Directed growth of graphene nanomesh in purified argon via chemical vapor deposition.
Graphene nanomeshes (GNMs), new graphene nanostructures with tunable bandgaps, are potential building blocks for future electronic or photonic devices, and energy storage and conversion materials. In previous works, GNMs have been successfully prepared on Cu foils by the H2 etching effect. In this paper, we investigated the effect of Ar on the preparation of GNMs, and how the mean density and shape of them vary with growth time. In addition, scanning electron microscopy (SEM) and high resolution transmission electron microscopy (TEM) revealed the typical hexagonal structure of GNM. Atomic force microscopy (AFM) and x-ray photoelectron spectroscopy (XPS) indicated that large copper oxide nanoparticles produced by oxidization in purified Ar can play an essential catalytic role in preparing GNMs. Then, we exhibited the key reaction details for each growth process and proposed a growth mechanism of GNMs in purified Ar.


Patient Navigation Improves Subsequent Breast Cancer Screening After a Noncancerous Result: Evidence from the Patient Navigation in Medically Underserved Areas Study.
Past efforts to assess patient navigation on cancer screening utilization have focused on one-time uptake, which may not be sufficient in the long term. This is partially due to limited resources for in-person, longitudinal patient navigation. We examine the effectiveness of a low-intensity phone- and mail-based navigation on multiple screening episodes with a focus on screening uptake after receiving noncancerous results during a previous screening episode. The is a secondary analysis of patients who participated in a randomized controlled patient navigation trial in Chicago. Participants include women referred for a screening mammogram, aged 50-74 years, and with a history of benign/normal screening results. Navigation services focused on identification of barriers and intervention via shared decision-making processes. A multivariable logistic regression intent-to-treat model was used to examine differences in odds of obtaining a screening mammogram within 2 years of the initial mammogram (yes/no) between navigated and non-navigated women. Sensitivity analyses were conducted to explore patterns across subsets of participants (e.g., navigated women successfully contacted before the initial appointment; women receiving care at Hospital C). The final sample included 2,536 women (741 navigated, 1,795 non-navigated). Navigated women exhibited greater odds of obtaining subsequent screenings relative to women in the standard care group in adjusted models and analyses including women who received navigation before the initial appointment. Our findings suggest that low-intensity navigation services can improve follow-up screening among women who receive a noncancerous result. Further investigation is needed to confirm navigation's impacts on longitudinal screening.


Vertebral fracture and bone mineral density in women receiving high dose glucocorticoids for treatment of autoimmune diseases.
To evaluate the factors influencing the occurrence of vertebral fracture in patients receiving high dose glucocorticoids (GC). A cross-sectional study was performed on women who had received at least 0.5 mg/kg of oral glucocorticoid for the treatment of autoimmune diseases for more than 1 month between 1998 and 2003. Logistic regression analysis and chi-square test were used to examine the effects of glucocorticoid dose and other factors on vertebral fractures. Receiver-operating characteristics curve (ROC) analysis was used to determine the bone mineral density (BMD) cutoff value for the risk of vertebral fracture. The study population comprised 160 women, including 35 with vertebral fractures. In ROC analysis, the BMD threshold of the risk of fracture for postmenopausal women (0.787 g/cm2 , T score -2.1) was lower than that for premenopausal women (0.843 g/cm2 , T score -1.7). Among patients with fractures, 7 of 16 premenopausal patients had normal BMD values (T score > -1), whereas only one of 19 postmenopausal patients showed a comparable level of BMD. Additionally, vertebral fracture was more frequent for patients with high total cholesterol values (> 280 mg/dl) than for those with normal total cholesterol values (< 220 mg/dl). Moreover, patients with high total cholesterol values had lower BMD values than those with normal total cholesterol values. The fact that vertebral fracture frequently occurred in premenopausal patients with normal BMD and evidence that hyperlipidemia correlated with fracture suggest the pathology of vertebral fracture secondary to high dose glucocorticoid therapy is multifactorial and possibly involves lipid metabolism.


PGF2α signaling drives fibrotic remodeling and fibroblast population dynamics in mice.
Idiopathic Pulmonary Fibrosis (IPF) is a chronic parenchymal lung disease characterized by repetitive alveolar cell injury, myofibroblast proliferation, and excessive extracellular matrix deposition for which unmet need persists for effective therapeutics. The bioactive eicosanoid, prostaglandin F2a, and its cognate receptor FPr (Ptfgr) are implicated as a TGFβ1 independent signaling hub for IPF. To assess this, we leveraged our published murine PF model (IER-SftpcI73T) expressing a disease-associated missense mutation in the surfactant protein C (Sftpc) gene. Tamoxifen treated IER-SftpcI73T mice develop an early multiphasic alveolitis and transition to spontaneous fibrotic remodeling by 28 days. IER-SftpcI73T mice crossed to a Ptgfr null (FPr-/-) line showed attenuated weight loss and gene dosage dependent rescue of mortality compared to FPr+/+ cohorts. IER-SftpcI73T/FPr-/- mice also showed reductions in multiple fibrotic endpoints for which administration of nintedanib was not additive. Single cell RNA sequencing, pseudotime analysis, and in vitro assays demonstrated Ptgfr expression predominantly within adventitial fibroblasts which were reprogrammed to an "inflammatory/transitional" cell state in a PGF2a/ FPr dependent manner. Collectively, the findings provide evidence for a role for PGF2a signaling in IPF, mechanistically identify a susceptible fibroblast subpopulation, and establish a benchmark effect size for disruption of this pathway in mitigating fibrotic lung remodeling.


Sensory registration and informational persistence.
The traditional view of iconic memory as a precategorical, high-capacity, quickly decaying visible memory has recently come under attack (e.g., Coltheart, 1980). Specifically, distinctions have been drawn between visible persistence, or the phenomenal trace of an extinguished stimulus, and informational persistence, knowledge about the visual properties of the stimulus. In the present research we tested two alternative conceptions of informational persistence. One conception is that visual information persists in a visual memory that begins at stimulus offset and lasts for 150-300 ms, independently of exposure duration. The second is that informational persistence arises from a nonvisual memory that contains spatial coordinates for displayed items along with identity codes for those items. Three experiments were conducted in which 3 X 3 letter arrays were presented for durations ranging from 50 to 500 ms. A single character mask presented at varying intervals after array offset cued report of an entire row of the array. Comparison of the cued row's masked and unmasked letters revealed that spatially-specific visual (i.e., maskable) information persisted after stimulus offset, regardless of exposure duration. This result favors the visual conception of informational persistence. But there was also support for the nonvisual conception: Accuracy increased and item intrusion errors decreased as stimulus duration increased. The implications of these results for models of informational persistence and for transsaccadic integration during reading are discussed.


Progress towards eliminating canine rabies: policies and perspectives from Latin America and the Caribbean.
Human rabies transmitted by dogs is considered a neglected disease that can be eliminated in Latin America and the Caribbean (LAC) by 2015. The aim of this paper is to discuss canine rabies policies and projections for LAC regarding current strategies for achieving this target and to critically review the political, economic and geographical factors related to the successful elimination of this deadly disease in the context of the difficulties and challenges of the region. The strong political and technical commitment to control rabies in LAC in the 1980s, started with the regional programme coordinated by the Pan American Health Organization. National and subnational programmes involve a range of strategies including mass canine vaccination with more than 51 million doses of canine vaccine produced annually, pre- and post-exposure prophylaxis, improvements in disease diagnosis and intensive surveillance. Rabies incidence in LAC has dramatically declined over the last few decades, with laboratory confirmed dog rabies cases decreasing from approximately 25 000 in 1980 to less than 300 in 2010. Dog-transmitted human rabies cases also decreased from 350 to less than 10 during the same period. Several countries have been declared free of human cases of dog-transmitted rabies, and from the 35 countries in the Americas, there is now only notification of human rabies transmitted by dogs in seven countries (Bolivia, Peru, Honduras, Haiti, Dominican Republic, Guatemala and some states in north and northeast Brazil). Here, we emphasize the importance of the political commitment in the final progression towards disease elimination. The availability of strategies for rabies control, the experience of most countries in the region and the historical ties of solidarity between countries with the support of the scientific community are evidence to affirm that the elimination of dog-transmitted rabies can be achieved in the short term. The final efforts to confront the remaining obstacles, like achieving and sustaining high vaccination coverage in communities that are most impoverished or in remote locations, are faced by countries that struggle to allocate sufficient financial and human resources for rabies control. Continent-wide cooperation is therefore required in the final efforts to secure the free status of remaining countries in the Americas, which is key to the regional elimination of human rabies transmitted by dogs.


Lessons learned from piloting mHealth informatics practice curriculum into a medical elective.
This case study reports the development and delivery of an mHealth elective piloted for first-year undergraduate medical students at Monash University (Australia) and the lessons learned by designers. The students were not as adept at using mHealth devices as the literature had predicted. Expert speakers using mHealth for practice perceptibly engaged students. Force-field analysis was a useful basis for devising end-user evaluative research tools for practice. Combining small- and large-group discussions with eLearning discussions promoted student engagement with new concepts and associated jargon. Assessment by mHealth informatics champions supported the students' independent learning. Promotion of mHealth curriculum must be transparent and clear. Our elective delivery was hampered by a lack of suitable mobile device ownership and limited availability of useful, free apps. Technological jargon required clarification. Educators require particular mHealth informatics and educational expertise to support mHealth pedagogies. This learning helps to prepare medical curriculum designers for addressing evolving mHealth practice horizons.


[Laminar analysis of evoked potentials of the cat visual cortex during prenatal ontogenesis].
A laminar analysis of visual evoked potentials recorded from the cortical striate zone in response to stimulation of the optic nerve was made on the cats foeti in the second half of antenatal development and on kittens in the first few days of their life. In all the investigated terms of prenatal ontogenesis, two negativity foci are distinctly revealed in the specific zones of the visual cortex. The first appears with the least latency in the middle cortical layers after an afferent volley inflow to the cortex. The second, which reaches a maximum in 40 to 50 msec appears in the superficial cortical structures. Analysis of the data obtained shows that the first excitation focus is due to the summation of EPSP in the neural elements of the middle cortical layers, while the second is caused by development of depolarization in the apical dendrites of the pyramidal neurones.


Comparison of the mechanical properties of the anterior lens capsule following manual capsulorhexis and femtosecond laser capsulotomy.
To evaluate and compare the mechanical properties of anterior capsule openings performed with the continuous curvilinear capsulorhexis (CCC) technique and femtosecond laser capsulotomy (FLC) in ex vivo porcine lens capsule specimens. Fresh porcine eyes were included in the study (CCC group, n = 50; FLC group, n = 30). The capsule openings were stretched with universal testing equipment until they ruptured. The rupture force and circumference stretching ratio were evaluated. The morphologic profile of the cut capsule edges was evaluated using scanning electron microscopy (SEM). The average rupture force was higher in the CCC group (median: 155 mN; interquartile range [IQR]: 129 to 201 mN; range: 71 to 294 mN) than in the FLC group (median: 119 mN; IQR: 108 to 128 mN; range: 91 to 142 mN) (P < .01, Mann-Whitney U test). The average circumference stretching ratio in the CCC group was greater (median: 150%; IQR: 146% to 156%; range: 136% to 161%) than in the FLC group (median: 148%; IQR: 145% to 150%; range: 141% to 154%) (P = .0468, Mann-Whitney U test). When less than 71 mN, no capsular tear occurred in either group. When less than 91 mN, no capsular tear occurred in the FLC group, whereas at 91 mN, the probability of capsular tears was 9% for the CCC group. SEM examination found that the CCC group had smooth edges, whereas those of the FLC group were gently serrated. According to the current results in a porcine eye model, FLC had less average resistance to capsule tear than CCC, but the weakest openings were seen in the CCC group.


Characterization of the SARS-CoV-2 S Protein: Biophysical, Biochemical, Structural, and Antigenic Analysis.
Coronavirus disease 2019 ( COVID-19 ) is a global health crisis caused by the novel severe acute respiratory syndrome coronavirus 2 ( SARS-CoV-2 ), and there is a critical need to produce large quantities of high-quality SARS-CoV-2 Spike ( S ) protein for use in both clinical and basic science settings. To address this need, we have evaluated the expression and purification of two previously reported S protein constructs in Expi293F ™ and ExpiCHO-S ™ cells, two different cell lines selected for increased expression of secreted glycoproteins. We show that ExpiCHO-S ™ cells produce enhanced yields of both SARS-CoV-2 S proteins. Biochemical, biophysical, and structural ( cryo-EM ) characterization of the SARS-CoV-2 S proteins produced in both cell lines demonstrate that the reported purification strategy yields high quality S protein (non-aggregated, uniform material with appropriate biochemical and biophysical properties). Importantly, we show that multiple preparations of these two recombinant S proteins from either cell line exhibit identical behavior in two different serology assays. We also evaluate the specificity of S protein-mediated host cell binding by examining interactions with proposed binding partners in the human secretome. In addition, the antigenicity of these proteins is demonstrated by standard ELISAs, and in a flexible protein microarray format. Collectively, we establish an array of metrics for ensuring the production of high-quality S protein to support clinical, biological, biochemical, structural and mechanistic studies to combat the global pandemic caused by SARS-CoV-2.


Werner protein cooperates with the XRCC4-DNA ligase IV complex in end-processing.
Werner syndrome is a rare human disease characterized by the premature onset of aging-associated pathologies, cancer predisposition, and genomic instability. The Werner protein (WRN), which is defective in Werner syndrome ( WS) patients, belongs to the RecQ family helicases and interacts with several DNA metabolic proteins, including DNA repair factors and telomere associated proteins. Nonhomologous end-joining (NHEJ) is an important pathway in the repair of DNA double strand breaks (DSBs), and the DNA-PK complex, composed of the heterodimer Ku 70/86 and the DNA-PK catalytic subunit (DNA-PKcs), together with the XRCC4-DNA ligase IV complex (X4L4), are major factors. One of the most prominent protein interactions of WRN is with Ku 70/86, and it is possible that WRN is involved in NHEJ via its associations with Ku 70/86 and DNA-PKcs. This study demonstrates that WRN physically interacts with the major NHEJ factor, X4L4, which stimulates WRN exonuclease but not its helicase activity. The human RecQ helicase, BLM, which possesses only helicase activity, does not bind to X4L4, and its helicase activity is not affected by X4L4. In a DNA end-joining assay, we find that a substrate, which is processed by WRN, is ligated by X4L4, thus further supporting the significance of their functional interaction.


How to Provide the Needed Protection from COVID-19 to Patients with Hematologic Malignancies.
Patients with hematologic malignancies are particularly vulnerable to COVID-19 infections, and upon a pooled data analysis of 24 publications, there is evidence that they have suboptimal antibody responses to COVID-19 vaccination and boosters. To provide them the needed additional protection from COVID-19, it is imperative to achieve a 100% full immunization rate in health care workers and adult caretakers, and to foster research to test higher doses and repeated rounds of COVID-19 vaccines and the use of passive immune prophylaxis and therapy.


HELQ is a dual-function DSB repair enzyme modulated by RPA and RAD51.
DNA double-stranded breaks (DSBs) are deleterious lesions, and their incorrect repair can drive cancer development1. HELQ is a superfamily 2 helicase with 3' to 5' polarity, and its disruption in mice confers germ cells loss, infertility and increased predisposition to ovarian and pituitary tumours2-4. At the cellular level, defects in HELQ result in hypersensitivity to cisplatin and mitomycin C, and persistence of RAD51 foci after DNA damage3,5. Notably, HELQ binds to RPA and the RAD51-paralogue BCDX2 complex, but the relevance of these interactions and how HELQ functions in DSB repair remains unclear3,5,6. Here we show that HELQ helicase activity and a previously unappreciated DNA strand annealing function are differentially regulated by RPA and RAD51. Using biochemistry analyses and single-molecule imaging, we establish that RAD51 forms a complex with and strongly stimulates HELQ as it translocates during DNA unwinding. By contrast, RPA inhibits DNA unwinding by HELQ but strongly stimulates DNA strand annealing. Mechanistically, we show that HELQ possesses an intrinsic ability to capture RPA-bound DNA strands and then displace RPA to facilitate annealing of complementary sequences. Finally, we show that HELQ deficiency in cells compromises single-strand annealing and microhomology-mediated end-joining pathways and leads to bias towards long-tract gene conversion tracts during homologous recombination. Thus, our results implicate HELQ in multiple arms of DSB repair through co-factor-dependent modulation of intrinsic translocase and DNA strand annealing activities.


Phytochrome signalling modulates the SA-perceptive pathway in Arabidopsis.
The interaction of phytochrome signalling with the SA signal transduction pathway has been investigated in Arabidopsis using single and multiple mutants affected in light perception (phyA and phyB deficient) and light-signal processing (psi2, phytochrome signalling). The induction of PR1 by SA and functional analogues has been found to strictly correlate with the activity of the signalling pathway controlled by both phyA and phyB photoreceptors. In darkness as well as dim light, and independently of a carbohydrate source, SA-induced PR gene expression as well as the hypersensitive response to pathogens (HR) are strongly reduced. Moreover, the initiation of HR also exhibits a strict dependence upon both the presence and the amplitude of a phytochrome-elicited signal. The growth of an incompatible strain of bacterial a pathogen (Pseudomonas syringae pv. tomato) was enhanced in phyA-phyB and decreased in psi2 mutants. While functional chloroplasts were found necessary for the development of an HR, the induction of PRs was strictly dependent on light, but independent of functional chloroplasts. Taken together, these data demonstrate that the light-induced signalling pathway interacts with the pathogen/SA-mediated signal transduction route. These results are summarized in a formalism that allows qualitative computer simulation.


Bilateral cranial nerve 6 palsy in a patient with multiple sclerosis and vitamin D-dependent rickets.
The development of multiple sclerosis (MS) is multifactorial. Elevated levels of vitamin D may lower the risk and reduce relapses by immunomodulatory mechanisms. Conversely, vitamin D-dependent rickets (VDDR), an inheritable form of rickets secondary to impairment in vitamin D synthesis or action, may increase MS risk. This has been described in three patients with VDDR type 1A. Here, we present a patient with VDDR type 2 - unclear if type 2A or 2B based on historical genetic testing - who subsequently developed MS. She presented with 8 weeks of binocular horizontal diplopia and was found to have 8 prism dioptres of esotropia in primary gaze and a mild limitation of abduction in both eyes. Radiological workup was consistent with MS demyelination. She was started on solumedrol infusions, with full resolution of the esotropia and abduction deficits. She has since been transitioned to ocrelizumab with vitamin D supplementation and has not had a relapse to date. It is important to consider MS in patients genetically predisposed to low vitamin D levels or functional impairment, as with VDDR. Vitamin D supplementation can achieve remission in some forms of VDDR, and its role in MS prevention in these patients should be considered. In patients with type 2A or 2B VDDR, who have impairment in receptor function, additional treatment modalities require investigation. Lastly, demyelination is a rare cause of bilateral cranial nerve 6 palsy. This case illustrates the importance of considering MS in cranial nerve palsies, particularly in patients with vitamin D deficiencies or functional impairment.


Sir John Struthers (1823-1899) and his ligament and arcade.
Sir John Struthers, Scottish anatomist, professor, and surgeon, was an early advocate of clinical training in medical education, and his impact is still visible today. He was one of the first prominent anatomists in the United Kingdom to endorse Charles Darwin's controversial theory of natural selection, and his research reflected a desire to illustrate these ideas in cadaveric specimens. Struthers is remembered eponymously for 2 connective tissue condensations in the arm, an arcade and ligament, which may entrap the ulnar and median nerves, respectively. He studied medicine at the University of Edinburgh, received a Doctor of Laws degree from the University of Glasgow, served on the General Medical Council from 1883 to 1891, was president of the Royal College of Surgeons from 1895 to 1897, and was knighted by Queen Victoria in 1898. Struthers' devotion to medical education and insistence on the importance of clinical training laid the foundation for current medical curricula around the world. His observations of sites of potential nerve entrapment in the arm are still taught to neurosurgical trainees today.


The use of regorafenib for patients with refractory metastatic colorectal cancer in clinical practice.
Patients in clinical practice are relatively vulnerable compared to those enrolled in clinical trials. We focused on analyzing the pattern of regorafenib use in routine clinical practice, which included initial starting dose and follow-up schedule. We also evaluated the efficacy and safety according to clinical regimen. We retrospectively reviewed the medical records of 134 Korean heavily pretreated metastatic colorectal cancer (mCRC) patients who had received regorafenib monotherapy as salvage treatment in routine clinical practice between January 2014 and January 2018. Among the 134 mCRC patients, the median age was 55 years (range, 22-80 years), and 51% had previously received four or more chemotherapy treatments. Thirty-eight (28.3%) patients had more than three metastatic lesions. As an initial starting dose, 120 mg regorafenib was mostly frequently used (n=65, 48.5%), followed by 80 mg (32.8%) and 160 mg (18.7%). The first follow-up after regorafenib initiation was most frequently at 28 days (45.5%), followed by 14 days (29.9%), 7 days (13.4%), and 21 days (11.2%). There was no significant difference in response rate according to initial dose of regorafenib (80 mg vs 120 mg vs 160 mg, 4.5% vs 1.5% vs 4.0%, P=0.596) or disease control rate (80 mg vs 120 mg vs 160 mg, 38.6% vs 29.2% vs 31.6%, P=0.299). Progression-free survival did not differ according to initial dose (80 mg vs 120 mg vs 160 mg, 2.8 months [95% CI 2.1-3.5] vs 2.2 months [95% CI 1.7-2.8] vs 1.9 months [95% CI 1.3-2.4], P=0.076). Grade 3/4 adverse events occurred in 17 (12.7%) patients and were not related to initial dose of regorafenib (P=0.126). Here, we present efficacy and safety data according to different initial doses of regorafenib in clinical practice. These data may provide useful information when using regorafenib for refractory mCRC in clinical practice.


The future of pharmaceutical care in France: a survey of final-year pharmacy students' opinions.
In the last decades, the provision of pharmaceutical care by community pharmacists has developed in OECD countries. These developments involved significant changes in professional practices and organization of primary care. In France, they have recently been encouraged by a new legal framework and favored by an increasing demand for health care (increase in the number of patients with chronic diseases) and reductions in services being offered (reduction in the number of general practitioners and huge regional disparities). This study aimed to investigate final-year pharmacy students' opinions on 1/expanding the scope of pharmacists' practices and 2/the potential barriers for the implementation of pharmaceutical care. We discussed these in the light of the experiences of pharmacists in Quebec, and other countries in Europe (United Kingdom and the Netherlands). All final-year students in pharmaceutical studies, preparing to become community pharmacists, at the University Paris-Descartes in Paris during 2010 (n = 146) were recruited. All of them were interviewed by means of a questionnaire describing nine "professional" practices by pharmacists, arranged in four dimensions: (1) screening and chronic disease management, (2) medication surveillance, (3) pharmacy-prescribed medication and (4) participation in health care networks. Respondents were asked (1) how positively they view the extension of their current practices, using a 5 point Likert scale and (2) their perception of potential professional, technical, organizational and/or financial obstacles to developing these practices. 143 (97.9%) students completed the questionnaire. Most of practices studied received a greater than 80% approval rating, although only a third of respondents were in favor of the sales of over-the-counter (OTC) drugs. The most significant perceived barriers were working time, remuneration and organizational problems, specifically the need to create a physical location for consultations to respect patients' privacy within a pharmacy. Despite remaining barriers to cross, this study showed that future French pharmacists were keen to develop their role in patient care, beyond the traditional role of dispensing. However, the willingness of doctors and patients to consent should be investigated and also rigorous studies to support or refute the positive impact of pharmaceutical care on the quality of care should be carried out.


Correlates and predictors of parenting self-efficacy in new fathers.
Parenting self-efficacy is a critical determinant of high-quality parenting behavior, but this aspect of parenting cognitions has been understudied for fathers. Longitudinal data from a sample of 182 fathers of firstborn infants in dual-earner families were used to assess how expectant fathers' rearing history, personality and personal characteristics, and family relationships were associated with their initial levels of parenting self-efficacy in the early postpartum period. Expectant fathers completed surveys assessing their rearing history, personality, and personal characteristics during the third trimester of pregnancy and reported on their perceptions of coparenting and parenting self-efficacy at three months postpartum. Results of hierarchical regression analyses showed that new fathers were at risk for lower parenting self-efficacy when they had greater attachment anxiety and neuroticism, believed that mothers are inherently better caretakers, and planned to use their own fathers as models for childrearing. In contrast, new fathers had greater parenting self-efficacy when they perceived their coparenting relationships with children's mothers more positively. These findings inform theory about the development of fathers' parenting cognitions and behavior and practice with expectant and new fathers, and, if replicated in a larger, more representative sample, may be used to identify expectant fathers at risk for low parenting self-efficacy and in the design of policy initiatives to enhance father-child relationships. (PsycInfo Database Record (c) 2022 APA, all rights reserved).


Urodele limb and tail regeneration in early biological thought: an essay on scientific controversy and social change.
Lazzaro Spallanzani (1729-1799) announced his discoveries of salamander tail and limb regeneration to Charles Bonnet (1729-1793) in the 1760's. The phenomenon soon became embroiled with the ongoing epigenesis/preformation controversy over the fundamental nature of generation. The concept of animal regeneration as a process linked to reproduction had emerged in 1740 with Abraham Trembley's (1710-1783) demonstration that a bisected hydra gives rise to two new, completely formed individuals. The discovery of urodele appendage regeneration revealed for the first time that a quadruped could regenerate and restore complex form, lizard tail regenerates having been recognized as only substitute structures. Moreover, regeneration of a quadruped appendage became problematic because it was not supposed to be possible and because it conflicted with prevailing opinion about the nature of higher organisms. Why animal regeneration in general engendered conflict transcends biological concerns and touches on personal philosophical commitments. Preformation had been adopted into orthodox theology as a validation of predestination and of the hierarchical structuring of man's relationships to nature and within society. Epigenetic interpretations of regeneration represented challenges to certain aspects of the extant social and political fabric in their extrapolation to ideas of what constituted natural order. Urodele regeneration as an integral part of the epigenesis/preformation debate therefore constituted a formative component of eighteenth century thought in a period of social and intellectual revolution.


Microfluidic Genipin Deposition Technique for Extended Culture of Micropatterned Vascular Muscular Thin Films.
The chronic nature of vascular disease progression requires the development of experimental techniques that simulate physiologic and pathologic vascular behaviors on disease-relevant time scales. Previously, microcontact printing has been used to fabricate two-dimensional functional arterial mimics through patterning of extracellular matrix protein as guidance cues for tissue organization. Vascular muscular thin films utilized these mimics to assess functional contractility. However, the microcontact printing fabrication technique used typically incorporates hydrophobic PDMS substrates. As the tissue turns over the underlying extracellular matrix, new proteins must undergo a conformational change or denaturing in order to expose hydrophobic amino acid residues to the hydrophobic PDMS surfaces for attachment, resulting in altered matrix protein bioactivity, delamination, and death of the tissues. Here, we present a microfluidic deposition technique for patterning of the crosslinker compound genipin. Genipin serves as an intermediary between patterned tissues and PDMS substrates, allowing cells to deposit newly-synthesized extracellular matrix protein onto a more hydrophilic surface and remain attached to the PDMS substrates. We also show that extracellular matrix proteins can be patterned directly onto deposited genipin, allowing dictation of engineered tissue structure. Tissues fabricated with this technique show high fidelity in both structural alignment and contractile function of vascular smooth muscle tissue in a vascular muscular thin film model. This technique can be extended using other cell types and provides the framework for future study of chronic tissue- and organ-level functionality.


Maternal mid-pregnancy C-reactive protein and risk of autism spectrum disorders: the early markers for autism study.
Maternal pregnancy levels of the inflammatory marker C-reactive protein (CRP) has been previously associated with autism spectrum disorder (ASD) in the offspring. We conducted a population-based nested case-control study with 500 children with ASD, 235 with developmental delay (DD) and 580 general population (GP) controls to further investigate whether elevated CRP during pregnancy increases the risk of ASD. Maternal CRP concentration was measured in archived serum collected during 15-19 weeks of pregnancy and genome-wide single-nucleotide polymorphism (SNP) data were generated. The levels of CRP were compared between ASD vs GP and DD vs GP. The genetic associations with CRP were assessed via linear regression. Maternal CRP levels in mid-pregnancy were lower in mothers of ASD compared with controls. The maternal CRP levels in the upper third and fourth quartiles were associated with a 45 and 44% decreased risk of ASD, respectively. Two SNPs at the CRP locus showed strong association with CRP levels but they were not associated with ASD. No difference was found between maternal CRP levels of DD and controls. The reasons for the lower levels of CRP in mothers of ASD are not known with certainty but may be related to alterations in the immune response to infectious agents. The biological mechanisms underlying this association remain to be clarified.


Expression of urokinase and urinary trypsin inhibitor in metastatic and non-metastatic murine Lewis lung carcinoma cells.
The murine Lewis lung carcinoma 3LL cells give rise to spontaneous and experimental lung metastasis in C57BL/6 mice. Tumor cells maintained by serial subcutaneous transplantation in mice retain their ability to form lung metastasis, while cells carried in vitro loose metastatic potential with time. In order to obtain the non-metastatic subline, 3LL cells selected for its high lung colonization potential was grown continuously in vitro for 24 weeks. The present study was undertaken to characterize the expression of both urokinase-type plasminogen activator (uPA) and urinary trypsin inhibitor (UTI) in the non-metastatic (3LL(-)) and the metastatic (3LL(+)) cells. Both cells were tested on the Matrigel for invasive ability using a modified Boyden chamber and assayed for expression of uPA and UTI. The 3LL(+) cells secreted 5 times more uPA (6.25 mu g per 10(6) cells per 24 h) than the 3LL(-) cells (1.25 mu g per 10(6) cells per 24 h). The 3LL(+) cells, which expressed 2 times more cell-surface receptor-bound enzymatically active uPA (0.32 +/- 0.06 OD405) than the 3LL(-) cells (0.15 +/- 0.03 OD405), had larger amounts of cell-surface receptor-bound uPA. On the other hands, UTI levels in the conditioned media was decreased 25-fold in the 3LL(+) cells (0.05 mu g/10(6) cells/24 h) compared to the 3LL(-) cells (1.25 mu g/10(6) cells/24 h). The 3LL(-) cells expressed significantly higher levels of cell-associated UTI as indicated by a cell ELISA (3LL(+), 0.30 +/- 0.04 OD450; 3LL(-), 1.30 +/- 0.21 OD450) and by Western blot analysis. Metastatic competence in the 3LL(+) tumor model is associated with increased expression and release of uPA, as well as decreased UTI production, consistent with a more invasive phenotype. These data support our hypothesis that UTI may contribute to the inhibition of uPA expression in tumor cells.


Location of pathogenic variants in PSEN1 impacts progression of cognitive, clinical, and neurodegenerative measures in autosomal-dominant Alzheimer's disease.
Although pathogenic variants in PSEN1 leading to autosomal-dominant Alzheimer disease (ADAD) are highly penetrant, substantial interindividual variability in the rates of cognitive decline and biomarker change are observed in ADAD. We hypothesized that this interindividual variability may be associated with the location of the pathogenic variant within PSEN1. PSEN1 pathogenic variant carriers participating in the Dominantly Inherited Alzheimer Network (DIAN) observational study were grouped based on whether the underlying variant affects a transmembrane (TM) or cytoplasmic (CY) protein domain within PSEN1. CY and TM carriers and variant non-carriers (NC) who completed clinical evaluation, multimodal neuroimaging, and lumbar puncture for collection of cerebrospinal fluid (CSF) as part of their participation in DIAN were included in this study. Linear mixed effects models were used to determine differences in clinical, cognitive, and biomarker measures between the NC, TM, and CY groups. While both the CY and TM groups were found to have similarly elevated Aβ compared to NC, TM carriers had greater cognitive impairment, smaller hippocampal volume, and elevated phosphorylated tau levels across the spectrum of pre-symptomatic and symptomatic phases of disease as compared to CY, using both cross-sectional and longitudinal data. As distinct portions of PSEN1 are differentially involved in APP processing by γ-secretase and the generation of toxic β-amyloid species, these results have important implications for understanding the pathobiology of ADAD and accounting for a substantial portion of the interindividual heterogeneity in ongoing ADAD clinical trials.


Diffuse lamellar keratitis in the femtosecond-assisted LASIK flap tunnel.
Here we report a case of a 29-year-old myopic female who underwent femtosecond laser-assisted in situ keratomileusis (LASIK) and, on the first postoperative day slit-lamp examination revealed a dense, white, granular reaction with the presence of some blood droplets (stage I diffuse lamellar keratitis [DLK]) in her left eye, specifically localized into the femtosecond LASIK flap tunnel (not extended to the flap interface). The patient received intensive treatment with topical corticosteroids and 5 days later the granular reaction had completely resolved. A new site of DLK, ie, the flap tunnel, in femtosecond-assisted LASIK is presented. DLK into the flap tunnel could be managed with corticosteroids if detected early, without affecting the flap interface.


Consensus recommendations for gastric emptying scintigraphy: a joint report of the American Neurogastroenterology and Motility Society and the Society of Nuclear Medicine.
This consensus statement from the members of the American Neurogastroenterology and Motility Society and the Society of Nuclear Medicine recommends a standardized method for measuring gastric emptying (GE) by scintigraphy. A low-fat, egg-white meal with imaging at 0, 1, 2, and 4 h after meal ingestion, as described by a published multicenter protocol, provides standardized information about normal and delayed GE. Adoption of this standardized protocol will resolve the lack of uniformity of testing, add reliability and credibility to the results, and improve the clinical utility of the GE test.


Susceptibility of quagga mussels (Dreissena rostriformis bugensis) to hot-water sprays as a means of watercraft decontamination.
The recent spread of dreissenid mussels to various bodies of water in the western US has sparked interest by many state and federal agencies to develop protocols to stop further expansion. Quagga mussels (Dreissena rostriformis bugensis) are of particular importance as they are currently the most widespread dreissenid species in the region. This project examined the susceptibility of quagga mussels to hot-water sprays at different temperatures and durations of spray contact at Lake Mead (Nevada-Arizona, USA). Emersed adult quagga mussels were exposed to hot-water sprays at 20, 40, 50, 54, 60, 70, and 80°C for 1, 2, 5, 10, 20, 40, 80, and 160 s. Sprays at ≥60°C for 5 s were shown to be 100% lethal. Sprays of 54°C for 10 s, 50°C for 20 s, and 40°C for 40 s also resulted in 100% mortality. A spray temperature of 60°C for 5 s is recommended for mitigating fouling by quagga mussels.


Geosmithia associated with bark beetles and woodborers in the western USA: taxonomic diversity and vector specificity.
Fungi in the genus Geosmithia (Ascomycota: Hypocreales) are frequent associates of bark beetles and woodborers that colonize hardwood and coniferous trees. One species, Geosmithia morbida, is an economically damaging invasive species. The authors surveyed the Geosmithia species of California and Colorado, USA, to (i) provide baseline data on taxonomy of Geosmithia and beetle vector specificity across the western USA; (ii) investigate the subcortical beetle fauna for alternative vectors of the invasive G. morbida; and (iii) interpret the community composition of this region within the emerging global biogeography of Geosmithia. Geosmithia was detected in 87% of 126 beetle samples obtained from 39 plant species. Twenty-nine species of Geosmithia were distinguished, of which 13 may be new species. Bark beetles from hardwoods, Cupressus, and Sequoia appear to be regular vectors, with Geosmithia present in all beetle gallery systems examined. Other subcortical insects appear to vector Geosmithia at lower frequencies. Overall, most Geosmithia have a distinct level of vector specificity (mostly high, sometimes low) enabling their separation to generalists and specialists. Plant pathogenic Geosmithia morbida was not found in association with any other beetle besides Pityophthorus juglandis. However, four additional Geosmithia species were found in P. juglandis galleries. When integrated with recent data from other continents, a global pattern of Geosmithia distribution across continents, latitudes, and vectors is emerging: of the 29 Geosmithia species found in the western USA, 12 have not been reported outside of the USA. The most frequently encountered species with the widest global distribution also had the broadest range of beetle vectors. Several Geosmithia spp. with very narrow vector ranges in Europe exhibited the similar degree of specialization in the USA. Such strong canalization in association could reflect an ancient origin of each individual association, or a recent origin and a subsequent diversification in North America.


Infliximab-Tumor Necrosis Factor Complexes Elicit Formation of Anti-Drug Antibodies.
Some patients develop anti-drug antibodies (ADAs), which reduce the efficacy of infliximab, a monoclonal antibody against tumor necrosis factor (TNF), in the treatment of immune-mediated diseases, including inflammatory bowel diseases. ADAs arise inconsistently, and it is not clear what factors determine their formation. We investigated features of the immune system, the infliximab antibody, and its complex with TNF that might contribute to ADA generation. C57BL/6 mice were given injections of infliximab and recombinant human TNF or infliximab F(ab')2 fragments. Blood samples were collected every 2-3 days for 2 weeks and weekly thereafter for up to 6 weeks; infliximab-TNF complexes and ADAs were measured by enzyme-linked immunosorbent assay (ELISA). Intestinal biopsy and blood samples were obtained from patients having endoscopy who had received infliximab therapy for inflammatory bowel diseases; infliximab-TNF complexes were measured with ELISA. Infliximab-specific plasma cells were detected in patient tissue samples by using mass cytometry. We studied activation of innate immune cells in peripheral blood mononuclear cells (PBMCs) from healthy donors incubated with infliximab or infliximab-TNF complexes; toll-like receptors (TLRs) were blocked with antibodies, endocytosis was blocked with the inhibitor PitStop2, and cytokine expression was measured by real-time polymerase chain reaction and ELISAs. Uptake of infliximab and infliximab-TNF complexes by THP-1 cells was measured with confocal microscopy. Mice given increasing doses of infliximab produced increasing levels of ADAs. Blood samples from mice given injections of human TNF and infliximab contained infliximab-TNF complexes; complex formation was associated with ADA formation with an area under the curve of 0.944 (95% confidence interval, 0.851-1.000; P = .003). Intestinal tissues from patients, but not blood samples, contained infliximab-TNF complexes and infliximab-specific plasma cells. Incubation of PBMCs with infliximab-TNF complexes resulted in a 4.74-fold increase in level of interleukin (IL) 1β (IL1B) messenger RNA (P for comparison = .005), increased IL1B protein secretion, and a 2.69-fold increase in the expression of TNF messenger RNA (P for comparison = 0.013) compared with control PBMCs. Infliximab reduced only IL1B and TNF expression. Antibodies against TLR2 or TLR4 did not block the increases in IL1B or TNF expression, but endocytosis was required. THP-1 cells endocytosed higher levels of infliximab-TNF complexes than infliximab alone. In mice, we found ADA formation to increase with dose of infliximab given and concentration of infliximab-TNF complexes detected in blood. Based on studies of human intestinal tissues and blood samples, we propose that infliximab-TNF complexes formed in the intestine are endocytosed by and activate innate immune cells, which increase expression of IL1B and TNF and production of antibodies against the drug complex. It is therefore important to optimize the infliximab dose to a level that is effective but does not activate an innate immune response against the drug-TNF complex.


Neuropeptide receptor transcriptome reveals unidentified neuroendocrine pathways.
Neuropeptides are an important class of molecules involved in diverse aspects of metazoan development and homeostasis. Insects are ideal model systems to investigate neuropeptide functions, and the major focus of insect neuropeptide research in the last decade has been on the identification of their receptors. Despite these vigorous efforts, receptors for some key neuropeptides in insect development such as prothoracicotropic hormone, eclosion hormone and allatotropin (AT), remain undefined. In this paper, we report the comprehensive cloning of neuropeptide G protein-coupled receptors from the silkworm, Bombyx mori, and systematic analyses of their expression. Based on the expression patterns of orphan receptors, we identified the long-sought receptor for AT, which is thought to stimulate juvenile hormone biosynthesis in the corpora allata (CA). Surprisingly, however, the AT receptor was not highly expressed in the CA, but instead was predominantly transcribed in the corpora cardiaca (CC), an organ adjacent to the CA. Indeed, by using a reverse-physiological approach, we purified and characterized novel allatoregulatory peptides produced in AT receptor-expressing CC cells, which may indirectly mediate AT activity on the CA. All of the above findings confirm the effectiveness of a systematic analysis of the receptor transcriptome, not only in characterizing orphan receptors, but also in identifying novel players and hidden mechanisms in important biological processes. This work illustrates how using a combinatorial approach employing bioinformatic, molecular, biochemical and physiological methods can help solve recalcitrant problems in neuropeptide research.


Hot-spot variations of Kaposi's sarcoma-associated herpesvirus latent nuclear antigen and application in genotyping by PCR-RFLP.
Kaposi's sarcoma-associated herpesvirus (KSHV, human herpesvirus-8) is aetiologically associated with Kaposi's sarcoma and several other lymphoproliferative disorders. The latent nuclear antigen (LNA) encoded by KSHV ORF73 has important functions in virus latent infection and shows molecular polymorphism. Sequence variations were identified in the internal repeat domain (IRD) of ORF73. DNA sequencing of ORF73 from one KSHV-infected cell line, PK-1, revealed that there were 558 bp (30.2%) deletions and 66 (3.6%) point mutations located mainly in repeat region 2, the glutamine-rich region of ORF73 IRD, compared with ORF73 of BC-1 KSHV. Similar sequence variations of ORF73 were also identified in two other isolates. None of the sequence variations caused any translational frame-shift in these four KSHV isolates examined, suggesting that LNA has a conservative function in virus latent infection. The frequent sequence variations in repeat region 2 of ORF73 IRD were also identified by PCR-RFLP genotyping in 26 KSHV isolates, suggesting that this region is a 'hot-spot' for genetic variations. Each Kaposi's sarcoma lesion sample contained one virus genotype with a unique RFLP pattern, indicating that in vivo KSHV infection was established with single predominate genotypes, which was further supported by the presence of invariable genotypes in multifocal lesions from individual KS patients. Four KSHV subtypes were classified based on the RFLP patterns that represent the patterns of DNA sequence variations in the ORF73 IRD. PCR-RFLP genotyping is capable of identifying LNA genetic variations and differentiating individual KSHV isolates, and thus may be useful for KSHV molecular epidemiology studies.


Inhibition of NF-kappaB1 and NF-kappaB2 activation in prostate cancer cells treated with antibody against the carboxyl terminal domain of GRP78: effect of p53 upregulation.
Ligation of cancer cell surface GRP78 by activated alpha2-macroglobulin (alpha2M*) triggers pro-proliferative and anti-apoptotic signaling pathways. Cancer patients who develop autoantibodies to the alpha2M* binding site in GRP78 have a poor prognosis since these antibodies are receptor agonists. The NF-kappaB family of transcription factors induces expression of genes affecting cell growth and differentiation. NF-kappaB1 plays a major regulatory role in controlling innate immunity and inflammation, whereas NF-kappaB2 plays a greater role in cancer cell proliferation. Here we report that treatment of prostate cancer cells with antibody directed against the carboxyl terminal domain of GRP78 inhibits alpha2M*-induced activation of NF-kappaB2 by approximately 50% while exerting a lesser effect of approximately 20% on NF-kappaB1 activation. Treatment of these cells nearly abolished alpha2M*-induced activation of IKKalpha involved in the activation of NF-kappaB2. This antibody also suppressed alpha2M*-induced phosphorylation of IKKalpha, IKKalpha/beta, IkappaBalpha, and IkappaBbeta as well as levels of NIK. Antibody treatment of cancer cells elevated pro-apoptotic p21WAF and p27kip while reducing cyclin D1 levels. These studies demonstrate that antibody directed against the carboxyl terminal domain of GRP78 inhibits the pro-proliferative NF-kappaB signaling cascade in cancer cells.


Arhgef1 regulates alpha5beta1 integrin-mediated matrix metalloproteinase expression and is required for homeostatic lung immunity.
Pulmonary immunity depends on the ability of leukocytes to neutralize potentially harmful and frequent insults to the lung, and appropriate regulation of leukocyte migration and adhesion is integral to this process. Arhgef1 is a hematopoietic-restricted signaling molecule that regulates leukocyte migration and integrin-mediated adhesion. To explore a possible regulatory role for Arhgef1 in pulmonary immunity we examined the lung and its leukocytes in wild-type and Arhgef1-deficient animals. Here we report that the lungs of Arhgef1-/- mice harbored significantly more leukocytes, increased expression and activity of matrix metalloproteinases (MMPs), airspace enlargement, and decreased lung elastance compared with wild-type lungs. Transfer of Arhgef1-/- lung leukocytes to wild-type mice led to airspace enlargement and impaired lung function, indicating that loss of Arhgef1 in leukocytes was sufficient to induce pulmonary pathology. Furthermore, we showed that Arhgef1-deficient peritoneal macrophages when either injected into the lungs of wild-type mice or cultured on fibronectin significantly increased expression and activity of MMPs relative to control macrophages, and the in vitro fibronectin induction was dependent on the alpha5beta1 integrin pair. Together these data demonstrate that Arhgef1 regulates alpha5beta1-mediated MMP expression by macrophages and that loss of Arhgef1 by leukocytes leads to pulmonary pathology.


Forensic application of laser-induced breakdown spectroscopy for the discrimination of questioned documents.
Document examination is an important forensic discipline and the legal system regularly needs the knowledge and skills of the scientific expert when questioned documents are involved in criminal or civil matters. Amongst the many aspects of the scientific examination of documents, elemental analysis can provide useful results. In this study, the evaluation of the analytical performance of a commercially available laser-induced breakdown spectroscopy (LIBS) instrument was conducted on office papers, writing inks, inkjet inks and laser printer toners. The paper sample set analysed consisted of 33 Australian paper specimens originating from the same production plant but representing different brands and/or batches. In addition, a total of 131 ink or toner samples were examined that included black and blue ballpoint inks, black inkjet inks, and black laser printer toners originating from several manufacturing sources, models and/or batches. Results from the LIBS method were compared against those obtained using more established elemental profiling method such as laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS). LIBS demonstrated detectable and significant differences between different batches of the same brand as well as between different brands of paper, ink and toner samples. The LIBS method provided comparable discrimination powers for the selected sample sets when compared to those obtained using LA-ICP-MS (discrimination from 99.8 and 100% of the sample pairs, depending on the sample subset under examination). LIBS is a suitable technique for the determination of elemental composition as part of a protocol for the examination of questioned documents.


Pathogenic Acanthamoeba spp secrete a mannose-induced cytolytic protein that correlates with the ability to cause disease.
The pathogenesis of Acanthamoeba keratitis begins when Acanthamoeba trophozoites bind specifically to mannosylated glycoproteins upregulated on the surfaces of traumatized corneal epithelial cells. When Acanthamoeba castellanii trophozoites are grown in methyl-alpha-D-mannopyranoside, they are induced to secrete a novel 133-kDa protein that is cytolytic to corneal epithelial cells. Clinical isolates of Acanthamoeba spp., and not the soil isolates, were proficient at producing a mannose-induced protein (MIP-133) and generating disease in Chinese hamsters. The purified protein was efficient at killing corneal epithelial cells, the first mechanistic barrier, by inducing apoptosis in a caspase 3-dependent pathway. Subsequent steps in pathogenesis require the amoebae to penetrate and degrade collagen. Only the clinical isolates tested were efficient at migrating through a collagenous matrix in vitro, presumably by MIP-133 degradation of both human type I and human type IV collagen. A chicken anti-MIP-133 antiserum effectively bound to the protein and blocked collagenolytic activity, migration, and cytopathic effects (CPE) against corneal cells in vitro. Chinese hamsters orally immunized with MIP-133 displayed a >30% reduction in disease. Immunoglobulin A isolated from immunized animals bound MIP-133 and blocked CPE on corneal cells in vitro. Animals induced to generate severe chronic infections displayed significant reductions in disease symptoms upon oral immunization postinfection. These data suggest that MIP-133 production might be necessary to initiate corneal disease and that it may play an important role in the subsequent steps of the pathogenic cascade of Acanthamoeba keratitis. Furthermore, as antibodies produced both prior to and after infection reduced clinical symptoms of disease, the protein may represent an important immunotherapeutic target for Acanthamoeba keratitis.


Dissecting the expression landscape of RNA-binding proteins in human cancers.
RNA-binding proteins (RBPs) play important roles in cellular homeostasis by controlling gene expression at the post-transcriptional level. We explore the expression of more than 800 RBPs in sixteen healthy human tissues and their patterns of dysregulation in cancer genomes from The Cancer Genome Atlas project. We show that genes encoding RBPs are consistently and significantly highly expressed compared with other classes of genes, including those encoding regulatory components such as transcription factors, miRNAs and long non-coding RNAs. We also demonstrate that a set of RBPs, numbering approximately 30, are strongly upregulated (SUR) across at least two-thirds of the nine cancers profiled in this study. Analysis of the protein-protein interaction network properties for the SUR and non-SUR groups of RBPs suggests that path length distributions between SUR RBPs is significantly lower than those observed for non-SUR RBPs. We further find that the mean path lengths between SUR RBPs increases in proportion to their contribution to prognostic impact. We also note that RBPs exhibiting higher variability in the extent of dysregulation across breast cancer patients have a higher number of protein-protein interactions. We propose that fluctuating RBP levels might result in an increase in non-specific protein interactions, potentially leading to changes in the functional consequences of RBP binding. Finally, we show that the expression variation of a gene within a patient group is inversely correlated with prognostic impact. Overall, our results provide a roadmap for understanding the impact of RBPs on cancer pathogenesis.


Diagnostic and prognostic indicators of omasal impaction in buffaloes (Bubalus bubalis).
Twelve of 46 female buffaloes with abdominal disorders were diagnosed with omasal impaction. They had been fed finely chopped machine-prepared straw. They were characterised by anorexia, an absence of defecation, abdominal distension, ruminal hypomotility or atony and a suspension of rumination. Omasal impaction was confirmed upon left flank laparorumenotomy on the basis of the size of the omasum and the consistency of its contents. After ruminal evacuation, a long flexible pipe was introduced through the reticulo-omasal orifice and the omasal contents were flushed back into the rumen with water under moderate pressure. Hyponatraemia, hypochloraemia, hypokalaemia and hypophosphataemia were consistent features in most cases. However, two buffaloes that later died had lower levels of plasma chloride, no reticulo-omasal orifice tone and were in an advanced stage of pregnancy. The level of total protein in peritoneal fluid was higher than normal, but the total white cell count was within the normal range. All the animals started passing faeces 36 to 48 hours after surgery. The presence of reticulo-omasal orifice tone and a plasma chloride level above 75 mmol/l were indicators of a good prognosis.


Accuracy of averaged auditory brainstem response amplitude and latency estimates.
The aims were to 1) establish which of the four algorithms for estimating residual noise level and signal-to-noise ratio (SNR) in auditory brainstem responses (ABRs) perform better in terms of post-average wave-V peak latency and amplitude errors and 2) determine whether SNR or noise floor is a better stop criterion where the outcome measure is peak latency or amplitude. The performance of the algorithms was evaluated by numerical simulations using an ABR template combined with electroencephalographic (EEG) recordings obtained without sound stimulus. The suitability of a fixed SNR versus a fixed noise floor stop criterion was assessed when variations in the wave-V waveform shape reflecting inter-subject variation was introduced. Over 100 hours of raw EEG noise was recorded from 17 adult subjects, under different conditions (e.g. sleep or movement). ABR feature accuracy was similar for the four algorithms. However, it was shown that a fixed noise floor leads to higher ABR wave-V amplitude accuracy; conversely, a fixed SNR yields higher wave-V latency accuracy. Similar performance suggests the use of the less computationally complex algorithms. Different stop criteria are recommended if the ABR peak latency or the amplitude is the outcome measure of interest.


Studies on assessment of traffic noise level in Aurangabad city, India.
With the rapid rate of urbanization of Aurangabad city due to the expanding industrialization, the problem of noise pollution has become a concern for urban dwellers and government authority too. Noise pollution due to vehicular traffic is one of the growing environmental problems of urban centers. The study deals with the assessment of traffic noise levels in Aurangabad city. With respect to the total number of vehicles passing the road in unit time, which was surveyed by direct count method, six different sites from Aurangabad city, viz., Nagar Naka, Kranti Chowk, CIDCO bus stand, Railway station area, Dhoot Hospital and Baba petrol pump were selected to study the vehicular noise level. Noise measurements were carried out at these six locations on both working day and holiday during the peak traffic hours, i.e. 8:00 a.m. - 11:a.m., 1:00 p.m. - 4:00 p.m. and 5:00 p.m. - 8:00 p.m., in the morning, afternoon and evening sessions, respectively, after 5 minutes time interval. The noise level was monitored using noise level meter. The results obtained from this investigation showed that the Nagar Naka, Kranti chowk and CIDCO bus stand area have dense traffic zones when compared with the Railway station area, Dhoot Hospital and Baba petrol pump. The minimum and the maximum noise levels are 74 and 86 dB, respectively, on working day and 70 and 81 dB, respectively, on holiday. The measured noise level values exceed the prescribed noise level.


Haemophilia A in a patient with testicular feminization.
A case of typical haemophilia A in phenotypically "hairless" women aged 18 with complete testicular feminization (primary amenorrhea, absence of palpated gonads, negative sex chromatin, fluorescence of Y chromosome in interphase nuclei, caryotype 46, XY by common and fluorescent methods) is reported in this paper. Both diseases are of familial character with transmission through female line. The propositus' father did not suffer from haemophilia. Signs of Morris syndrome (delay of menses, absence of secondary hair) are present in the propositus' mother and sister. The propositus' niece, the daughter of her sister, also suffered from testicular feminization, but without any haemophilia, probably due to the crossing-over. The analysis of the pedigree gives no information in favour of sex-linked or autosome-dominant sex limited inheritance of testicular feminization. Haemophilia A in the propositus is characterized by the very low factor-VIII level-1.66%, and typical joints bleedings since 3 years. At the age of 18 the patient had major surgery for a haemophilic thigh pseudotumor. There was rapid consolidation of the fracture and contracture was erradicated. In spite of severe factor VIII deficiency the course of haemophilia in the propositus is clinically milder than in male haemophiliacs in her family and in the general population. The similar findings were reviewed in literature including the case of hemyzygous haemophilia with testicular feminization and described women-homozygotes. The suggestion is made that the course of haemophilia in the propositus is affected by the female phenotype. The psychologica status of the patient and the possibility of professional rehabilitation by surgical treatment is discussed. The need for detailed cytogenetical examination of the persons with "female" haemophilia or the other sex-linked diseases to establish the correct diagnosis and for exclusion of the possible mosaicism is discussed.


Deoxyribonucleic acid methylation profiling of single human blastocysts by methylated CpG-island amplification coupled with CpG-island microarray.
To study whether methylated CpG-island (CGI) amplification coupled with microarray (MCAM) can be used to generate DNA (deoxyribonucleic acid) methylation profiles from single human blastocysts. A pilot microarray study with methylated CpG-island amplification applied to human blastocyst genomic DNA and hybridized on CpG-island microarrays. University research laboratory. Five cryopreserved sibling 2-pronuclear zygotes that were surplus to requirements for clinical treatment by in vitro fertilization were donated with informed consent from a patient attending Bourn Hall Clinic, Cambridge, United Kingdom. None. Successful generation of genome-wide DNA methylation profiles at CpG islands from individual human blastocysts, with common genomic regions of DNA methylation identified between embryos. Between 472 and 734 CpG islands were methylated in each blastocyst, with 121 CpG islands being commonly methylated in all 5 blastocysts. A further 159 CGIs were commonly methylated in 4 of the 5 tested blastocysts. Methylation was observed at a number of CGIs within imprinted-gene, differentially methylated regions (DMRs), including placental and preimplantation-specific DMRs. The MCAM method is capable of providing comprehensive DNA methylation data in individual human blastocysts.


Equine catechol estrogen 4-hydroxyequilenin is a more potent inhibitor of the variant form of catechol-O-methyltransferase.
Catechol-O-methyltransferase (COMT) plays an important role in the inactivation of biologically active and toxic catechols. It has been shown that COMT is genetically polymorphic with a wild-type and variant form where a valine has been substituted with a methionine. Several, but not all, epidemiological studies have shown that women, homozygous with the variant form, have an increased risk of developing breast cancer. Previously, we showed that 4-hydroxyequilenin (4-OHEN), a cytotoxic/genotoxic equine catechol estrogen metabolite, is both a substrate of COMT and an irreversible inhibitor of the methylation activity of COMT in vitro. To further understand the mechanism(s) of the association between the breast cancer risk and the COMT polymorphism, it was of interest to study the effect of the Val/Met polymorphism on COMT-catalyzed catechol estrogen methylation and 4-OHEN-mediated inhibition. In the present study, Michaelis-Menten analysis showed no difference between the relative ability of each form to methylate 4-OHEN. However, we found that the COMT variant form was more susceptible to 4-OHEN-mediated irreversible inactivation. Electrospray ionization mass spectrometry and SDS-gel analysis of COMT modified by 4-OHEN revealed that inhibition mechanisms include alkylation and/or oxidation of certain amino acids. In addition, site-directed mutagenesis experiments showed that Cys33 played a more important role in the variant form of COMT demonstrated by the fact that the C33A mutant of the variant form of COMT decreased its catalytic capability more dramatically as compared with that of wild type. Furthermore, thermotropic studies indicated that the variant form was more thermolabile, which suggested that the valine to methionine substitution may have changed the secondary/tertiary structure of the variant form of COMT, making it more susceptible to 4-OHEN and heat inactivation. These data suggest that 4-OHEN-mediated inhibition of the variant form of COMT in vivo might affect the detoxification efficiency of endogenous and/or exogenous catechol estrogens and play a role in the association between breast cancer risk and COMT polymorphism.


High-performance affinity monolith chromatography: development and evaluation of human serum albumin columns.
Several immobilization methods were explored for the preparation of high-performance affinity monolithic columns containing human serum albumin (HSA). These monoliths were based on a copolymer of glycidyl methacrylate and ethylene dimethacrylate. In one method, the epoxy groups of this copolymer were used directly for the immobilization of HSA through its amine residues (i.e., the epoxy method); in other approaches, these epoxy groups were converted to diols for later use in the carbonyldiimidazole, disuccinimidyl carbonate, and Schiff base methods. Each HSA monolith was evaluated in terms of its total protein content and its retention of several model compounds, including (R/S)-warfarin and D/L-tryptophan. The greatest amount of immobilized HSA was obtained by the Schiff base method, whereas the epoxy method gave the lowest protein content. The Schiff base method also gave the best resolution in chiral separations of (R/S)-warfarin and D/L-tryptophan. All of the immobilization methods gave similar relative activities for HSA in its binding to (R)- and (S)-warfarin, but some differences were noted in the activity of the immobilized HSA for D- and L-tryptophan. The efficiency of these monoliths was found to be greater than that of silica-based HSA columns for (R/S)-warfarin (i.e., analytes with high retention), but little or no difference was seen for D- and L-tryptophan (analytes with weak retention).


Apoptosis-inducing, anti-angiogenic and anti-migratory effects of a dinuclear Pd(II) complex on breast cancer: A promising novel compound.
Because of the high mortality and morbidity rate of breast cancer, successful management of the disease requires synthesis of novel compounds. To this end, ongoing attempts to create new candidates include synthesis of multinuclear metal complexes. The high DNA binding affinity and cytotoxic activity of these complexes makes them promising as breast cancer treatments. This study investigated anti-growth/cytotoxic effect of the dinuclear Pd(II) complex on breast cancer cell lines (MCF-7, MDA-MB-231) using various methods of staining, flow cytometry, and immunoblotting. The study conducted colony formation, invasion, and migration assays were to assess the effect of the complex on metastasis. Increased caspase-3/7 levels and positive annexin V staining were observed in both cell lines, proving apoptosis. Altered TNFR1 and TRADD expression with caspase-8 cleavage followed by BCL-2 inactivation with loss of mitochondrial membrane potential confirmed the presence of apoptosis in MCF-7 and MDA-MB-231, regardless of p53 expression status. The results implied anti-migration properties. Finally, the study used the CAM assay to assess antiangiogenic properties and showed that the complex inhibited angiogenesis. The study concluded the dinuclear Pd(II) complex warrants further in vivo experiments to show its potential in the treatment of breast cancer.


[Primary hyperthyroidism. Our experience].
The present study was performed in ten cases of hyperparathyroidism with a history of recurrent renal colic with or without passing calculi. Most of these patients had undergone stone surgery. Diagnosis was based on patient history, and metabolic and radiologic work up, and confirmed histologically following surgical exploration of the neck and removal of the pathologic parathyroid gland.


Measuring the Efficiency of Automation-Aided Performance in a Simulated Baggage Screening Task.
The present study replicated and extended prior findings of suboptimal automation use in a signal detection task, benchmarking automation-aided performance to the predictions of several statistical models of collaborative decision making. Though automated decision aids can assist human operators to perform complex tasks, operators often use the aids suboptimally, achieving performance lower than statistically ideal. Participants performed a simulated security screening task requiring them to judge whether a target (a knife) was present or absent in a series of colored X-ray images of passenger baggage. They completed the task both with and without assistance from a 93%-reliable automated decision aid that provided a binary text diagnosis. A series of three experiments varied task characteristics including the timing of the aid's judgment relative to the raw stimuli, target certainty, and target prevalence. Automation-aided performance fell closest to the predictions of the most suboptimal model under consideration, one which assumes the participant defers to the aid's diagnosis with a probability of 50%. Performance was similar across experiments. Results suggest that human operators' performance when undertaking a naturalistic search task falls far short of optimal and far lower than prior findings using an abstract signal detection task.


European Union policy on smokeless tobacco: a statement in favour of evidence based regulation for public health.
This statement is an updated version of one released by the same authors in February 2003. The statement was produced to follow up the Royal College of Physicians (RCP) Tobacco Advisory Group report "Protecting smokers, saving lives: the case for a tobacco and nicotine regulatory authority", which argued for an evidence based regulatory approach to smokeless tobacco and harm reduction and posed a series of questions that regulators must address in relation to smokeless tobacco. The purpose of this statement is to provide arguments of fact and principle to follow the RCP's report and to outline the public health case for changing existing European Union (EU) regulation in this area. A review of regulation in relation to harm reduction and regulation of tobacco products other than cigarettes is required in Article 11 of EU directive 2001/37/EC, and this is a contribution towards forming a consensus in the European public health community about what policy the EU should adopt in the light of this review, or following ongoing legal action that may potentially strike out the existing regulation altogether. We believe that the partial ban applied to some forms of smokeless tobacco in the EU should be replaced by regulation of the toxicity of all smokeless tobacco. We hold this view for public health reasons: smokeless tobacco is substantially less harmful than smoking and evidence from Sweden suggests it is used as a substitute for smoking and for smoking cessation. To the extent there is a "gateway" it appears not to lead to smoking, but away from it and is an important reason why Sweden has the lowest rates of tobacco related disease in Europe. We think it is wrong to deny other Europeans this option for risk reduction and that the current ban violates rights of smokers to control their own risks. For smokers that are addicted to nicotine and cannot or will not stop, it is important that they can take advantage of much less hazardous forms of nicotine and tobacco-the alternative being to "quit or die". and many die. While nicotine replacement therapies (NRT) may have a role in harm reduction, tobacco based harm reduction options may reach more smokers and in a different, market based, way. Chewing tobacco is not banned or regulated in the EU but is often highly toxic, and our proposal could remove more products from the market than it permitted. We believe that the EU policy on smokeless tobacco should adapt to new scientific knowledge and that the European Commission should bring forward proposals to amend or replace Article 8 of directive 2001/37/EC with a new regulatory framework. Canada has developed testing regimens for tobacco constituents and these could be readily adapted to the European situation. A review of EU policy in this area is required no later than December 2004, and we believe the Commission should expedite the part of its review that deals with harm reduction and regulation of tobacco products other than cigarettes so as to reconsider its policy on smokeless tobacco. We held this view before Swedish Match brought its legal proceedings to challenge EU legislation and we will continue to hold these views if its action fails.


PREPL deficiency: delineation of the phenotype and development of a functional blood assay.
PurposePREPL deficiency causes neonatal hypotonia, ptosis, neonatal feeding difficulties, childhood obesity, xerostomia, and growth hormone deficiency. Different recessive contiguous gene deletion syndromes involving PREPL and a variable combination of SLC3A1 (hypotonia-cystinuria syndrome), CAMKMT (atypical hypotonia-cystinuria syndrome), and PPM1B (2p21 deletion syndrome) have been described. In isolated PREPL deficiency, previously described only once, the absence of cystinuria complicates the diagnosis. Therefore, we developed a PREPL blood assay and further delineated the phenotype.MethodsClinical features of new subjects with PREPL deficiency were recorded. The presence of PREPL in lymphocytes and its reactivity with an activity-based probe were evaluated by western blot.ResultsFive subjects with isolated PREPL deficiency, three with hypotonia-cystinuria syndrome, and two with atypical hypotonia-cystinuria syndrome had nine novel alleles. Their IQs ranged from 64 to 112. Adult neuromuscular signs included ptosis, nasal dysarthria, facial weakness, and variable proximal and neck flexor weakness. Autonomic features are prevalent. PREPL protein and reactivity were absent in lymphocytes from subjects with PREPL deficiency, but normal in the clinically similar Prader-Willi syndrome.ConclusionPREPL deficiency causes neuromuscular, autonomic, cognitive, endocrine, and dysmorphic clinical features. PREPL is not deficient in Prader-Willi syndrome. The novel blood test should facilitate the confirmation of PREPL deficiency.


Exploring the phylogeography and population dynamics of the giant deer (Megaloceros giganteus) using Late Quaternary mitogenomes.
Late Quaternary climatic fluctuations in the Northern Hemisphere had drastic effects on large mammal species, leading to the extinction of a substantial number of them. The giant deer (Megaloceros giganteus) was one of the species that became extinct in the Holocene, around 7660 calendar years before present. In the Late Pleistocene, the species ranged from western Europe to central Asia. However, during the Holocene, its range contracted to eastern Europe and western Siberia, where the last populations of the species occurred. Here, we generated 35 Late Pleistocene and Holocene giant deer mitogenomes to explore the genetics of the demise of this iconic species. Bayesian phylogenetic analyses of the mitogenomes suggested five main clades for the species: three pre-Last Glacial Maximum clades that did not appear in the post-Last Glacial Maximum genetic pool, and two clades that showed continuity into the Holocene. Our study also identified a decrease in genetic diversity starting in Marine Isotope Stage 3 and accelerating during the Last Glacial Maximum. This reduction in genetic diversity during the Last Glacial Maximum, coupled with a major contraction of fossil occurrences, suggests that climate was a major driver in the dynamics of the giant deer.


Comparative medicine.
Many scientists are conducting research on human diseases which cannot be transmitted readily to laboratory animals or duplicated in the laboratory. Information offered by animal disease models should be compiled and made available to these scientists through the publication of extensive lists of animal disease models and annotated bibliographies for specific conditions.


Utility of Ambulance Data for Real-Time Syndromic Surveillance: A Pilot in the West Midlands Region, United Kingdom.
Introduction The Public Health England (PHE; United Kingdom) Real-Time Syndromic Surveillance Team (ReSST) currently operates four national syndromic surveillance systems, including an emergency department system. A system based on ambulance data might provide an additional measure of the "severe" end of the clinical disease spectrum. This report describes the findings and lessons learned from the development and preliminary assessment of a pilot syndromic surveillance system using ambulance data from the West Midlands (WM) region in England. Hypothesis/Problem Is an Ambulance Data Syndromic Surveillance System (ADSSS) feasible and of utility in enhancing the existing suite of PHE syndromic surveillance systems? An ADSSS was designed, implemented, and a pilot conducted from September 1, 2015 through March 1, 2016. Surveillance cases were defined as calls to the West Midlands Ambulance Service (WMAS) regarding patients who were assigned any of 11 specified chief presenting complaints (CPCs) during the pilot period. The WMAS collected anonymized data on cases and transferred the dataset daily to ReSST, which contained anonymized information on patients' demographics, partial postcode of patients' location, and CPC. The 11 CPCs covered a broad range of syndromes. The dataset was analyzed descriptively each week to determine trends and key epidemiological characteristics of patients, and an automated statistical algorithm was employed daily to detect higher than expected number of calls. A preliminary assessment was undertaken to assess the feasibility, utility (including quality of key indicators), and timeliness of the system for syndromic surveillance purposes. Lessons learned and challenges were identified and recorded during the design and implementation of the system. The pilot ADSSS collected 207,331 records of individual ambulance calls (daily mean=1,133; range=923-1,350). The ADSSS was found to be timely in detecting seasonal changes in patterns of respiratory infections and increases in case numbers during seasonal events. Further validation is necessary; however, the findings from the assessment of the pilot ADSSS suggest that selected, but not all, ambulance indicators appear to have some utility for syndromic surveillance purposes in England. There are certain challenges that need to be addressed when designing and implementing similar systems. Todkill D , Loveridge P , Elliot AJ , Morbey RA , Edeghere O , Rayment-Bishop T , Rayment-Bishop C , Thornes JE , Smith G . Utility of ambulance data for real-time syndromic surveillance: a pilot in the West Midlands region, United Kingdom. Prehosp Disaster Med. 2017;32(6):667-672.


Mind-body practices, interoception and pain: a scoping review of behavioral and neural correlates.
Chronic pain is a significant source of suffering in the United States, and many individuals increasingly turn towards yoga for pain relief. However, little is known regarding how yoga improves pain. Herein we seek to examine the scope of the literature linking mind-body practices, pain and interoception; an emerging mechanism by which yoga may improve chronic pain. This scoping review followed the five-stage methodological framework proposed by Arksey and O'Malley to examine behavioral and neural correlates of interoception in mind-body practices and pain. A broad search of the Pubmed, CINAHL, SportDiscus, Scopus, PsychInfo, and SocIndex databases was conducted, utilizing three clusters of search terms: (1) interoceptive terms, (2) mind-body terms, and (3) pain terms. A combined total of 690 articles were screened, and 24 findings included for analysis. Sixteen studies examined interoceptive outcomes in response to mind-body practices for chronic pain, and 8 studies examined interoceptive outcomes in response to evoked-pain tasks in experienced mind-body practitioners. Only three studies linked yoga, interoception and pain. This review relied on the broader mind-body literature to inform our analyses as the literature examining yoga, pain and interoception remains limited. Interoceptive techniques including attending to and acceptance of bodily sensations, appear to be key therapeutic mechanisms in mind-body practices for chronic pain. Future yoga-based interventions would benefit examining interoceptive outcomes and integrating interoceptive strategies to facilitate the pain-modulating benefits of yoga.


Structure-function relationships of the intact aIF2alpha subunit from the archaeon Pyrococcus abyssi.
Eukaryotic and archaeal initiation factor 2 (e- and aIF2, respectively) are heterotrimeric proteins (alphabetagamma) supplying the small subunit of the ribosome with methionylated initiator tRNA. The gamma subunit forms the core of the heterotrimer. It resembles elongation factor EF1-A and ensures interaction with Met-tRNA(i)(Met). In the presence of the alpha subunit, which is composed of three domains, the gamma subunit expresses full tRNA binding capacity. This study reports the crystallographic structure of the intact aIF2alpha subunit from the archaeon Pyrococcus abyssi and that of a derived C-terminal fragment containing domains 2 and 3. The obtained structures are compared with those of N-terminal domains 1 and 2 of yeast and human eIF2alpha and with the recently determined NMR structure of human eIF2alpha. We show that the three-domain organization in the alpha subunit is conserved in archaea and eukarya. Domains 1 and 2 form a rigid body linked to a mobile third domain. Sequence comparisons establish that the most conserved regions in the aIF2alpha polypeptide lie at opposite sides of the protein, within domain 1 and domain 3, respectively. These two domains are known to exhibit RNA binding capacities. We propose that domain 3, which is known to glue the alpha subunit onto the gamma subunit, participates in Met-tRNA(i)(Met) binding while domain 1 recognizes either rRNA or mRNA on the ribosome. Thereby, the observed structural mobility within the e- and aIF2alpha molecules would be an integral part of the biological function of this subunit in the heterotrimeric e- and aIF2alphabetagamma factors.


[Giant uterine myoma].
Giant uterine tumors, defined as weighing 11.4 kg (25 lb) or more, are uncommon. The last cases reported were published on May, 2003 by Oelsner and collaborators. We report the case of a 45-year old woman with a large abdominal mass and three-day history of constipation and respiratory difficulty. Total abdominal hysterectomy and bilateral salpingo-oophorectomy was performed, and a giant uterine myoma, which weighted 12.4 kg (27.3 lb), was found. The patient's postoperative course was uneventful and she was discharged on the fourth postoperative day.


A computer data base for information on cancer treatment.
The Physician Data Query (PDQ) system is a clinically oriented computer data base developed to make recent information on cancer treatment widely available to the medical community. It represents an effort by the National Cancer Institute to promote diffusion of information about the treatment of cancer throughout the country, facilitate access to clinical trials, and accelerate the practical application of advances in research. The computer system provides information about state-of-the-art cancer treatment, which is updated monthly by an editorial board. It also includes a file of active cancer-research protocols and a directory of physicians and organizations providing cancer care to which physicians can gain access by geographic location as well as other features. PDQ was designed for physicians who may not be familiar with computers, to permit them to search for and display information without learning a specialized search language. PDQ uses a computer mainframe, which allows a large amount of data to be stored and made available to physicians rapidly and accurately. Transmission of information about cancer over commercial telecommunication networks gives health professionals access to PDQ by means of a computer terminal and local telephone lines.


Synovectomy of the hip in patients with juvenile rheumatoid arthritis.
There is a lack of data on the functional effect of open hip synovectomy in a large number of patients with juvenile rheumatoid arthritis evaluated with a validated assessment tool. Between 1985 and 1997, sixty-seven open hip-joint synovectomies were carried out in fifty-six patients with juvenile rheumatoid arthritis. Fifty-five hips (82%) had radiographic changes that were stage III or higher according to the system of Larsen et al. Hip function was evaluated preoperatively and after a mean of fifty months with the Merle d'Aubigné hip score. Sixty-five (97%) of the sixty-seven hips were available for follow-up. The mean total Merle d'Aubigné hip score (and standard error of the mean) was significantly improved from 9.5 +/- 2.5 points at baseline to 16.3 +/- 1.0 points at the time of follow-up (p < 0.001). The individual scores for pain, mobility, and walking ability were significantly increased as well (all p < 0.001). Eighty-five percent of the hips were observed to have a very great or great improvement in function. A concomitant soft-tissue release was performed in seven hips, and nine hips required surgical dislocation. Surgical complications included two superficial wound hematomas that did not require intervention; osteonecrosis of the femoral head was not observed. Five hips required total hip arthroplasty during the follow-up period. Thus, the survival rate for the hips was 94% at a mean of four years following the synovectomy. Open hip synovectomy in patients with juvenile rheumatoid arthritis is a safe procedure that can improve hip-joint function for up to five years.


A corona virus tracker for clinicians and students: Assessing education during an evolving phenomenon.
This article was migrated. The article was marked as recommended.


Overt hyperthyroidism and hypothyroidism during pregnancy.
The present manuscript provides a definition for, and evaluates the prevalence and maternal/fetal/child impact of, overt hyperthyroidism and overt hypothyroidism. The prevalence of overt hyperthyroidism is 0.5% and the prevalence of overt hyperthyroidism is 0.3%. Overt maternal hyperthyroidism is associated with heart failure, preeclampsia, preterm delivery, still birth, and neonatal mortality. Overt maternal hypothyroidism is associated with preeclampsia, gestational hypertension, cretinism, fetal deaths, and spontaneous abortion. A cost-effective analysis for screening and treating overt thyroid disease during pregnancy is warranted.


Novel tetracycline resistance determinant isolated from an environmental strain of Serratia marcescens.
Resistances to tetracycline and mercury were identified in an environmental strain of Serratia marcescens isolated from a stream highly contaminated with heavy metals. As a step toward addressing the mechanisms of coselection of heavy metal and antibiotic resistances, the tetracycline resistance determinant was cloned in Escherichia coli. Within the cloned 13-kb segment, the tetracycline resistance locus was localized by deletion analysis and transposon mutagenesis. DNA sequence analysis of an 8.0-kb region revealed a novel gene [tetA(41)] that was predicted to encode a tetracycline efflux pump. Phylogenetic analysis showed that the TetA(41) protein was most closely related to the Tet(39) efflux protein of Acinetobacter spp. yet had less than 80% amino acid identity with known tetracycline efflux pumps. Adjacent to the tetA(41) gene was a divergently transcribed gene [tetR(41)] predicted to encode a tetracycline-responsive repressor protein. The tetA(41)-tetR(41) intergenic region contained putative operators for TetR(41) binding. The tetA(41) and tetR(41) promoters were analyzed using lacZ fusions, which showed that the expression of both the tetA(41) and tetR(41) genes exhibited TetR(41)-dependent regulation by subinhibitory concentrations of tetracycline. The apparent lack of plasmids in this S. marcescens strain, as well as the presence of metabolic genes adjacent to the tetracycline resistance locus, suggested that the genes were located on the S. marcescens chromosome and may have been acquired by transduction. The cloned Tet 41 determinant did not confer mercury resistance to E. coli, confirming that Tet 41 is a tetracycline-specific efflux pump rather than a multidrug transporter.


Angiotensin I conversion by the microcirculation of the nonhuman primate.
Previous studies have shown that angiotensin I (AI) is converted to angiotensin II (AII) by converting enzyme (CE) or by tonin. Since all work on tonin has been done in the rodent, its relevance to the primate is yet to be shown. This study examines the conversion of AI to AII by the cheek pouch microcirculation of the monkey (macaca fascicularis). In 9 of the 11 monkeys studied, the conversion of AI to AII was blocked by converting enzyme inhibitor (CEI). However, in 2 older monkeys, AI conversion was not altered by CEI although the vascular response to AI was attenuated by both the AII antagonist (saralasin) and the antibody to AII (Ab-AII). In these 2 older animals, renin substrate caused vasoconstriction that was not altered by CEI, but was reduced by saralasin and Ab-AII. It is concluded that the tonin-angiotensin system is not active in the young macaque, but may be present in the older animals.


Enhanced rosmarinic acid biosynthesis in Solenostemon scutellarioides culture: a precursor-feeding strategy.
The aim of this study was to employ precursor-feeding strategy for the improved production of rosmarinic acid (RA) in Solenostemon scutellarioides in vitro. The cultures were fed with precursors, namely l-phenylalanine (Phe), l-tyrosine (Tyr) and cucumber juice (CJ), at different concentrations. Phe (100 mg L(-1)) and Tyr (400 mg L(-1)) caused ∼1.5- and 2.1-fold increase in RA accumulation within 48 h. CJ (50 mg L(-1)) feeding displayed highest RA content (∼1.6-fold) in 72 h. In this study, we focused on the function of individual precursor on key enzymes involved in RA biosynthesis. The phenylalanine ammonia lyase activity was significantly upregulated after Phe (100 mg L(-1)) feeding, while tyrosine aminotransferase and hydroxyphenylpyruvate reductase activities were improved with Tyr (400 mg L(-1)) treatment. However, rosmarinic acid synthase activity was significantly enhanced by all three precursors. In synergy study, Phe (100 mg L(-1)) + Tyr (400 mg L(-1)) could enhance (∼3.1-fold) RA biosynthesis within 48 h.


Gait analysis of pregnant patients with lumbopelvic pain using inertial sensor.
Lumbopelvic pain (LPP) is one of the most common discomforts during pregnancy. However, few studies have evaluated relation between LPP and gait in pregnancy quantitatively. This study aimed to investigate the relation between the LPP and gait characteristics such as symmetry, stability, and the degree of motion during pregnancy. Gait data were collected for fifty-two pregnant women between the third and tenth month of pregnancy on smooth, horizontal walkway by using inertial measurement sensor units attached to the participants' lumbar. The degrees of trunk movement, movement symmetry, gait variability, and symmetry of rotation were expressed as the root mean square (RMS), autocorrelation peak (AC), coefficient of variance (CV), and the degree of asymmetry at the approximate amount of angular variation (DA) respectively, which were calculated from measured acceleration data and angular velocity data. An independent t-test was performed to investigate differences in these gait parameters between LPP group and pain free group classified according to the presence or absence of the pain, which is evaluated by using a questionnaire. In addition, LPP group was divided into 5 subgroups based on the types of pain, and the differences between the groups were also investigated by using a one way ANOVA. Rotational asymmetry was observed in movement of the roll direction of the LPP patients. The DA of the roll angle of the LPP group was significantly greater than that in the pain free group (0.140 ± 0.093 vs. 0.077 ± 0.053, respectively; p = 0.004). In the analysis of pain complications, the significant difference in DA of roll angle, and CV of yaw angle were observed. The results indicated that motion asymmetry of both rotation and translation increased significantly in LPP patients' gait.


Degradation of peptide drugs by immobilized digestive proteases.
An in vitro assay using immobilized digestive enzymes and LC/MS has been developed to measure the susceptibility of orally administered peptide drugs to hydrolysis by the digestive system. Six different bioactive peptides and peptide drugs were digested using an established in vitro system incorporating four sets of immobilized digestive enzymes, which simulated gastric digestion in the stomach, digestion by pancreatic enzymes in the intestinal lumen, and digestion by mucosal peptidases at the intestinal brush border. Hydrolysis products were rapidly identified using LC/MS and coincided with those expected based on the substrate specificities of the immobilized enzymes. The LC/MS system consisted of a reversed phase HPLC connected to a mass spectrometer through a continuous-flow fast atom bombardment ionization system. Data acquired on the susceptibility of peptide drugs to hydrolysis by digestive enzymes could be used during the formulation of orally administered drugs to protect them from degradation prior to absorption in the gut. Also, this assay could be used to quickly identify those compounds in a structurally related series of new drugs that are most resistant to digestive proteases.