributing to their high degree of acidification. Their soils are acidic, low in weatherable minerals, and even with large reductions in SO(4) and associated acid deposition, it may take decades before these systems recover from depletion of exchangeable Ca, Mg, and K.


Distribution of toxic elements and transfer from the environment to humans traced by using lead isotopes. A case of study in the Sarno River basin, south Italy.
The results of a large geochemical study on various environmental media (soil, stream sediment, groundwater, surface water, lettuce and human hair) of the Sarno River basin, which is one of the most polluted areas in Italy, are presented. Further, it aims to deepen our understanding of the distribution of Pb and its isotope composition for the differentiation between natural and anthropogenic metal sources. Our results show the environmental media to be significantly enriched in Cr, Cu, Pb, Hg, Zn, and to a lesser extent in Sb, Cd and Ni compared to the natural local background variation. The numerous industrial activities (mainly tanneries) have caused environmental pollution especially Cr and Hg in soils and sediment samples. Such contamination is also evident in lettuce and in the hair of the resident population, which shows particularly high values for both Cr and Hg. The unusually high As, Be and Sn concentrations arise mostly from natural sources due to the volcanic nature of the investigated area. Lead isotope measurements indicate a trend suggesting mixing between two end-members, one of clear natural origin (geogenic) and another related to human activities (anthropogenic). Lead isotope results demonstrate that Pb in hair of inhabitants is similar to those in the local topsoil and that gasoline is one of the main, but not the only source of metal pollution. The most important exposure risks within the study area are associated with toxic elements levels in topsoil and stream sediment, and the ingestion of locally grown lettuce. The high concentrations of these elements in hair are a further confirmation of this exposure pathway.


Creatine maintains intestinal homeostasis and protects against colitis.
Creatine, a nitrogenous organic acid, replenishes cytoplasmic ATP at the expense of mitochondrial ATP via the phosphocreatine shuttle. Creatine levels are maintained by diet and endogenous synthesis from arginine and glycine. Glycine amidinotransferase (GATM) catalyzes the rate-limiting step of creatine biosynthesis: the transfer of an amidino group from arginine to glycine to form ornithine and guanidinoacetate. We screened 36,530 third-generation germline mutant mice derived from N-ethyl-N-nitrosourea-mutagenized grandsires for intestinal homeostasis abnormalities after oral administration of dextran sodium sulfate (DSS). Among 27 colitis susceptibility phenotypes identified and mapped, one was strongly correlated with a missense mutation in Gatm in a recessive model of inheritance, and causation was confirmed by CRISPR/Cas9 gene targeting. Supplementation of homozygous Gatm mutants with exogenous creatine ameliorated the colitis phenotype. CRISPR/Cas9-targeted (Gatmc/c ) mice displayed a normal peripheral immune response and immune cell homeostasis. However, the intestinal epithelium of the Gatmc/c mice displayed increased cell death and decreased proliferation during DSS treatment. In addition, Gatmc/c colonocytes showed increased metabolic stress in response to DSS with higher levels of phospho-AMPK and lower levels of phosphorylation of mammalian target of rapamycin (phospho-mTOR). These findings establish an in vivo requirement for rapid replenishment of cytoplasmic ATP within colonic epithelial cells in the maintenance of the mucosal barrier after injury.


Firing up the nature/nurture controversy: bioethics and genetic determinism.
It is argued here that bioethicists might inadvertently be promoting genetic determinism: the idea that genes alone determine human traits and behaviours. Discussions about genetic testing are used to exemplify how they might be doing so. Quite often bioethicists use clinical cases to support particular moral obligations or rights as if these cases were representative of the kind of information we can acquire about human diseases through genetic testing, when they are not. On other occasions, the clinical cases are presented in simplistic ways that portray genetic testing as yielding information more accurate than it actually is. It is concluded that, because of the problematic implications that the ideology of genetic determinism might have for individuals' wellbeing and for our public policies, bioethicists should be careful to present these issues in ways that do not promote questionable ideas about the causal role of genes in human diseases and behaviours.


Increased stroke risk among patients with open-angle glaucoma: a 10-year follow-up cohort study.
Although several studies showed the association between stroke and open-angle glaucoma (OAG), there is still lack of longitudinal studies based on large populations. Therefore, in this study, we investigated the risk of stroke after OAG diagnosis over a 10-year follow-up period. We performed a retrospective nationwide propensity score-matched cohort study. OAG and comparison groups were selected from a large database from the Korean National Health Insurance Service, comprising 1 025 340 random subjects. The OAG group comprised patients with an initial diagnosis of OAG between January 2004 and December 2007 (n=1520), and the comparison group comprised randomly selected patients (five per glaucoma patient; n=7570). Each cohort was tracked until 2013 for stroke development. Cox proportional hazard regression analysis was performed to determine possible association RESULTS: OAG was associated with increased stroke incidence (HR=1.20, 95% CI 1.03 to 1.40). Hypertension, diabetes mellitus, chronic renal failure, atrial fibrillation, hyperlipidaemia, increasing age and male gender also increased the incidences of stroke. Risk of stroke for patients with OAG was greater in the older age group (≥65 years, HR=1.23, 95% CI 1.02 to 1.47) than in the younger age group (<65 years, HR=1.12, 95% CI 0.86 to 1.46), and greater in males (HR=1.31, 95% CI 1.06 to 1.60) than in females (HR=1.10, 95% CI 0.88 to 1.38). Patients who were diagnosed with OAG were more likely to experience subsequent stroke than comparison group without OAG, and the risk was greater for older adults and males.


Biosynthesis of Copper Nanoparticles with Medicinal Plants Extracts: From Extraction Methods to Applications.
Copper nanoparticles (CuNPs) can be synthesized by green methods using plant extracts. These methods are more environmentally friendly and offer improved properties of the synthesized NPs in terms of biocompatibility and functional capabilities. Traditional medicine has a rich history of utilization of herbs for millennia, offering a viable alternative or complementary option to conventional pharmacological medications. Plants of traditional herbal use or those with medicinal properties are candidates to be used to obtain NPs due to their high and complex content of biocompounds with different redox capacities that provide a dynamic reaction environment for NP synthesis. Other synthesis conditions, such as salt precursor concentration, temperature, time synthesis, and pH, have a significant effect on the characteristics of the NPs. This paper will review the properties of some compounds from medicinal plants, plant extract obtention methods alternatives, characteristics of plant extracts, and how they relate to the NP synthesis process. Additionally, the document includes diverse applications associated with CuNPs, starting from antibacterial properties to potential applications in metabolic disease treatment, vegetable tissue culture, therapy, and cardioprotective effect, among others.


Period Prevalence of Ketamine-Propofol Admixture "Ketofol" in the Operating Room among Anesthesia Providers at an Academic Medical Center.
The primary aim of this study was to determine the period prevalence of the single-syringe ketamine-propofol admixture used for sedation and induction among anesthesia providers during a 5-year period before and after educational sessions addressing barriers to its use. Secondary aims were to determine barriers to its use and address the most prevalent concerns through educational sessions. Surveys were administered to certified and student registered nurse anesthetists, anesthesia residents, and anesthesiologists at Mayo Clinic Rochester, MN before and after educational sessions addressing common barriers. Identified barriers were addressed by oral and/or electronic presentations with identical content. Pre-education period prevalence for sedation was 110 (43%) and 64 (25%) for induction. Identified barriers were uncertainty of benefit in 62 respondents (23%), mixed controlled substance disposal in 48 (18%), regulatory/institutional policies in 20 (7%), and compatibility in 9 (3%). Post-education period prevalence for sedation was 102 (44%), and induction 63 (27%). No concerns were noted in 72% of the post-education group verses 42% in the pre-education group (p<0.01). No concerns were reported in 51% of the electronic only education group verses 64% in the oral education group (p<0.01). The period prevalence of "ketofol" was greater for sedation than induction. The period prevalence following education showed a slight increase in both sedation and induction use. There was a significant reduction in barriers following education, with oral presentations being more effective than electronic only. Period prevalence was increasing following education; however, allowing more time may have shown a significant practice change.


Short-term upper limb immobilization affects action-word understanding.
The present study aimed to investigate whether well-established associations between action and language can be altered by short-term upper limb immobilization. The dominant arm of right-handed participants was immobilized for 24 hours with a rigid splint fixed on the hand and an immobilization vest restraining the shoulder, arm, and forearm. The control group did not undergo such immobilization. In 2 experiments, participants had to judge whether a verb involved movements of the hands or feet. In Experiment 1, the response times for controls were shorter for hand-action verbs than for foot-action verbs, whereas there was no significant difference in the immobilized group. Experiment 2 confirmed these results with a pre/posttest procedure. Shorter response times were shown for hand-action verbs than for foot-action verbs in the pretests and posttests for the control group and in the pretest for the immobilized group (i.e., before immobilization). This difference was not observed for participants undergoing 24 hr of hand immobilization, who showed little progress in assessing hand-action verbs between pretest and posttest. Moreover, participants with the highest motor imagery capacities clearly demonstrated shorter response times in Experiment 2 for both hand-action and foot-action verbs, regardless of hand immobilization. Overall, these findings demonstrate for the first time that short-term sensorimotor deprivation can affect action verb processing. We discuss our results in light of the embodiment view, which considers that cognition is grounded in sensorimotor experiences. (PsycINFO Database Record


[Screening domestic violence. A German-language screening instrument for domestic violence against women].
Domestic violence is frequent. But up to now there is no screening instrument available in German which would allow a simple assessment. In this article a short screening interview is published that allows the identification of women who became victims of domestic violence. Such a screening interview has not been published in German speaking countries until now. A screening interview originally developed in English speaking countries called "Partner Violence Screen" (PVS) was translated, modified and validated in a population of female patients of a crisis intervention ward. The original version of the PVS consisted of 3 items which have been extended by two items, so that the modified version of the PVS is composed of 5 items now. In a validation study this instrument was compared to a much more detailed, 30 item self rating scale "Index of Spouse Abuse" (ISA). In addition to the validation of the PVS a life-time version of the PVS was developed which refers to the entire life period since the 18th birthday. The original version of the PVS showed a sensitivity of 0.79 and a specificity of 0.70. In the modified version "Screening Partner Violence" the sensitivity was 0.80 and the specificity 0.78. This screening instrument, which was translated and further developed by the authors, proved to be helpful for identifying domestic violence. With this instrument a screening interview is available for the first time in German speaking countries that can be accomplished with women in different institutions without losing much time.


Laparoscopic fundoplication: 5-year follow-up.
There are few published reports on outcomes of 5 or more years following laparoscopic fundoplication. Gastroesophageal reflux disease (GERD) specific quality of life questionnaires (QOLRAD), short form health surveys (SF12), and queries regarding current medication use and long-term satisfaction were mailed to all patients who underwent laparoscopic fundoplication at our institution. Results are reported as mean +/- SEM. Seventy-six patients underwent laparoscopic fundoplication (63 Nissen, 13 Toupet) between November 1992 and December 1997. Fifty-two patients completed questionnaires (68%). Mean follow-up was 5.1 +/- 0.2 years (range, 4-9 years). Mean QOLRAD scores were 5.8 +/- 0.2, (scale 0-7, a higher score reflecting improved QOL), which is comparable to the general population (6.0 mean). SF-12 mental and physical scores were 46.6 +/- 1.7 and 34.2 +/- 1.6, respectively, versus 50.7 and 51.2 for the general population. Forty-seven patients (92%) would have the procedure again. Eleven (21%) remained on antisecretory medications (15% proton pump inhibitor and 6% H2 receptor antagonists). None of the 11 patients underwent 24-hour pH testing to document persistent acid exposure. Furthermore, postoperative symptoms of heartburn, dysphagia, and abdominal bloating were rated as none to mild in the majority of patients. Laparoscopic fundoplication is an effective long-term treatment for GERD, resulting in high patient satisfaction, improved quality of life, and elimination of antisecretory medicines in the majority of patients.


Involvement of AAA ATPase AipA in endocytosis of the arginine permease AoCan1 depending on AoAbp1 in Aspergillus oryzae.
AAA ATPases widely exist in many organisms and function in various organelles. However, there is little information about AAA ATPase functioning in endocytosis. In Aspergillus oryzae, we previously discovered a putative AAA ATPase AipA that would be involved in endocytosis. Here, we further examined the function of AipA and AoAbp1 in endocytosis using enhanced green fluorescent protein (EGFP)-tagged arginine permease AoCan1 as an endocytic marker. In the ΔaipA strain, endocytosis of AoCan1-EGFP was more facilitated than the control strain, suggesting that AipA negatively regulates endocytosis. In contrast, in the ΔAoabp1 strain, endocytosis of AoCan1-EGFP was delayed compared with the control strain, suggesting that AoAbp1 positively functions in endocytosis. In addition, in the ΔaipAΔAoabp1 strain, endocytosis of AoCan1-EGFP was delayed. AipA localized at the endocytic collar of the hyphal tip, only in the presence of AoAbp1, suggesting AipA functions downstream of AoAbp1 in endocytosis. Moreover, we investigated the aipA-overexpressing strain, and found that endocytosis of AoCan1-EGFP was inhibited. Furthermore, we examined strains expressing aipAK542A or aipAE596Q, which decreased ATPase activity, in the backgrounds of complementation or overexpression, respectively, and found that AoCan1-EGFP endocytosis was promoted. These results suggested that AAA ATPase activity of AipA is important for its function in endocytosis.


EndothelinB receptor on guinea pig small intestinal smooth muscle cells.
We investigated the binding characteristics of the endothelin (ET) receptor and the mechanism by which ET induces contraction of longitudinal smooth muscle cells of the guinea pig small intestine by using vasoactive intestinal contractor (VIC), a mouse variant of ET-2. A functional receptor for VIC was found to exist on longitudinal smooth muscle cells. These cells showed a similar binding of and contractile response to ET-1, ET-2, and ET-3. Inhibitors of both intracellular and extracellular Ca2+ movement attenuated the VIC-induced contraction of longitudinal smooth muscle cells. These results suggest that smooth muscle cells of the guinea pig small intestine express the ETB receptor that primarily mediates the contractile effect on smooth muscle cells. In addition, ET-induced contraction depends on intracellular as well as extracellular Ca2+.