The Burden of Cancer in Asian Americans: A Report of National Mortality Trends by Asian Ethnicity.
Asian Americans (AA) are the fastest growing U.S. population, and when properly distinguished by their ethnic origins, exhibit substantial heterogeneity in socioeconomic status, health behaviors, and health outcomes. Cancer is the second leading cause of death in the United States, yet trends and current patterns in the mortality burden of cancer among AA ethnic groups have not been documented. We report age-adjusted rates, standardized mortality ratios, and modeled trends in cancer-related mortality in the following AA ethnicities: Asian Indians, Chinese, Filipinos, Japanese, Koreans, and Vietnamese, from 2003 to 2011, with non-Hispanic whites (NHW) as the reference population. For most cancer sites, AAs had lower cancer mortality than NHWs; however, mortality patterns were heterogeneous across AA ethnicities. Stomach and liver cancer mortality was very high, particularly among Chinese, Koreans, and Vietnamese, for whom these two cancer types combined accounted for 15% to 25% of cancer deaths, but less than 5% of cancer deaths in NHWs. In AA women, lung cancer was a leading cause of death, but (unlike males and NHW females) rates did not decline over the study period. Ethnicity-specific analyses are critical to understanding the national burden of cancer among the heterogeneous AA population. Our findings highlight the need for disaggregated reporting of cancer statistics in AAs and warrant consideration of tailored screening programs for liver and gastric cancers. Cancer Epidemiol Biomarkers Prev; 25(10); 1371-82. ©2016 AACR.


'This year I will not put her to work': the production/reproduction nexus in Burkina Faso.
Global advocacy campaigns increasingly highlight the negative impact of reproductive morbidity on economic productivity and development in order to justify donor investment in maternal health. Anthropological approaches nuance such narrow economic estimations of reproductive health. Drawing on ethnographic fieldwork from Burkina Faso in West Africa, this paper analyses the dynamic, and sometimes contradictory, relationship between women's work and reproductive health in impoverished communities. Specifically, it examines the consequences of life-threatening 'near-miss' obstetric complications for women's work across domestic, agricultural and economic spheres over a four-year period. Such events provide a window onto the diverse ways in which production and reproduction are intimately linked within women's everyday lives. Reproduction and production entail sources of potential empowerment and enhancement, as well as potential threats, to health and well-being. In the aftermath of 'near-miss' events, the realms of reproduction and production sometimes jeopardise each other and at other times reinforce each other, while strength in one domain can compensate for weakness in the other. Women's experiences thus reveal how 'production' and 'reproduction' are mutually constituted, challenging the purely instrumental accounts of pregnancy-related 'productivity loss' that dominate current global health discourse.


Detecting ATM-dependent chromatin modification in DNA damage response.
Loss of function or mutation of the ataxia-telangiectasia mutated gene product (ATM) results in inherited genetic disorders characterized by neurodegeneration, immunodeficiency, and cancer. Ataxia-telangiectasia mutated (ATM) gene product belongs to the PI3K-like protein kinase (PIKKs) family and is functionally implicated in mitogenic signal transduction, chromosome condensation, meiotic recombination, cell-cycle control, and telomere maintenance. The ATM protein kinase is primarily activated in response to DNA double strand breaks (DSBs), the most deleterious form of DNA damage produced by ionizing radiation (IR) or radiomimetic drugs. It is detected at DNA damage sites, where ATM autophosphorylation causes dissociation of the inactive homodimeric form to the activated monomeric form. Interestingly, heat shock can activate ATM independent of the presence of DNA strand breaks. ATM is an integral part of the sensory machinery that detects DSBs during meiosis, mitosis, or DNA breaks mediated by free radicals. These DNA lesions can trigger higher order chromatin reorganization fuelled by posttranslational modifications of histones and histone binding proteins. Our group, and others, have shown that ATM activation is tightly regulated by chromatin modifications. This review summarizes the multiple approaches used to discern the role of ATM and other associated proteins in chromatin modification in response to DNA damage.


Nucleotide Substitution Patterning within the Meloidogyne rDNA D3 Region and Its Evolutionary Implications.
Evolutionary relationships based on nucleotide variation within the D3 26S rDNA region were examined among acollection of seven Meloidogyne hapla isolates and seven isolates of M. arenaria, M. incognita, and M. javanica. Using D3A and D3B primers, a 350-bp region was PCR amplified from genomic DNA and double-stranded nucleotide sequence obtained. Phylogenetic analyses using three independent clustering methods all provided support for a division between the automictic M. hapla and the apomictic M. arenaria, M. incognita, and M. javanica. A nucleotide sequence character distinguishing M. hapla from the three apomictic species was a 3-bp insertion within the interior of the D3 region. The three apomictic species shared a common D3 haplotype, suggesting a recent branching. Single M. hapla individuals contained two different haplotypes, differentiated by a Sau3AI restriction site polymorphism. Isolates of M. javanica appeared to have only one haplotype, while M. incognita and M. arenaria maintained more than one haplotype in an isolate.


Childhood and adolescent psychotic experiences and risk of mental disorder: a systematic review and meta-analysis.
Psychotic experiences (PEs) are common in childhood and adolescence and their association with mental disorders is well-established. We aim to conduct a quantitative synthesis the literature on the relationship between childhood and adolescent PEs and (i) any mental disorder; and (ii) specific categories of mental disorder, while stratifying by study design. Three electronic databases (PUBMED, PsycINFO and EMBASE) were searched from inception to August 2017 for all the published literature on childhood and adolescent PEs and mental disorder (outcome) in non-help-seeking community samples. Study quality was assessed using a recognised quality assessment tool for observational studies. Two authors conducted independent data extraction. Pooled odds ratios were calculated for mental disorders using random-effects models. Additional analyses were conducted investigating different categories of mental disorder while stratifying by study design. Fourteen studies from 13 community samples (n = 29 517) were identified with 9.8% of participants reporting PEs. PEs were associated with a three-fold increased risk of any mental disorder [odds ratio (OR) 3.08, confidence interval (CI) 2.26-4.21, k = 12]. PEs were associated with four-fold increase risk of psychotic disorder (OR 3.96, CI 2.03-7.73, population-attributable-fraction: 23.2%, k = 5). In addition, PEs were associated with an increased risk of affective disorders, anxiety disorders, behavioural disorders and substance-use disorders. Few longitudinal studies have investigated childhood and adolescent PEs and subsequent non-psychotic disorders which limited a meaningful synthesis and interpretation of these results. This meta-analysis confirms that PEs are prevalent in childhood and adolescent community samples and are associated with a variety of mental disorders beyond psychotic disorders. Further longitudinal research is necessary to fully determine the longitudinal relationship between PEs and non-psychotic disorders.


KAP1 controls endogenous retroviruses in embryonic stem cells.
More than forty per cent of the mammalian genome is derived from retroelements, of which about one-quarter are endogenous retroviruses (ERVs). Some are still active, notably in mice the highly polymorphic early transposon (ETn)/MusD and intracisternal A-type particles (IAP). ERVs are transcriptionally silenced during early embryogenesis by histone and DNA methylation (and reviewed in ref. 7), although the initiators of this process, which is essential to protect genome integrity, remain largely unknown. KAP1 (KRAB-associated protein 1, also known as tripartite motif-containing protein 28, TRIM28) represses genes by recruiting the histone methyltransferase SETDB1, heterochromatin protein 1 (HP1) and the NuRD histone deacetylase complex, but few of its physiological targets are known. Two lines of evidence suggest that KAP1-mediated repression could contribute to the control of ERVs: first, KAP1 can trigger permanent gene silencing during early embryogenesis, and second, a KAP1 complex silences the retrovirus murine leukaemia virus in embryonic cells. Consistent with this hypothesis, here we show that KAP1 deletion leads to a marked upregulation of a range of ERVs, in particular IAP elements, in mouse embryonic stem (ES) cells and in early embryos. We further demonstrate that KAP1 acts synergistically with DNA methylation to silence IAP elements, and that it is enriched at the 5' untranslated region (5'UTR) of IAP genomes, where KAP1 deletion leads to the loss of histone 3 lysine 9 trimethylation (H3K9me3), a hallmark of KAP1-mediated repression. Correspondingly, IAP 5'UTR sequences can impose in cis KAP1-dependent repression on a heterologous promoter in ES cells. Our results establish that KAP1 controls endogenous retroelements during early embryonic development.


Columnar distribution of catecholaminergic neurons in the ventrolateral periaqueductal gray and their relationship to efferent pathways.
The periaqueductal gray (PAG) is a critical brain region involved in opioid analgesia and provides efferents to descending pathways that modulate nociception. In addition, the PAG contains ascending pathways to regions involved in the regulation of reward, including the substantia nigra (SN) and the ventral tegmental area (VTA). SN and VTA contain dopaminergic neurons that are critical for the maintenance of positive reinforcement. Interestingly, the PAG is also reported to contain a population of dopaminergic neurons. In this study, the distribution of catecholaminergic neurons within the ventrolateral (vl) PAG was examined using immunocytochemical methods. In addition, the catecholaminergic PAG neurons were examined to determine whether these neurons are integrated into ascending (VTA, SN) and descending rostral ventral medulla (RVM) efferent pathways from this region. The immunocytochemical analysis determined that catecholaminergic neurons in the PAG are both dopaminergic and noradrenergic and these neurons have a distinct rostrocaudal distribution within the ventrolateral column of PAG. Dopaminergic neurons were concentrated rostrally and were significantly smaller than noradrenergic neurons. Combined immunocytochemistry and tract tracing methods revealed that catecholaminergic neurons are distinct from, but closely associated with, both ascending and descending efferent projection neurons. Finally, by electron microscopy, catecholaminergic neurons showed close dendritic appositions with other neurons in PAG, suggesting a possible nonsynaptic mechanism for regulation of PAG output by these neurons. In conclusion, our data indicate that there are two populations of catecholaminergic neurons in the vlPAG that form dendritic associations with both ascending and descending efferents suggesting a possible nonsynaptic modulation of vlPAG neurons.


Assessment of myocardial perfusion with contrast two-dimensional echocardiography.
Myocardial contrast echocardiography (MCE) is a new technique capable of assessing regional myocardial perfusion in vivo in real time. At present, this technique involves the intraaortic or intracoronary injection of microbubbles of air. As these microbubbles traverse the myocardium, they produce opacification of the myocardium in concomitantly performed echocardiographic images. In animal models, MCE has been demonstrated to assess accurately the in vivo risk area (region of the myocardium at risk for necrosis after acute coronary occlusion). It has also been shown to provide quantitative information on regional myocardial blood flow (both antegrade and collateral). This technique has been demonstrated to be safe in humans. In clinical studies it has been shown to be a useful adjunct to cardiac catheterization, particularly in the assessment of coronary blood flow reserve and collateral blood flow. MCE is also used in the operating room to assess regional myocardial perfusion before and after bypass graft operations. The microbubbles used for MCE were shown to opacify the left ventricular cavity after their injection into a peripheral vein. If myocardial opacification after venous injection can be achieved, MCE will have the potential for the simultaneous noninvasive in vivo assessment of regional myocardial perfusion and function in humans.


Using Tri-Axial Accelerometry in Daily Elite Swim Training Practice.
Background: Coaches in elite swimming carefully design the training programs of their swimmers and are keen on achieving strict adherence to those programs by their athletes. At present, coaches usually monitor the compliance of their swimmers to the training program with a stopwatch. However, this measurement clearly limits the monitoring possibilities and is subject to human error. Therefore, the present study was designed to examine the reliability and practical usefulness of tri-axial accelerometers for monitoring lap time, stroke count and stroke rate in swimming. Methods: In the first part of the study, a 1200 m warm-up swimming routine was measured in 13 elite swimmers using tri-axial accelerometers and synchronized video recordings. Reliability was determined using the typical error of measurement (TEM) as well as a Bland-Altman analysis. In the second part, training compliance both within and between carefully prescribed training sessions was assessed in four swimmers in order to determine the practical usefulness of the adopted accelerometric approach. In these sessions, targets were set for lap time and stroke count by the coach. Results: The results indicated high reliability for lap time (TEM = 0.26 s, bias = 0.74 [0.56 0.91] with limits of agreement (LoA) from -1.20 [-1.50 -0.90] to 2.70 [2.40 3.00]), stroke count (TEM 0.73 strokes, bias = 0.46 [0.32 0.60] with LoA from -1.70 [-1.94 -1.46] to 2.60 [2.36 2.84]) and stroke rate (TEM 0.72 str∙min-1, bias = -0.13 [-0.20 -0.06] with LoA from -2.20 [-2.32 -2.08] to 1.90 [1.78 2.02]), while the results for the monitoring of training compliance demonstrated the practical usefulness of our approach in daily swimming training. Conclusions: The daily training of elite swimmers can be accurately and reliably monitored using tri-axial accelerometers. They provide the coach with more useful information to guide and control the training process than hand-clocked times.


Vigor among health-care professionals at the workplace: the role of intra- and inter-personal resources.
Feeling vigorous throughout the workday in a medical facility despite exposure to daily job-related stress is essential for productive work-related behavior and for the subjective well-being of health-care professionals. The current study explored the contribution of an intra-personal resource (i.e. coping flexibility) and an inter-personal resource (i.e. social support) to the explained variance of vigor among nurses and physicians. Two hundred two hospital personnel completed self-report questionnaires regarding personal and professional data, vigor, coping flexibility and social support. The results revealed that the intra-personal resource coping flexibility, was positively associated with vigor while the inter-personal resource social support was not found to be associated with vigor. In addition, older age and higher self-rated health positively associated with feeling vigor. The current study shed light on the role of intra-personal resources in feeling vigorous throughout stressful workdays that characterize the workplace of hospital personnel. Tailoring interventions that may enhance coping flexibility among hospital personnel can increase their vigor which in turn may beneficially contribute to their job performance.


Long-term effects of a somatostatin analogue on renal haemodynamics and hypertrophy in diabetic rats.
1. To determine whether treatment with octreotide, a somatostatin analogue, may diminish or prevent long-term diabetic renal hypertrophy and nephropathy, uninephrectomized streptozotocin-diabetic rats maintained under moderate glycaemic control (approximately 300 mg/dl) were treated with either placebo (n = 10 rat/group) or octreotide for 14 weeks. Uninephrectomized non-diabetic rats given either placebo or octreotide served as controls. 2. Average body weight was diminished and kidney weight, daily urinary protein excretion, glomerular filtration rate and renal plasma flow were elevated in both diabetic groups relative to controls. 3. Administration of octreotide reduced average body weight and packed cell volume in non-diabetic and diabetic rats compared with their respective controls, but did not affect glomerular hyperfiltration or the increase in urinary protein excretion. 4. Histological examination at 14 weeks disclosed unequivocal glomerular hypertrophy and mild glomerular and tubulointerstitial lesions consistent with early diabetic renal alterations in all diabetic rats, but there was no independent effect of octreotide treatment. 5. Thus, long-term treatment with octreotide did not afford protection against the development of renal hypertrophy-hyperfiltration and the evolution of early diabetic nephropathy in rats.


A systematic literature review of the disease burden in patients with recessive dystrophic epidermolysis bullosa.
Recessive dystrophic epidermolysis bullosa (RDEB) is a genetic collagen disorder characterized by skin fragility leading to blistering, wounds, and scarring. There are currently no approved curative therapies. The objective of this manuscript is to provide a comprehensive literature review of the disease burden caused by RDEB. A systematic literature review was conducted in MEDLINE and Embase in accordance with PRISMA guidelines. Observational and interventional studies on the economic, clinical, or humanistic burden of RDEB were included. Sixty-five studies were included in the review. Patients had considerable wound burden, with 60% reporting wounds covering more than 30% of their body. Increases in pain and itch were seen with larger wound size. Chronic wounds were larger and more painful than recurrent wounds. Commonly reported symptoms and complications included lesions and blistering, anemia, nail dystrophy and loss, milia, infections, musculoskeletal contractures, strictures or stenoses, constipation, malnutrition/nutritional problems, pseudosyndactyly, ocular manifestations, and dental caries. Many patients underwent esophageal dilation (29-74%; median dilations, 2-6) and gastrostomy tube placement (8-58%). In the severely affected population, risk of squamous cell carcinoma (SCC) was 76% and mortality from SCC reached 84% by age 40. Patients with RDEB experienced worsened quality of life (QOL), decreased functioning and social activities, and increased pain and itch when compared to other EB subtypes, other skin diseases, and the general population. Families of patients reported experiencing high rates of burden including financial burden (50-54%) and negative impact on private life (79%). Direct medical costs were high, though reported in few studies; annual payer-borne total medical costs in Ireland were $84,534 and annual patient-borne medical costs in Korea were $7392. Estimated annual US costs for wound dressings ranged from $4000 to $245,000. Patients spent considerable time changing dressings: often daily (13-54% of patients) with up to three hours per change (15-40%). Patients with RDEB and their families/caregivers experience significant economic, humanistic, and clinical burden. Further research is needed to better understand the costs of disease, how the burden of disease changes over the patient lifetime and to better characterize QOL impact, and how RDEB compares with other chronic, debilitating disorders.


NMDA/AMPA ratio impacts state transitions and entrainment to oscillations in a computational model of the nucleus accumbens medium spiny projection neuron.
We describe a computational model of the principal cell in the nucleus accumbens (NAcb), the medium spiny projection (MSP) neuron. The model neuron, constructed in NEURON, includes all of the known ionic currents in these cells and receives synaptic input from simulated spike trains via NMDA, AMPA, and GABAA receptors. After tuning the model by adjusting maximal current conductances in each compartment, the model cell closely matched whole-cell recordings from an adult rat NAcb slice preparation. Synaptic inputs in the range of 1000-1300 Hz are required to maintain an "up" state in the model. Cell firing in the model required concurrent depolarization of several dendritic branches, which responded independently to afferent input. Depolarization from action potentials traveled to the tips of the dendritic branches and increased Ca2+ influx through voltage-gated Ca2+ channels. As NMDA/AMPA current ratios were increased, the membrane showed an increase in hysteresis of "up" and "down" state dwell times, but intrinsic bistability was not observed. The number of oscillatory inputs required to entrain the model cell was determined to be approximately 20% of the "up" state inputs. Altering the NMDA/AMPA ratio had a profound effect on processing of afferent input, including the ability to entrain to oscillations in afferent input in the theta range (4-12 Hz). These results suggest that afferent information integration by the NAcb MSP cell may be compromised by pathology in which the NMDA current is altered or modulated, as has been proposed in both schizophrenia and addiction.


Synthesis and preferred all-syn conformation of C3-symmetrical N-(hetero)arylmethyl triindoles.
A new series of C(3)-symmetrical N-(hetero)arylmethyl triindoles has been synthesized in a straightforward procedure. The structure and conformation in the solid state have been determined for three derivatives (3, 4, and 6) by X-ray crystallographic analysis. In all three cases, the molecules adopt a tripodal conformation with all of the flexible arms directed towards the same side, thereby delimiting an inner cavity. Compound 6 crystallizes and forms C(3)-symmetric dimeric cagelike complexes. Guest molecules of chloroform and water are confined within the resulting cavities with stabilization by different intermolecular interactions; this highlights the potential of these compounds in the construction of supramolecular systems. A computational analysis has been performed to predict the most stable conformers. As a general trend, a preference for a conformation with all branches directed to the same side has been predicted. Comparison between theoretical and experimental results indicates that the computational level selected for the present study, B3LYP/6-31G*, is able to reproduce both the minimum energy conformations and the rotation barriers about the N--CH(2) bond.


Pars plana vitrectomy with juxtapapillary laser photocoagulation versus vitrectomy without juxtapapillary laser photocoagulation for the treatment of optic disc pit maculopathy: the results of the KKESH International Collaborative Retina Study Group.
To compare the functional and anatomic outcomes of pars plana vitrectomy (PPV) with juxtapapillary laser photocoagulation (JLP) versus vitrectomy without JLP in optic disc pit maculopathy. This was a multicentre, retrospective study of 46 consecutive patients with optic disc pit maculopathy presenting at tertiary eye centres between 1992 and 2012. Indications for surgery included distorted or decreased vision. Surgical intervention included PPV, posterior vitreous detachment, with or without gas tamponade. Twenty-four patients received laser photocoagulation at the temporal edge of the optic disc pit (group A) and 22 patients had no laser (group B). Postoperative best-corrected visual acuity (BCVA) and optical coherence tomography findings were the main outcome measures. Mean follow-up was 44 months (range 12-98 months). BCVA in group A improved significantly from 0.7 logMAR (20/100) preoperatively to 0.5 logMAR (20/60) postoperatively (p=0.017). In group B, BCVA improved from 0.7 logMAR (20/100) preoperatively to 0.4 logMAR (20/40) postoperatively (p=0.014). The difference in final BCVA between groups was not statistically significant (p=0.693). The mean central macular thickness (CMT) in group A improved significantly from 750 μm preoperatively to 309 μm at last follow-up (p<0.0001). The mean CMT in group B improved from 616 μm preoperatively to 291 μm at last follow-up (p=0.028). The difference in final CMT between groups was not statistically significant (p=0.747). PPV with JLP for optic disc pit maculopathy had similar functional and anatomic outcomes compared with vitrectomy without JLP.


Protein kinase C epsilon and genetic networks in osteosarcoma metastasis.
Osteosarcoma (OS) is the most common primary malignant tumor of the bone, and pulmonary metastasis is the most frequent cause of OS mortality. The aim of this study was to discover and characterize genetic networks differentially expressed in metastatic OS. Expression profiling of OS tumors, and subsequent supervised network analysis, was performed to discover genetic networks differentially activated or organized in metastatic OS compared to localized OS. Broad trends among the profiles of metastatic tumors include aberrant activity of intracellular organization and translation networks, as well as disorganization of metabolic networks. The differentially activated PRKCε-RASGRP3-GNB2 network, which interacts with the disorganized DLG2 hub, was also found to be differentially expressed among OS cell lines with differing metastatic capacity in xenograft models. PRKCε transcript was more abundant in some metastatic OS tumors; however the difference was not significant overall. In functional studies, PRKCε was not found to be involved in migration of M132 OS cells, but its protein expression was induced in M112 OS cells following IGF-1 stimulation.


Complex antibody profile changes in an experimental autoimmune glaucoma animal model.
Increased serum antibodies against heat shock protein 27 (HSP27) have been identified in patients with glaucoma. Immunization with HSP27 caused retinal ganglion cell (RGC) loss in animals. The authors analyzed whether HSP27 immunization not only causes RGC loss but also affects systemic antibody patterns. Rats were immunized with HSP27 and were surveyed for 4, 5, and 6 weeks (groups 1-3). Control animals were humanely killed after 6 weeks (group 4). Intraocular pressure was measured before and 2 and 4 weeks after immunization. Fundus images were taken at the same time. Retinal flatmounts were prepared, and Brn-3a labeled RGCs were counted. Serum was collected during the study to detect antibody patterns against retinal antigens through Western blot analysis and mass spectrometry techniques. Patterns were analyzed by multivariate statistical techniques, and biomarkers were identified with the use of mass spectrometry. No significant changes in intraocular pressure were observed, and no fundus abnormalities were noted. The animals immunized with HSP27 showed lower RGC density than controls (P < 0.05). Two and 4 weeks after immunization, we detected a significant difference in antibody profiles between groups 1 and 4 (P < 0.05) and groups 3 and 4 (P < 0.05). Proteins with different antibody level expression after immunization included heat shock protein 90, alpha-enolase, and glyceraldehyde-3-phosphate dehydrogenase. After immunization with HSP27, animals showed IOP-independent RGC loss and changes in serum antibody patterns. Thus, this model might be a beneficial approach to study the development and effects of anti-retinal antibodies and their involvement in RGC loss.


Balancing measurement uncertainty against financial benefits: comparison of in situ and ex situ analysis of contaminated land.
The uncertainty of measurements taken for the purpose of characterizing contaminated land can subsequently cause decision errors, which can produce significant, financial consequences. Given the site-specific costs, such as those associated with the measurements or with site misclassification, the important question addressed is "Are the measurements of acceptable quality for that given objective or fit-for-purpose"? It is often considered by investigators that using a standard operating procedure (SOP) with an approved analytical method will give an acceptable level of uncertainty. This is despite evidence that sampling is usually the predominant source of uncertainty, not the chemical analyses, mainly as a result of the contaminant heterogeneity within sampling locations at a site. One in situ and one ex situ measurement technique were used to represent these two contrasting approaches to characterizing a site contaminated with lead in topsoil. The measurement uncertainty, from both sampling and analyses, was estimated for the two techniques, and its fitness-for-purpose was assessed using the innovative optimized contaminated land investigation (OCLI) method. It is objectively demonstrated by the OCLI method that the in situ method (portable X-ray fluorescence) was three times more cost-effective than the ex situ (AAS) method at characterizing a contaminated site, despite generating higher uncertainty on individual measurements.


The influence of deer browsing on the reproductive biology of Canada yew (Taxus canadensis marsh.) : III. Sex expression.
Browsed Canada yew (Taxus canadensis) populations have a higher proportion of males and a lower proportion of monoecious plants than unbrowsed yew populations. The proportion of monoecious plants increases with time following protection from browsing suggesting that deer browsing causes male-biased sex expression in Canada yew. In contrast, results from comparing browsed and unbrowsed populations, exclosure studies, and browse simulation experiments indicate that strobilus ratios and phenotypic gender of browsed yews may be female-biased. In part, these results correspond to the influence of size on sex expression in Canada yew; small yews tend to be male, but if monoecious, have female-biased strobilus ratios. Large yews are monoecious, but have male-biased strobilus ratios. There is, however, no consistent relationship between size and gender in Canada yew, suggesting that in some circumstances, yews shift allocation to female function in response to browsing.


Multi-Scale Continuum Modeling of Biological Processes: From Molecular Electro-Diffusion to Sub-Cellular Signaling Transduction.
This article provides a brief review of multi-scale modeling at the molecular to cellular scale, with new results for heart muscle cells. A finite element-based simulation package (SMOL) was used to investigate the signaling transduction at molecular and sub-cellular scales (http://mccammon.ucsd.edu/smol/, http://FETK.org) by numerical solution of time-dependent Smoluchowski equations and a reaction-diffusion system. At the molecular scale, SMOL has yielded experimentally-validated estimates of the diffusion-limited association rates for the binding of acetylcholine to mouse acetylcholinesterase using crystallographic structural data. The predicted rate constants exhibit increasingly delayed steady-state times with increasing ionic strength and demonstrate the role of an enzyme's electrostatic potential in influencing ligand binding. At the sub-cellular scale, an extension of SMOL solves a non-linear, reaction-diffusion system describing Ca2+ ligand buffering and diffusion in experimentally-derived rodent ventricular myocyte geometries. Results reveal the important role for mobile and stationary Ca2+ buffers, including Ca2+ indicator dye. We found that the alterations in Ca2+-binding and dissociation rates of troponin C (TnC) and total TnC concentration modulate subcellular Ca2+ signals. Model predicts that reduced off-rate in whole troponin complex (TnC, TnI, TnT) versus reconstructed thin filaments (Tn, Tm, actin) alters cytosolic Ca2+ dynamics under control conditions or in disease-linked TnC mutations. The ultimate goal of these studies is to develop scalable methods and theories for integration of molecular-scale information into simulations of cellular-scale systems.


Characterization of cytoplasmic and nuclear genomes in the colorless alga Polytoma. I. Ultrastructural analysis of organelles.
Electron microscope studies have been made on the fine structure of the colorless biflagellate, Polytoma obtusum, with main emphasis on the structural organization of the mitochondria and the leucoplast. Both organelles have been demonstrated to contain DNA aggregates as well as ribosomal particles within their matrix material. Reconstructions from serial showed that (a) the mitochondria were highly convoluted and irregular in shape and size, and (b) the leucoplast was a single cup-shaped entity, with large starch grains, localized at the posterior end, and multiple sites of DNA aggregates. The starch-containing compartments appeared to be interconnected by narrow tubular or sheetlike bridges. Cytoplasmic invaginations into the plastid, often containing mitochondria, were of frequent occurrence, and membranes of mitochondria and the leucoplast appeared to be closely apposed. Membranes elements, both sheetlike and vesicular, were also present in the matrix. The Polytoma leucoplast was, in certain respects, morphologically similar to the plastids of various photosynthetic mutants of Chlamydomonas, most of which show Menedelian segregation. It is suggested that Polytoma arose from a Chlamydomonas-like ancestor, possibly through combined mutational processess of both chloroplast and nuclear genomes. Since Polytoma leucoplasts contain both DNA and ribosomal particles, it is probable that these organelles still possess semiautonomy and limited ability for protein synthesis.


A plaque assay for feline panleukopenia virus.
Plaque formation with representative strains of feline panleukopenia virus (FPV) has been obtained using a permanent line of feline kidney cells under agarose overlay. FPV-infected cells appear as white plaques after neutral red staining. Plaque size is determined by the extent of cell division in the infected monolayer. FPV assay by the plaque procedure is rapid and gives infectivity titres which exceed those determined by the common inclusion body and immunofluorescent assays of FPV by a factor of about 100 and 10, respectively. Moreover, the plaque assay offers an effective means for the quantification of neutralizing antibodies in feline sera as well as for the detection of heat-stable substances in bovine sera which strongly interfere with replication of the virus.


Animal Models of Hepatitis C Virus Infection.
Hepatitis C virus (HCV) is an important and underreported infectious disease, causing chronic infection in ∼71 million people worldwide. The limited host range of HCV, which robustly infects only humans and chimpanzees, has made studying this virus in vivo challenging and hampered the development of a desperately needed vaccine. The restrictions and ethical concerns surrounding biomedical research in chimpanzees has made the search for an animal model all the more important. In this review, we discuss different approaches that are being pursued toward creating small animal models for HCV infection. Although efforts to use a nonhuman primate species besides chimpanzees have proven challenging, important advances have been achieved in a variety of humanized mouse models. However, such models still fall short of the overarching goal to have an immunocompetent, inheritably susceptible in vivo platform in which the immunopathology of HCV could be studied and putative vaccines development. Alternatives to overcome this include virus adaptation, such as murine-tropic HCV strains, or the use of related hepaciviruses, of which many have been recently identified. Of the latter, the rodent/rat hepacivirus from Rattus norvegicus species-1 (RHV-rn1) holds promise as a surrogate virus in fully immunocompetent rats that can inform our understanding of the interaction between the immune response and viral outcomes (i.e., clearance vs. persistence). However, further characterization of these animal models is necessary before their use for gaining new insights into the immunopathogenesis of HCV and for conceptualizing HCV vaccines.


Trapping and assembly of living colloids at water-water interfaces.
We study the assembly of inert and living colloids in a two-phase water-water system that provides an environment that can sustain bacteria, providing a new structure with rich potential to confine and structure microbial communities. The water-water system, formed via phase separation of a casein and xanthan mixture, forms a 3-D structure of coexisting casein-rich and xanthan-rich phases. Fluorescent labelling and confocal microscopy reveal the attachment of these living colloids, including Escherichia coli and Pseudomonas aeruginosa, at the interface between the two phases. Inert colloids also become trapped at the interfaces, suggesting that the observed attachment can be attributed to capillarity. Over time, these structures coarsen and eventually degrade, illustrating the dynamic nature of these systems. This system lays the foundation for future studies of the interplay of physicochemical properties of the fluid interfaces and bulk phases and microbial responses they provoke to induce complex spatial organization, to study species which occupy distinct niches, and to optimize efficient microbial cross-feeding or protection from competitors.


Genomic diversity of Escherichia coli from healthy children in rural Gambia.
Little is known about the genomic diversity of Escherichia coli in healthy children from sub-Saharan Africa, even though this is pertinent to understanding bacterial evolution and ecology and their role in infection. We isolated and whole-genome sequenced up to five colonies of faecal E. coli from 66 asymptomatic children aged three-to-five years in rural Gambia (n = 88 isolates from 21 positive stools). We identified 56 genotypes, with an average of 2.7 genotypes per host. These were spread over 37 seven-allele sequence types and the E. coli phylogroups A, B1, B2, C, D, E, F and Escherichia cryptic clade I. Immigration events accounted for three-quarters of the diversity within our study population, while one-quarter of variants appeared to have arisen from within-host evolution. Several isolates encode putative virulence factors commonly found in Enteropathogenic and Enteroaggregative E. coli, and 53% of the isolates encode resistance to three or more classes of antimicrobials. Thus, resident E. coli in these children may constitute reservoirs of virulence- and resistance-associated genes. Moreover, several study strains were closely related to isolates that caused disease in humans or originated from livestock. Our results suggest that within-host evolution plays a minor role in the generation of diversity compared to independent immigration and the establishment of strains among our study population. Also, this study adds significantly to the number of commensal E. coli genomes, a group that has been traditionally underrepresented in the sequencing of this species.


Sex and Rate Change Differences in QT/RR Hysteresis in Healthy Subjects.
While it is now well-understood that the extent of QT interval changes due to underlying heart rate differences (i.e., the QT/RR adaptation) needs to be distinguished from the speed with which the QT interval reacts to heart rate changes (i.e., the so-called QT/RR hysteresis), gaps still exist in the physiologic understanding of QT/RR hysteresis processes. This study was designed to address the questions of whether the speed of QT adaptation to heart rate changes is driven by time or by number of cardiac cycles; whether QT interval adaptation speed is the same when heart rate accelerates and decelerates; and whether the characteristics of QT/RR hysteresis are related to age and sex. The study evaluated 897,570 measurements of QT intervals together with their 5-min histories of preceding RR intervals, all recorded in 751 healthy volunteers (336 females) aged 34.3 ± 9.5 years. Three different QT/RR adaptation models were combined with exponential decay models that distinguished time-based and interval-based QT/RR hysteresis. In each subject and for each modelling combination, a best-fit combination of modelling parameters was obtained by seeking minimal regression residuals. The results showed that the response of QT/RR hysteresis appears to be driven by absolute time rather than by the number of cardiac cycles. The speed of QT/RR hysteresis was found decreasing with increasing age whilst the duration of individually rate corrected QTc interval was found increasing with increasing age. Contrary to the longer QTc intervals, QT/RR hysteresis speed was faster in females. QT/RR hysteresis differences between heart rate acceleration and deceleration were not found to be physiologically systematic (i.e., they differed among different healthy subjects), but on average, QT/RR hysteresis speed was found slower after heart rate acceleration than after rate deceleration.


The atomic structure of Mengo virus at 3.0 A resolution.
The structure of Mengo virus, a representative member of the cardio picornaviruses, is substantially different from the structures of rhino- and polioviruses. The structure of Mengo virus was solved with the use of human rhinovirus 14 as an 8 A resolution structural approximation. Phase information was then extended to 3 A resolution by use of the icosahedral symmetry. This procedure gives promise that many other virus structures also can be determined without the use of the isomorphous replacement technique. Although the organization of the major capsid proteins VP1, VP2, and VP3 of Mengo virus is essentially the same as in rhino- and polioviruses, large insertions and deletions, mostly in VP1, radically alter the surface features. In particular, the putative receptor binding "canyon" of human rhinovirus 14 becomes a deep "pit" in Mengo virus because of polypeptide insertions in VP1 that fill part of the canyon. The minor capsid peptide, VP4, is completely internal in Mengo virus, but its association with the other capsid proteins is substantially different from that in rhino- or poliovirus. However, its carboxyl terminus is located at a position similar to that in human rhinovirus 14 and poliovirus, suggesting the same autocatalytic cleavage of VP0 to VP4 and VP2 takes place during assembly in all these picornaviruses.


The structure and function of the anterolateral ligament of the knee: a systematic review.
The purpose of this systematic review was to evaluate the anatomic structure and function of the anterolateral ligament (ALL) of the knee. The Medline, Embase, and Cochrane databases were screened for all studies related to the ALL of the knee. Two reviewers independently reviewed all eligible articles and the references of these articles. Inclusion and exclusion criteria were applied to all searched studies. Quality assessment was completed for the included studies. Nineteen studies were identified for final analysis. Pooled analysis identified the ALL in 430 of 449 knees (96%) examined. The ligament was found to originate from the region of the lateral femoral epicondyle and insert on the proximal tibia midway between the Gerdy tubercle and the fibular head. The ALL was found to be 34.1 to 41.5 mm in length, 5.1 to 8.3 mm in width above the lateral meniscus, and 8.9 to 11.2 mm in width below the lateral meniscus. By use of magnetic resonance imaging, the ALL was identified in 93% of knees examined (clinical, 64 of 70; cadaveric, 16 of 16). In one case study the ligament was clearly visualized by ultrasound examination. Histologic analysis across 3 studies showed characteristics consistent with ligamentous tissue. Though not shown in biomechanical studies, it is hypothesized that the ALL provides anterolateral stability to the knee, preventing anterolateral subluxation of the proximal tibia on the femur. One study identified a network of peripheral nerves, suggesting a proprioceptive function of the ALL. This systematic review shows the ALL to be a distinct structure with a consistent origin and insertion sites. The ALL is an extra-articular structure with a clear course from the lateral femoral epicondyle region, running anteroinferiorly, to the proximal tibia at a site midway between the Gerdy tubercle and the head of the fibula. The function of this ligament is theorized to provide anterolateral knee stability. Level IV, systematic review of cadaveric and imaging studies.


The impact of osteotomy grade and location on regional and global alignment following cervical deformity surgery.
Correction of cervical deformity (CD) often involves different types of osteotomies to address sagittal malalignment. This study assessed the relationship between osteotomy grade and vertebral level on alignment and clinical outcomes. Retrospective review of a multi-center prospectively collected CD database. CD was defined as at least one of the following: C2-C7 Cobb >10°, cervical lordosis (CL) >10°, C2-C7 sagittal vertical axis (cSVA) >4 cm, and chin-brow vertical angle > 25°. Patients were evaluated for level and type of cervical osteotomy. 86 CD patients were included (61.4 ± 10.6 years, 66.3% female, body mass index 29.1 kg/m2). 141 osteotomies were in the cervical spine and 79 were in the thoracic spine. There were 19 major osteotomies performed, with 47% at T1. Patients with an osteotomy in the cervical spine improved in T1 slope minus CL (TS - CL), CL, and C2 slope (all P < 0.05). Patients with upper thoracic osteotomies improved in TS - CL, cSVA, C2-T3, C2-T3 sagittal vertical axis (SVA), and C2 slope (all P < 0.05). Minor osteotomies in the upper thoracic spine showed improvement in cSVA (63 mm to 49 mm, P = 0.022), C2-T3 (P = 0.007), and SVA (-16 mm to 27 mm, P < 0.001). The greatest amount of C2-T3 angular change occurred for patients with a major osteotomy at T2 (39.1° change), then T3 (15.7°), C7 (16.9°°), and T1 (13.5°°). Patients with a major osteotomy in the upper thoracic spine showed similar radiographic changes from pre- to post-operative as patients with three or more minor osteotomies, although C2-T3 SVA trended toward greater improvement with a major osteotomy (-22.5 mm vs. +5.9 mm, P = 0.058) due to lever arm effect. CD patients undergoing osteotomies in the cervical and upper thoracic spine experienced improvement in TS--CL and C2 slope. In the upper thoracic spine, multiple minor osteotomies achieved similar alignment changes to major osteotomies at a single level, while a major osteotomy focused at T2 had the greatest overall impact in cervicothoracic and global alignment in CD patients.


Drosophila myc regulates organ size by inducing cell competition.
Experiments in both vertebrates and invertebrates have illustrated the competitive nature of growth and led to the idea that competition is a mechanism of regulating organ and tissue size. We have assessed competitive interactions between cells in a developing organ and examined their effect on its final size. We show that local expression of the Drosophila growth regulator dMyc, a homolog of the c-myc protooncogene, induces cell competition and leads to the death of nearby wild-type cells in developing wings. We demonstrate that cell competition is executed via induction of the proapoptotic gene hid and that both competition and hid function are required for the wing to reach an appropriate size when dMyc is expressed. Moreover, we provide evidence that reproducible wing size during normal development requires apoptosis. Modulating dmyc levels to create cell competition and hid-dependent cell death may be a mechanism used during normal development to control organ size.


Manipulating chemistry through nanoparticle morphology.
We demonstrate that the protonation chemistry of molecules adsorbed at nanometer distances from the surface of anisotropic gold nanoparticles can be manipulated through the effect of surface morphology on the local proton density of an organic coating. Direct evidence of this remarkable effect was obtained by monitoring surface-enhanced Raman scattering (SERS) from mercaptobenzoic acid and 4-aminobenzenethiol molecules adsorbed on gold nanostars. By smoothing the initially sharp nanostar tips through a mild thermal treatment, changes were induced on protonation of the molecules, which can be observed through changes in the measured SERS spectra. These results shed light on the local chemical environment near anisotropic colloidal nanoparticles and open an alternative avenue to actively control chemistry through surface morphology.


Burden of illness imposed by severe sepsis in Switzerland.
This study aims to determine the burden of illness imposed by severe sepsis in Switzerland by evaluating the direct and indirect patient-related costs for critically ill patients with severe sepsis. In order to estimate the direct costs a retrospective analysis was undertaken using records from 61 adult patients treated in three intensive care units (ICUs) in three different University hospitals in Switzerland, in 2001. Resource use was determined by a bottom up approach and valued using centre-specific unit costs for medication, nutrition, blood products, disposables and official tariffs for laboratory and microbiology analysis, diagnostic services, and clinical procedures. By adding centre-specific personnel and basic bed (hotel) costs total direct costs in the ICU were calculated. Indirect costs resulting from unfitness for work, early retirement, and premature death were calculated using official Swiss statistics for the years 1998-2000. The mean total direct costs for a severely septic patient are CHF 41,790 (+/- 33,222 CHF) or CHF 3244 (+/- 757 CHF) per day. Nonsurvivors cause significantly higher costs than survivors (CHF 45,956 vs. CHF 37,759, p <0.001). The total intensive care costs in Switzerland due to severe sepsis amount to CHF 146-355 million. Indirect costs were estimated to range from CHF 347 to 844 million (predominantly due to premature death). Consequently the burden of illness of severe sepsis can be estimated to range from CHF 493 to 1199 million per year in Switzerland (1 CHF = 0.662 Euro in 2001). Patients suffering from severe sepsis in Switzerland have a high mortality rate and spend a prolonged time in the ICU, leading to high direct and indirect costs. Particularly productivity losses due to premature death represent a considerable burden to the Swiss society.


Candida tropicalis Etr1p and Saccharomyces cerevisiae Ybr026p (Mrf1'p), 2-enoyl thioester reductases essential for mitochondrial respiratory competence.
We report here on the identification and characterization of novel 2-enoyl thioester reductases of fatty acid metabolism, Etr1p from Candida tropicalis and its homolog Ybr026p (Mrf1'p) from Saccharomyces cerevisiae. Overexpression of these proteins in S. cerevisiae led to the development of significantly enlarged mitochondria, whereas deletion of the S. cerevisiae YBR026c gene resulted in rudimentary mitochondria with decreased contents of cytochromes and a respiration-deficient phenotype. Immunolocalization and in vivo targeting experiments showed these proteins to be predominantly mitochondrial. Mitochondrial targeting was essential for complementation of the mutant phenotype, since targeting of the reductases to other subcellular locations failed to reestablish respiratory growth. The mutant phenotype was also complemented by a mitochondrially targeted FabI protein from Escherichia coli. FabI represents a nonhomologous 2-enoyl-acyl carrier protein reductase that participates in the last step of the type II fatty acid synthesis. This indicated that 2-enoyl thioester reductase activity was critical for the mitochondrial function. We conclude that Etr1p and Ybr026p are novel 2-enoyl thioester reductases required for respiration and the maintenance of the mitochondrial compartment, putatively acting in mitochondrial synthesis of fatty acids.


Organellar gene transcription and early seedling development are affected in the rpoT;2 mutant of Arabidopsis.
An Arabidopsis mutant that exhibited reduced root length was isolated from a population of activation-tagged T-DNA insertion lines in a screen for aberrant root growth. This mutant also exhibited reduced hypocotyl length as well as a delay in greening and altered leaf shape. Molecular genetic analysis of the mutant indicated a single T-DNA insertion in the gene RpoT;2 encoding a homolog of the phage-type RNA polymerase (RNAP), that is targeted to both mitochondria and plastids. A second T-DNA-tagged allele also showed a similar phenotype. The mutation in RpoT;2 affected the light-induced accumulation of several plastid mRNAs and proteins and resulted in a lower photosynthetic efficiency. In contrast to the alterations in the plastid gene expression, no major effect of the rpoT;2 mutation on the accumulation of examined mitochondrial gene transcripts and proteins was observed. The rpoT;2 mutant exhibited tissue-specific alterations in the transcript levels of two other organelle-directed nuclear-encoded RNAPs, RpoT;1 and RpoT;3. This suggests the existence of cross-talk between the regulatory pathways of the three RNAPs through organelle to nucleus communication. These data provide an important information on a role of RpoT;2 in plastid gene expression and early plant development.


Increased capsaicin receptor TRPV1 nerve fibres in the inflamed human oesophagus.
Gastro-oesophageal reflux disease (GORD) patients commonly describe symptoms of heartburn and chest pain. The capsaicin receptor vanilloid receptor 1 (TRPV1) (VR1) is a cation channel expressed by sensory neurones and activated by heat, acid pH and ethanol, which may trigger burning pain. To study the distribution of TRPV1-expressing nerve fibres in oesophageal mucosal biopsies from patients with symptomatic oesophagitis and in control subjects. Biopsies were taken at gastroscopy from the distal oesophagus of seven symptomatic oesophagitis patients and seven asymptomatic patients undergoing investigation for iron-deficiency anaemia. These biopsies were studied by immunohistochemistry using affinity-purified antibodies to TRPV1 and to the neuronal marker peripherin. The density of oesophageal epithelial TRPV1 innervation was assessed by calculating the proportion of papillae in each oesophageal epithelium biopsy specimen containing TRPV1-immunoreactive fibres. TRPV1-immunoreactive nerves were distributed within the lamina propria in healthy subjects and in oesophagitis patients. The percentage of papillae positive for TRPV1 was elevated in oesophagitis patients compared with controls. Peripherin fibre density was not significantly different between the groups. TRPV1-immunoreactive sensory nerve fibres are expressed in human oesophageal mucosa both in health and in disease. Increased TRPV1 expression in the inflamed oesophagus may mediate the heartburn in oesophagitis, and TRPV1 blockers may provide novel treatment.


2021 EULAR points to consider to support people with rheumatic and musculoskeletal diseases to participate in healthy and sustainable paid work.
As part of its strategic objectives for 2023, EULAR aims to improve the work participation of people with rheumatic and musculoskeletal diseases (RMDs). One strategic initiative focused on the development of overarching points to consider (PtC) to support people with RMDs in healthy and sustainable paid work participation. EULAR's standardised operating procedures were followed. A steering group identified six research areas on paid work participation. Three systematic literature reviews, several non-systematic reviews and two surveys were conducted. A multidisciplinary taskforce of 25 experts from 10 European countries and Canada formulated overarching principles and PtC after discussion of the results of literature reviews and surveys. Consensus was obtained through voting, with levels of agreement obtained anonymously. Three overarching principles and 11 PtC were formulated. The PtC recognise various stakeholders are important to improving work participation. Five PtC emphasise shared responsibilities (eg, obligation to provide active support) (PtC 1, 2, 3, 5, 6). One encourages people with RMDs to discuss work limitations when necessary at each phase of their working life (PtC 4) and two focus on the role of interventions by healthcare providers or employers (PtC 7, 8). Employers are encouraged to create inclusive and flexible workplaces (PtC 10) and policymakers to make necessary changes in social and labour policies (PtC 9, 11). A research agenda highlights the necessity for stronger evidence aimed at personalising work-related support to the diverse needs of people with RMDs. Implementation of these EULAR PtC will improve healthy and sustainable work participation of people with RMDs.


Effect of Equisetum arvense and Stevia rebaudiana extracts on growth and mycotoxin production by Aspergillus flavus and Fusarium verticillioides in maize seeds as affected by water activity.
Cereals are a very important part of the human and animal diets. However, agricultural products can be contaminated by moulds and their mycotoxins. Plant extracts, particularly those of Equisetum arvense and Stevia rebaudiana have been reported previously to contain antioxidant compounds which may have antifungal properties. In this study, E. arvense and S. rebaudiana extracts were tested for their control of mycotoxigenic fungi in maize. The extracts were tested separately and as a mixture for their effect on growth of Aspergillus flavus and Fusarium verticillioides. Extracts were added to unsterilised inoculated maize at different water activity (a(w)) levels (0.85-0.95). Moulds were inoculated and incubated for 30 days. Results confirmed that the extract of E. arvense and a mixture 1:1 of Equisetum-Stevia may be effective for the inhibition of both growth of A. flavus and aflatoxin production at high water activity levels (pre-harvest conditions). In general, growth of the F. verticillioides was reduced by the use of plant extracts, especially at 0.95 a(w). However, fumonisin presence was not significantly affected. E. arvense and S. rebaudiana extracts could be developed as an alternative treatment to control aflatoxigenic mycobiota in moist maize.


Refractive surgery in the United States Army, 2000-2003.
To examine the history, current status, outcomes, and future direction of the Army Warfighter Refractive Eye Surgery Program (WRESP), which was established to reduce the limitations posed by corrective eyewear in combat arms soldiers. Retrospective study. Sixteen thousand one hundred eleven Army service members who underwent refractive surgery between May 2000 and September 2003. Results were collected from monthly WRESP reports and from questionnaires administered to refractive surgery patients returning from deployments to southwest Asia. Soldiers rated the impact of refractive surgery on their ability to perform select operational tasks as well as their overall readiness. Visual acuity (VA) and patient satisfaction. Between May 2000 and September 30, 2003, 32 068 eyes of 16 111 soldiers were treated. Postoperative uncorrected VA was better than or equal to 20/20 in 85.6%, 20/25 in 92.4%, and 20/40 in 98.2% of eyes with at least 3 months' follow-up, and 93.7% of 175 surveyed patients rated their overall readiness better or much better after surgery. This program has provided excellent outcomes and enhanced the overall readiness of over 16 000 Army service members. Reports of night vision difficulties, LASIK flap dislocation, and dry eye are infrequent, and do not seem to have a significant negative impact on military operations or individual readiness. This article contains additional online-only material available at http://www.ophsource.com/periodicals/ophtha.


Seroepidemiological survey of Taenia saginata cysticercosis in Kenya.
A sero-epidemiological study of Taenia saginata cysticercosis was carried out to determine the prevalence and distribution of the infection in three provinces of Kenya. Serum samples and meat inspection records were collected from cattle at slaughter at export and district abattoirs. Cattle origin and the presence of T. saginata cysticerci were noted as was the prevalence of other helminths such as Echinococcus granulosus and Fasciola gigantica. Serum samples were screened for circulating parasite antigen using a monoclonal antibody-based enzyme-linked immunosorbent assay (Ag-ELISA) and for ante-parasite antibody by indirect ELISA (Ab-ELISA). Eighty per cent of the sera were collected from cattle from the Rift Valley Province of Kenya. The prevalence of T. saginata cysticercosis and the other helminth infections varied between districts and was particularly high in Narok. Animal husbandry practices in arid areas such as Narok may be particularly conducive to transmission. The potential value of the Ag-ELISA for use in sero-epidemiological studies was verified by this study. It detected at least twice as many cases as T. saginata cysticercosis as meat inspection and, of the three methods investigated, was considered the most valuable.


Effect of recombinant IL-10 on cultured fetal rat alveolar type II cells exposed to 65%-hyperoxia.
Hyperoxia plays an important role in the genesis of lung injury in preterm infants. Although alveolar type II cells are the main target of hyperoxic lung injury, the exact mechanisms whereby hyperoxia on fetal alveolar type II cells contributes to the genesis of lung injury are not fully defined, and there have been no specific measures for protection of fetal alveolar type II cells. The aim of this study was to investigate (a) cell death response and inflammatory response in fetal alveolar type II cells in the transitional period from canalicular to saccular stages during 65%-hyperoxia and (b) whether the injurious stimulus is promoted by creating an imbalance between pro- and anti-inflammatory cytokines and (c) whether treatment with an anti-inflammatory cytokine may be effective for protection of fetal alveolar type II cells from injury secondary to 65%-hyperoxia. Fetal alveolar type II cells were isolated on embryonic day 19 and exposed to 65%-oxygen for 24 h and 36 h. Cells in room air were used as controls. Cellular necrosis was assessed by lactate dehydrogenase-release and flow cytometry, and apoptosis was analyzed by TUNEL assay and flow cytometry, and cell proliferation was studied by BrdU incorporation. Release of cytokines including VEGF was analyzed by ELISA, and their gene expressions were investigated by qRT-PCR. 65%-hyperoxia increased cellular necrosis, whereas it decreased cell proliferation in a time-dependent manner compared to controls. 65%-hyperoxia stimulated IL-8-release in a time-dependent fashion, whereas the anti-inflammatory cytokine, IL-10, showed an opposite response. 65%-hyperoxia induced a significant decrease of VEGF-release compared to controls, and similar findings were observed on IL-8/IL-10/VEGF genes expression. Preincubation of recombinant IL-10 prior to 65%-hyperoxia decreased cellular necrosis and IL-8-release, and increased VEGF-release and cell proliferation significantly compared to hyperoxic cells without IL-10. The present study provides an experimental evidence that IL-10 may play a potential role in protection of fetal alveolar type II cells from injury induced by 65%-hyperoxia.


Study protocol for a randomised placebo-controlled trial of pramipexole in addition to mood stabilisers for patients with treatment resistant bipolar depression (the PAX-BD study).
Treatment Resistant Bipolar Depression (TRBD) is a major contributor to the burden of disease associated with Bipolar Disorder (BD). Treatment options for people experiencing bipolar depression are limited to three interventions listed by National Institute for Health and Care: lamotrigine, quetiapine and olanzapine, of which the latter two are often not well tolerated. The majority of depressed people with BD are therefore prescribed antidepressants despite limited efficacy. This demonstrates an unmet need for additional interventions. Pramipexole has been shown to improve mood symptoms in animal models of depression, in people with Parkinson's Disease and two proof of principle trials of pramipexole for people with BD who are currently depressed. The PAX-BD study, funded by the United Kingdom (UK) National Institute for Health Research, aims to extend previous findings by assessing the efficacy, safety and health economic impact of pramipexole in addition to mood stabilisers for patients with TRBD. A randomised, double-blind, placebo controlled design is conducted in a naturalistic UK National Health Service setting. An internal pilot study to examine feasibility and acceptability of the study design is included. Participants with TRBD are screened from National Health Service secondary care services in up to 40 mental health trusts in the UK, with the aim of recruiting approximately 414 participants into a pre-randomisation phase to achieve a target of 290 randomised participants. Primary safety and efficacy measures are at 12 weeks following randomisation, with follow up of participants to 52 weeks. The primary outcome is depressive symptoms as measured by Quick Inventory for Depressive Symptomatology - Self Report. Secondary outcomes include changes in anxiety, manic symptoms, tolerability, acceptability, quality of life and cost-effectiveness. Outcome measures are collected remotely using self-report tools implemented online, and observer-rated assessments conducted via telephone. ANCOVA will be used to examine the difference in rating scale scores between treatment arms, and dependent on compliance in completion of weekly self-report measures. A mixed effects linear regression model may also be used to account for repeated measures. ISRCTN72151939. Registered on 28 August 2019, http://www.isrctn.com/ISRCTN72151939 Protocol Version: 04-FEB-2021, Version 9.0.


Resveratrol attenuates behavioral impairments and reduces cortical and hippocampal loss in a rat controlled cortical impact model of traumatic brain injury.
Resveratrol (3,5,4'-trihydroxystilbene) is a plant-derived small molecule that is protective against multiple neurological and systemic insults. To date, no studies have explored the potential for resveratrol to provide behavioral protection in adult animals in the setting of traumatic brain injury (TBI). Using 50 male Sprague-Dawley rats, we employed the controlled cortical impact (CCI) model to ascertain whether post-injury administration of resveratrol would reduce the severity of the well-described cognitive and motor deficits associated with the model. Contusion volumes and hippocampal neuronal numbers were also measured to characterize the tissue and neuronal-sparing properties, respectively, of resveratrol. We found that 100 mg/kg, but not 10 mg/kg, of intraperitoneal resveratrol administered after injury provides significant behavioral protection in rats sustaining CCI. Specifically, rodents treated with 100 mg/kg of resveratrol showed improvements in motor performance (beam balance and beam walking) and testing of visuospatial memory (Morris water maze). Behavioral protection was correlated with significantly reduced contusion volumes, preservation of CA1 and CA3 hippocampal neurons, and protection from overt hippocampal loss as a result of incorporation into the overlying cortical contusion in resveratrol-treated animals. Although the mechanisms by which resveratrol mediates its neuroprotection is unclear, the current study adds to the growing literature identifying resveratrol as a potential therapy for human brain injury.


The binding and distribution of albendazole and its principal metabolites in Giardia duodenalis.
Trophozoites of the protozoan parasite Giardia duodenalis were exposed to various albendazole concentrations for 4 h, washed, fixed and incubated with antibodies raised against albendazole and its two major metabolites albendazole sulphoxide and albendazole sulphone. Tubulin antibodies were also used. A peroxidase- or FITC-conjugated secondary antibody was used to detect the primary antibody with transmission electron microscopy or confocal laser scanning microscopy, respectively. Albendazole, a benzimidazole compound, was detected in the mid-dorsal region of trophozoites, albendazole sulphoxide in the posterior-dorsal region and albendazole sulphone in clusters above the median bodies. Tubulin was recognised in the ventral disk. This is the first indication that G. duodenalis may be capable of metabolising albendazole and the potential path of the metabolised drug traced within the trophozoite. Fluorescence measurements revealed that albendazole sulphoxide binding decreased and albendazole sulphone binding increased with exposure of the trophozoites to increasing albendazole concentration. This indicates that if albendazole was being metabolised by trophozoites, it occurred to a greater extent following exposure to higher albendazole concentrations.


Gasdermin D (GSDMD) as a new target for the treatment of infection.
The discovery of a previously unknown protein, gasdermin D (GSDMD), as the key effector that leads to pyroptosis and NETosis has created much excitement. Since its initial report in Oct. 2015, more than 200 papers have been published on studies of the structure and mechanism of GSDMD and its homologues. The clear connection between infection and inflammasome activation made GSDMD a promising target for the development of anti-infection treatment. In this mini review, we discuss first the current understanding of the structure and mechanism of GSDMD, focusing on its potential as a druggable target, and then recent efforts in the development of inhibitors to interfere with the pore-forming function of GSDMD and thus alleviate the detrimental effects due to pyroptotic cell death.


Rediscovering the value of families for psychiatric genetics research.
As it is likely that both common and rare genetic variation are important for complex disease risk, studies that examine the full range of the allelic frequency distribution should be utilized to dissect the genetic influences on mental illness. The rate limiting factor for inferring an association between a variant and a phenotype is inevitably the total number of copies of the minor allele captured in the studied sample. For rare variation, with minor allele frequencies of 0.5% or less, very large samples of unrelated individuals are necessary to unambiguously associate a locus with an illness. Unfortunately, such large samples are often cost prohibitive. However, by using alternative analytic strategies and studying related individuals, particularly those from large multiplex families, it is possible to reduce the required sample size while maintaining statistical power. We contend that using whole genome sequence (WGS) in extended pedigrees provides a cost-effective strategy for psychiatric gene mapping that complements common variant approaches and WGS in unrelated individuals. This was our impetus for forming the "Pedigree-Based Whole Genome Sequencing of Affective and Psychotic Disorders" consortium. In this review, we provide a rationale for the use of WGS with pedigrees in modern psychiatric genetics research. We begin with a focused review of the current literature, followed by a short history of family-based research in psychiatry. Next, we describe several advantages of pedigrees for WGS research, including power estimates, methods for studying the environment, and endophenotypes. We conclude with a brief description of our consortium and its goals.


Nitric oxide level in seminal plasma and its relation with sperm DNA damages.
Evidence supports the involvement of nitric oxide (NO) in a variety of male reproductive processes such as spermatogenesis, spermiogenesis, sperm motion, sperm metabolism and sperm capacitation. However, low concentration of NO is essential in biology and physiology of spermatozoa, but high amounts of NO is toxic and has negative effects on sperm functions. On the other hand, it is established that high amounts of NO have detrimental effects on DNA. The integrity of sperm DNA is an important factor in successful fertility and embryo development. It is hypothesized that supra physiological concentrations of NO in seminal plasma cause sperm DNA damage. The aim of this study was to determine sperm DNA damage by comet assay and its correlation with NO level in seminal plasma of fertile and infertile men. Semen samples were collected from 45 patients and 70 healthy donors. The stable metabolites of NO (nitrite and nitrate) in seminal plasma were measured by Griess assay and DNA damage was determined using single cell gel electrophoresis (comet) assay method. The NO concentration in the seminal plasma of infertile males was significantly higher than fertile males (5.74+/-1.01 microM/L vs. 3.88+/-0.53 microM/L). There was a significant positive correlation between the NO concentration and sperm DNA comet value in infertile males (P<0.01, R=0.598). These results indicate that the overproduction of NO in genital tract of infertile males has a potential pathogenetic role in the reduction of sperm DNA integrity.


Patterns of treatment expectation and the physician-patient relationship perceived by women receiving traditional Chinese medicine treatment for menstrual symptoms: a Q-methodology study.
The recurrence of menstrual symptoms markedly interferes with the daily life, social functioning, work disability and quality of life of women. Patient perception of healthcare services is underexplored but crucial for understanding how to efficiently develop healthcare practices. To identify and describe the different patterns of treatment expectation and physician-patient relationships perceived by women receiving traditional Chinese medicine treatment for menstrual symptoms. A two-stage data collection design was used. In the first stage, in-depth interviews with 40 participants were conducted; the interview data were used for content analysis. Q statements were developed on the basis of the content analysis results. In the second stage, a series of Q sorts was performed by 60 other participants to subjectively rank the Q statements. The results of factor analysis revealed that four factors retained in the final model accounted for 56% of total variance. Women associated with Factor 1 had experienced few negative physician-patient interactions; these women were relatively young (31.6 years) and had mild perimenstrual mood discomfort (6.4). Women who loaded on Factor 2 preferred physician guidance and encountered few barriers to adherence; these participants were older (38.6 years) and had the most severe perimenstrual mood discomfort (9.5) among the four groups. The women in agreement with Factor 3 tended to patiently wait for treatment effects; these participants had the highest scores for both cyclic pelvic pain (4.9) and perimenstrual physical discomfort (8.8). The women associated with Factor 4 demanded effective treatment and had the lowest scores for both cyclic pelvic pain (3.8) and perimenstrual physical discomfort (6.8). The exploration of clustering patients according to their perspectives could influence healthcare providers to acknowledge patient expectations and enable effective communication between physicians and patients.


Visualization of custom-tailored iron oxide nanoparticles chemistry, uptake, and toxicity.
Nanoparticles of iron oxide generated by wearing of vehicles have been modelled with a tailored solution of size-uniform engineered magnetite particles produced by the Bradley reaction, a solvothermal metal-organic approach rendering hydrophilic particles. The latter does not bear any pronounced surface charge in analogy with that originating from anthropogenic sources in the environment. Physicochemical properties of the nanoparticles were thoroughly characterized by a wide range of methods, including XPD, TEM, SEM, DLS and spectroscopic techniques. The magnetite nanoparticles were found to be sensitive for transformation into maghemite under ambient conditions. This process was clearly revealed by Raman spectroscopy for high surface energy magnetite particles containing minor impurities of the hydromaghemite phase and was followed by quantitative measurements with EXAFS spectroscopy. In order to assess the toxicological effects of the produced nanoparticles in humans, with and without surface modification with ATP (a model of bio-corona formed in alveolar liquid), a pathway of potential uptake and clearance was modelled with a sequence of in vitro studies using A549 lung epithelial cells, lymphocyte 221-B cells, and 293T embryonal kidney cells, respectively. Raman microscopy unambiguously showed that magnetite nanoparticles are internalized within the A549 cells after 24 h co-incubation, and that the ATP ligand is retained on the nanoparticles throughout the uptake process. The toxicity of the nanoparticles was estimated using confocal fluorescence microscopy and indicated no principal difference for unmodified and modified particles, but revealed considerably different biochemical responses. The IL-8 cytokine response was found to be significantly lower for the magnetite nanoparticles compared to TiO(2), while an enhancement of ROS was observed, which was further increased for the ATP-modified nanoparticles, implicating involvement of the ATP signalling pathway in the epithelium.


Maternal cotinine level during pregnancy and birthweight for gestational age.
Recent studies have found that cotinine is a better predictor of birthweight than the number of cigarettes smoked in pregnancy. In this paper we test this hypothesis and use cotinine to explore the effect of environmental tobacco smoke (ETS) on birthweight. In all, 1254 white women were interviewed at booking, 28 and 36 weeks about the number and brand of cigarette smoked. Cotinine was assayed from blood samples taken on the day of interview. The outcome was birthweight for gestational age. There was good agreement between self-reported smoker/non-smoker status and maternal cotinine with 1.3% women mis-reported as non-smokers at booking, 0.6% and 1.8% mis-reported at 28 and 36 weeks respectively. Among smokers, cotinine was more closely related to birthweight than the number of cigarettes smoked at all three time points (r = -0.25 versus r = -0.16 at booking). A reduction in cotinine between booking and 28 weeks was associated with increased birthweight but the effect was not statistically significant. Among non-smokers the association between birthweight and cotinine was not statistically significant after adjusting for maternal height, parity, sex and gestational age. Difference in mean birthweight between non-smokers in the lower and upper quintiles of cotinine was 0.2% (95% CI: -2.4, 2.8). Pooling the results of 10 studies plus our own gave an estimated difference in mean birthweight between women unexposed and exposed to passive smoke of 31 g (95% CI: 19, 44). Cotinine is a better predictor of birthweight than the reported number of cigarettes smoked. If biochemical analysis is impossible, then self-reported smoking habit should be obtained prospectively using a structured approach. Any effect on birthweight of maternal passive smoking during pregnancy is small compared with the effects of maternal active smoking.


Suppressor of cytokine signaling (SOCS) 1 inhibits type I interferon (IFN) signaling via the interferon alpha receptor (IFNAR1)-associated tyrosine kinase Tyk2.
Type I IFNs are critical players in host innate and adaptive immunity. IFN signaling is tightly controlled to ensure appropriate immune responses as imbalance could result in uncontrolled inflammation or inadequate responses to infection. It is therefore important to understand how type I IFN signaling is regulated. Here we have investigated the mechanism by which suppressor of cytokine signaling 1 (SOCS1) inhibits type I IFN signaling. We have found that SOCS1 inhibits type I IFN signaling not via a direct interaction with the IFN α receptor 1 (IFNAR1) receptor component but through an interaction with the IFNAR1-associated kinase Tyk2. We have characterized the residues/regions involved in the interaction between SOCS1 and Tyk2 and found that SOCS1 associates via its SH2 domain with conserved phosphotyrosines 1054 and 1055 of Tyk2. The kinase inhibitory region of SOCS1 is also essential for its interaction with Tyk2 and inhibition of IFN signaling. We also found that Tyk2 is preferentially Lys-63 polyubiquitinated and that this activation reaction is inhibited by SOCS1. The consequent effect of SOCS1 inhibition of Tyk2 not only results in a reduced IFN response because of inhibition of Tyk2 kinase-mediated STAT signaling but also negatively impacts IFNAR1 surface expression, which is stabilized by Tyk2.


Preparation of polymeric carriers for drug delivery with different shape and size using an electric jet.
A method for generating poly(lactic-co-glycolic acid) and polycaprolactone biodegradable particles of different size and shape using a jet generated in an electric field is elucidated. These particles are suitable for use as drug carriers and the method can be developed into a mass production route. The effect of different parameters such as applied voltage, collecting distance, flow rate and polymer concentration on inducing size and shape differences in these particles was studied. It was found that the flow rate, polymer concentration and collecting distance have a significant impact on the size of the generated particles and by changing the collecting distance a systematic reduction in the particle size by at least an order of magnitude (10microm-100nm) can be achieved. By using a high polymer concentration (30 wt. %) the shape and surface morphology of these particles can also be controlled from spherical to fibrous, and smooth to irregular, respectively, which presently is an interesting strategy and concept in drug delivery. This method is very useful as a one-step generator of different sizes of drug carriers with morphological variations.


Systems of care for ST-elevation myocardial infarction in India.
The prevalence of coronary artery disease and ST-elevation myocardial infarction (STEMI) are increasing in India. Although recent publications have focused on improving preventive measures in developing countries, less attention has been placed on the acute management of STEMI. Recent policy changes in India have provided new opportunities to address existing barriers but require greater investment and support in the coming years.


Energy Balance Coexists With Disproportionate Macronutrient Consumption Across Pretraining, During Training, and Posttraining Among Indian Junior Soccer Players.
To evaluate energy expenditure, energy intake, and nutrient adequacy of Indian junior soccer players. Forty junior national-level soccer players (Under-12 and Under-16 age groups) were assessed for 3-day weighed food records and 3-day energy expenditure. Energy and nutrient intake was analyzed from food records, and energy expenditure was measured using a portable metabolic analyzer and activity records. Nutrient adequacy was determined by comparing intake with prevailing recommendations. Players exhibited no significant difference between energy intake (boys = 3062 [340.9] and girls = 2243 [320.3] kcal·d-1) and expenditure (boys = 2875 [717.3] and girls = 2442 [350.3] kcal·d-1). Across age groups, the Under-12 boys showed positive energy balance as against energy deficits in Under-16. Girls showed energy deficits, although not significant. There were 58% of girls showing energy availability <30 kcal·kg-1 fat-free mass, of which 37% were Under-16 players. Carbohydrates contributed to >60% of energy expenditure among 95.2% boys and 73.7% girls. Among 52.4% boys and 47.4% girls, <25% of energy expenditure was contributed by fat. More than 95% players consumed <1 g·kg-1 carbohydrates pretraining and 100% of them consumed >1.2 g·kg-1 carbohydrates posttraining. Junior soccer players consumed more than recommended carbohydrates in the diet, although not aligning with the pretraining, during training, and posttraining meal requirements. Considering the energy deficits observed among Under-16 players, a suitable dietary modification is warranted.


Integrating genomics for chickpea improvement: achievements and opportunities.
Integration of genomic technologies with breeding efforts have been used in recent years for chickpea improvement. Modern breeding along with low cost genotyping platforms have potential to further accelerate chickpea improvement efforts. The implementation of novel breeding technologies is expected to contribute substantial improvements in crop productivity. While conventional breeding methods have led to development of more than 200 improved chickpea varieties in the past, still there is ample scope to increase productivity. It is predicted that integration of modern genomic resources with conventional breeding efforts will help in the delivery of climate-resilient chickpea varieties in comparatively less time. Recent advances in genomics tools and technologies have facilitated the generation of large-scale sequencing and genotyping data sets in chickpea. Combined analysis of high-resolution phenotypic and genetic data is paving the way for identifying genes and biological pathways associated with breeding-related traits. Genomics technologies have been used to develop diagnostic markers for use in marker-assisted backcrossing programmes, which have yielded several molecular breeding products in chickpea. We anticipate that a sequence-based holistic breeding approach, including the integration of functional omics, parental selection, forward breeding and genome-wide selection, will bring a paradigm shift in development of superior chickpea varieties. There is a need to integrate the knowledge generated by modern genomics technologies with molecular breeding efforts to bridge the genome-to-phenome gap. Here, we review recent advances that have led to new possibilities for developing and screening breeding populations, and provide strategies for enhancing the selection efficiency and accelerating the rate of genetic gain in chickpea.


Early stages of phase selection in MOF formation observed in molecular Monte Carlo simulations.
Metal-organic frameworks (MOF) comprising metal nodes bridged by organic linkers show great promise because of their guest-specific gas sorption, separation, drug-delivery, and catalytic properties. The selection of metal node, organic linker, and synthesis conditions in principle offers engineered control over both structure and function. For MOFs to realise their potential and to become more than just promising materials, a degree of predictability in the synthesis and a better understanding of the self-assembly or initial growth processes is of paramount importance. Using cobalt succinate, a MOF that exhibits a variety of phases depending on synthesis temperature and ligand to metal ratio, as proof of concept, we present a molecular Monte Carlo approach that allows us to simulate the early stage of MOF assembly. We introduce a new Contact Cluster Monte Carlo (CCMC) algorithm which uses a system of overlapping "virtual sites" to represent the coordination environment of the cobalt and both metal-metal and metal-ligand associations. Our simulations capture the experimentally observed synthesis phase distinction in cobalt succinate at 348 K. To the best of our knowledge this is the first case in which the formation of different MOF phases as a function of composition is captured by unbiased molecular simulations. The CCMC algorithm is equally applicable to any system in which short-range attractive interactions are a dominant feature, including hydrogen-bonding networks, metal-ligand coordination networks, or the assembly of particles with "sticky" patches, such as colloidal systems or the formation of protein complexes.


Host-parasite interactions and trypanosome morphogenesis: a flagellar pocketful of goodies.
Trypanosomes are characterised by the possession of a single flagellum and a subpellicular microtubule cytoskeleton. The flagellum is more than an organelle for motility; its position and polarity along with the sub-pellicular cytoskeleton enables the morphogenesis of a distinct flagellar pocket and the flagellar basal body is responsible for positioning and segregating the kinetoplast--the mitochondrial genome. Recent work has highlighted the molecules and morphogenesis of these cytoskeletal/flagellum structures and how dynamic events, occurring in the flagellar pocket and kinetoplast, are critical for host-parasite interactions.


Cell polarity and spindle orientation in the distal epithelium of embryonic lung.
A proper balance between self-renewal and differentiation of lung-specific progenitors at the distal epithelial tips is absolutely required for normal lung morphogenesis. Cell polarity and mitotic spindle orientation play a critical role in the self-renewal/differentiation of epithelial cells and can impact normal physiological processes, including epithelial tissue branching and differentiation. Therefore, understanding the behavior of lung distal epithelial progenitors could identify innovative solutions to restoring normal lung morphogenesis. Yet little is known about cell polarity, spindle orientation, and segregation of cell fate determinant in the embryonic lung epithelium, which contains progenitor cells. Herein, we provide the first evidence that embryonic lung distal epithelium is polarized and highly mitotic with characteristic perpendicular cell divisions. Consistent with these findings, mInsc, LGN, and NuMA polarity proteins, which control spindle orientation, are asymmetrically localized in mitotic distal epithelial progenitors of embryonic lungs. Furthermore, the cell fate determinant Numb is asymmetrically distributed at the apical side of distal epithelial progenitors and segregated to one daughter cell in most mitotic cells. These findings provide evidence for polarity in distal epithelial progenitors of embryonic lungs and provide a framework for future translationally oriented studies in this area.


A WINning Technique: The Wire-in-Needle Feasibility Study.
Dynamic ultrasound guidance reduces complications associated with central venous catheter placement. However, successful central venous cannulation often remains challenging, particularly in hypotensive patients. The new wire-in-needle (WIN) technique can further increase periprocedural safety. Here, a needle is "preloaded" with a guidewire that is then advanced toward the tip of needle. The vein is then cannulated using long-axis ultrasound guidance. To evaluate the feasibility and safety profile of the WIN technique. Medical students, and resident and attending physicians participated in this study. After a brief lecture and practice session on the WIN technique, they underwent a skills assessment evaluating different aspects of both techniques. Participants then completed a survey assessing their prior experience regarding procedural ultrasound, and their assessment of the WIN technique. Sixty clinicians participated. The assessment of both techniques revealed no significant differences in the number of needle redirections, cannulation attempts, number of arterial punctures, or overall dexterity with the procedure. The WIN technique was faster (45.9 vs. 61.5 s, p = 0.0005) than the traditional technique. More participants confirmed the accurate position of the guidewire in the vein (75% vs. 95%, p = 0.002). More than 90% of study participants met the predefined safety aspects of the WIN technique. Almost all participants reported that they plan on using the WIN technique in their clinical practice. This study demonstrates that the WIN technique can be learned quickly and easily by clinicians with various levels of training. In this study, using manikins, it was as successful and safe as the traditional short-axis approach.


Determination of motility forces of bovine sperm cells using an "optical funnel".
An optical funnel, a new technique for the evaluation of the force of a microorganism, was applied to the determination of the motility force of bovine sperm cells. In this approach, sperm cells, suspended in an aqueous solution, are introduced into a flow cell, to which radiation pressure is applied from the direction opposite to a medium flow. The sperm cell, which is moving in a stream, is captured by radiation pressure and forced to move to the position at which the force induced by the laser radiation is equal to the force induced by a medium flow. The sperm cell then escapes by its own power on the way to this equilibrium (entrapping) position. The radiation force increases with decreasing distance from the focal point, and as a result, the force of the sperm cell can be determined by measuring the position where the sperm cell escaped against the laser irradiation field. The motility force of the sperm cell was measured in aqueous solution at different pH values and potassium ion concentrations. It was possible to measure more than 250 sperm cells in 3 h. Thus, the optical funnel has potential for use as a rapid and repetitive means for the determination of the motility force of the sperm cell.


The role of dendritic cells in shaping the immune response.
Dendritic cells are central to the initiation of primary immune responses. They are the only antigen-presenting cell capable of stimulating naive T cells, and hence they are pivotal in the generation of adaptive immunity. Dendritic cells also interact with and influence the response of cells of the innate immune system. The manner in which dendritic cells influence the responses in cells of both the innate and adaptive immune systems has consequences for the bias of the adaptive response that mediates immunity to infection after vaccination or infection. It also provides an opportunity to intervene and to influence the response, allowing ways of developing appropriate vaccination strategies. Mouse and human studies have identified myeloid, lymphoid and plasmacytoid dendritic cells. Studies in domesticated animals with agents of specific infectious diseases have confirmed the applicability of certain of the generic models developed from mice or from in vitro studies on human cells. In vivo and ex vivo studies in cattle have demonstrated the existence of a number of subpopulations of myeloid dendritic cells. These cells differ in their ability to stimulate T cells and in the cytokines that they produce, observations clearly having important implications for the bias of the T-cell response. Dendritic cells also interact with the innate immune system, inducing responses that potentially bias the subsequent adaptive response.


Psychopathological Features of Bipolar Depression: Italian Validation of the Bipolar Depression Rating Scale (I-BDRS).
Background: Aim of the study was the validation of the Bipolar Disorder Rating Scale (BDRS) in an Italian population. Secondary aim was the evaluation of differences between unipolar and bipolar depression and between bipolar I and II depressed patients. Method: 125 Bipolar Disorder and 60 Major Depressive Disorder patients were administered an Italian translation of the BDRS (I-BDRS), Hamilton Depression Rating Scale (HDRS), Montgomery-Asberg Depression Rating Scale (MADRS), Young Mania Rating Scale (YMRS) and Temperament and Character Inventory-Revised (TCI-R). Results: I-BDRS showed considerable validity and reliability. Factor analysis found 3 subscales, two linked to depressive symptoms and one to mixed symptoms. Measures concerning depression (MADRS and HAM-D) were positively related to the I-BDRS's subscales, but mostly to the two subscales measuring depression. In mixed symptoms, the mean of the bipolar group was significantly higher than the unipolar group suggesting that the BDRS was able to distinguish between unipolar and bipolar depressed patients. Conclusion: I-BDRS is a valid scale for the measurement of depression in BD patients, with a notable internal consistency (Cronbach's α 0.82), a significant consistency between items/total (Cronbach's α from 0.80 to 0.82) and positive correlation with other scales (MADRS r = 0.67, p < 0.001; HDRS r = 0.81, p < 0.001; YMRS r = 0.46 p < 0.0001). The mixed state sub-scale shows usefulness in differentiating bipolar from unipolar patients. I-BDRS could be a sensitive tool, both in pure depression and in mixed states, and could be used in the everyday screening and treatment of Bipolar Disorder.