The regulation of chromosome segregation via centromere loops.
Biophysical studies of the yeast centromere have shown that the organization of the centromeric chromatin plays a crucial role in maintaining proper tension between sister kinetochores during mitosis. While centromeric chromatin has traditionally been considered a simple spring, recent work reveals the centromere as a multifaceted, tunable shock absorber. Centromeres can differ from other regions of the genome in their heterochromatin state, supercoiling state, and enrichment of structural maintenance of chromosomes (SMC) protein complexes. Each of these differences can be utilized to alter the effective stiffness of centromeric chromatin. In budding yeast, the SMC protein complexes condensin and cohesin stiffen chromatin by forming and cross-linking chromatin loops, respectively, into a fibrous structure resembling a bottlebrush. The high density of the loops compacts chromatin while spatially isolating the tension from spindle pulling forces to a subset of the chromatin. Paradoxically, the molecular crowding of chromatin via cohesin and condensin also causes an outward/poleward force. The structure allows the centromere to act as a shock absorber that buffers the variable forces generated by dynamic spindle microtubules. Based on the distribution of SMCs from bacteria to human and the conserved distance between sister kinetochores in a wide variety of organisms (0.4 to 1 micron), we propose that the bottlebrush mechanism is the foundational principle for centromere function in eukaryotes.


Dactylogyrids (Platyhelminthes: Monogenea) from Sudanese Labeo Spp., with a Description of Dogielius Sennarensis n. Sp. and a Redescription of Dogielius Flosculus Guégan, Lambert & Euzet, 1989.
Dactylogyrid monogeneans of Labeo horie Heckel, 1847 and L. niloticus (Linnaeus, 1758) (Cyprinidae) were surveyed at two sites on the River Nile in Sudan. The present study reports the presence of ten species of Dactylogyrus Diesing, 1850 and three species of Dogielius Bychowsky, 1936 based on a morphometric evaluation of the sclerotised structures. The species found include: Dactylogyrus nathaliae Guégan, Lambert & Euzet, 1988; D. rastellus Guégan, Lambert & Euzet, 1988; D. retroversus Guégan, Lambert & Euzet, 1988; D. senegalensis Paperna, 1969, D. yassensis Musilová, Řehulková & Gelnar, 2009 and five other undescribed species of Dactylogyrus. The genus Dogielius was represented by Dogielius flosculus Guégan, Lambert & Euzet, 1989; the newly identified D. sennarensis n. sp., and one undescribed Dogielius species. While D. sennarensis n. sp. resembles D. intorquens, it differs from this species and other congeners by having a longer ventral bar and anchor points and nosclerotised vagina. In addition, this study redescribes D. flosculus based on the morphology of specimens collected from L. horie. All specimens studied had a single large vagina, in contrast to the original description which reported a vagina composed of two unconnected parts. All dactylogyrid species in this study represent new host and geographical records.


Rapid Screening for CRISPR-Directed Editing of the Drosophila Genome Using white Coconversion.
Adoption of a streamlined version of the bacterial clustered regular interspersed short palindromic repeat (CRISPR)/Cas9 defense system has accelerated targeted genome engineering. The Streptococcus pyogenes Cas9 protein, directed by a simplified, CRISPR-like single-guide RNA, catalyzes a double-stranded DNA break at a specific genomic site; subsequent repair by end joining can introduce mutagenic insertions or deletions, while repair by homologous recombination using an exogenous DNA template can incorporate new sequences at the target locus. However, the efficiency of Cas9-directed mutagenesis is low in Drosophila melanogaster Here, we describe a strategy that reduces the time and effort required to identify flies with targeted genomic changes. The strategy uses editing of the white gene, evidenced by altered eye color, to predict successful editing of an unrelated gene-of-interest. The red eyes of wild-type flies are readily distinguished from white-eyed (end-joining-mediated loss of White function) or brown-eyed (recombination-mediated conversion to the whitecoffee allele) mutant flies. When single injected G0 flies produce individual G1 broods, flies carrying edits at a gene-of-interest were readily found in broods in which all G1 offspring carried white mutations. Thus, visual assessment of eye color substitutes for wholesale PCR screening of large numbers of G1 offspring. We find that end-joining-mediated mutations often show signatures of microhomology-mediated repair and that recombination-based mutations frequently involve donor plasmid integration at the target locus. Finally, we show that gap repair induced by two guide RNAs more reliably converts the intervening target sequence, whereas the use of Lig4169 mutants to suppress end joining does not improve recombination efficacy.


New developments in SPME, Part 1: The use of vapor-phase deprotonation and on-fiber derivatization with alkylchloroformates in the analysis of preparations containing amphetamines.
Due to their high polarity and low vapor pressure, most amine salts of amphetamine-type drugs are not directly amenable to headspace recovery using solid-phase microextraction (SPME). Described in this article is a simple vapor-phase procedure for the conversion of solid drug salt samples into their free bases by the use of triethylamine. This process can be conducted simultaneously with headspace SPME, the outcome being that solid drug salts can be sampled directly for GC-MS without the need for dissolution and chemical processing. Potential applications for this methodology include the noninvasive recovery of drug traces from objects such as banknotes and garments. This new process for recovery of amphetamine-type drugs has been combined with on-fiber derivatization using alkylchloroformates. This extra step was included to improve the chromatographic performance of analytes and allow for the resolution of drug enantiomers.


Examination of the potential for using chemical analysis as a surrogate for sensory analysis.
The application of a multi-block statistical analysis method, known as Common Components and Specific Weight Analysis, to the determination of connections between sensory descriptors and analytical data for Hunter Valley Semillon is described. Sixteen wines were used in the data analysis with 15 sensory descriptors and 10 analytical measurements available for each wine. The multi-block analysis simplifies the comparison between the data sets and allows relationships between the sensory and analytical parameters to be readily ascertained, more effectively than a linear regression approach. A sweetness zone established the connections between several sensory descriptors and analytical measurements based on fructose. Glucose was not part of the sweetness connections, although glycerol was connected to the sensory sweetness descriptors. Sensory assessment of acidity was positively related to the titratable acidity and pH was negatively related. The malic acid concentration was also negatively related to sensory acidity and the possible reasons for this are described. Several sensory descriptors including toast, honey and kerosene were found to be in opposition to the sweetness sensory parameters and not connected to any analytical parameters. The outcomes of this multi-block treatment indicate the potential for using analytical measurements as a surrogate for sensory analysis.


Cardiac Surgery in Canada During the COVID-19 Pandemic: A Guidance Statement From the Canadian Society of Cardiac Surgeons.
On March 11, 2020, the World Health Organization declared that COVID-19 was a pandemic.1 At that time, only 118,000 cases had been reported globally, 90% of which had occurred in 4 countries.1 Since then, the world landscape has changed dramatically. As of March 31, 2020, there are now nearly 800,000 cases, with truly global involvement.2 Countries that were previously unaffected are currently experiencing mounting rates of the novel coronavirus infection with associated increases in COVID-19-related deaths. At present, Canada has more than 8000 cases of COVID-19, with considerable variation in rates of infection among provinces and territories.3 Amid concerns over growing resource constraints, cardiac surgeons from across Canada have been forced to make drastic changes to their clinical practices. From prioritizing and delaying elective cases to altering therapeutic strategies in high-risk patients, cardiac surgeons, along with their heart teams, are having to reconsider how best to manage their patients. It is with this in mind that the Canadian Society of Cardiac Surgeons (CSCS) and its Board of Directors have come together to formulate a series of guiding statements. With strong representation from across the country and the support of the Canadian Cardiovascular Society, the authors have attempted to provide guidance to their colleagues on the subjects of leadership roles that cardiac surgeons may assume during this pandemic: patient assessment and triage, risk reduction, and real-time sharing of expertise and experiences.


Consensus report: Preventive measures for Crimean-Congo Hemorrhagic Fever during Eid-al-Adha festival.
Crimean-Congo hemorrhagic fever (CCHF) is endemic in Eurasian countries such as, Turkey, Pakistan, Afghanistan and Iran. CCHF virus is spread by the Hyalomma tick, which is found mainly on cattle and sheep. Muslim countries, in which these animals are sacrificed during Eid-Al-Adha, are among the countries where CCHF is endemic, and it has been observed that CCHF is associated with practices surrounding the Eid-ad-Adha festival. The dates for Eid-Al-Adha drift 10 days earlier in each year according to Georgian calendar. In previous years Eid-al-Adha occurred in autumn-winter months however in the next 10-15 years it will be take place in the summer months when CCHF is more prevalent. This may lead to a rise in the number of cases due to increased dissemination of CCHF virus with uncontrolled animal movements in and between countries. This consensus report focuses on the variable practices regarding animal handling in different regions and possible preventative measures to reduce the incidence of CCHF. Environmental hygiene and personal protection are essential parts of prevention. There is a need for international collaborative preparedness and response plans for prevention and management of CCHF during Eid-Al-Adha in countries where the disease is prevalent.


Comparison of vacuum matrix-assisted laser desorption/ionization (MALDI) and atmospheric pressure MALDI (AP-MALDI) tandem mass spectrometry of 2-dimensional separated and trypsin-digested glomerular proteins for database search derived identification.
Mass spectrometric based sequencing of enzymatic generated peptides is widely used to obtain specific sequence tags allowing the unambiguous identification of proteins. In the present study, two types of desorption/ionization techniques combined with different modes of ion dissociation, namely vacuum matrix-assisted laser desorption/ionization (vMALDI) high energy collision induced dissociation (CID) and post-source decay (PSD) as well as atmospheric pressure (AP)-MALDI low energy CID, were applied for the fragmentation of singly protonated peptide ions, which were derived from two-dimensional separated, silver-stained and trypsin-digested hydrophilic as well as hydrophobic glomerular proteins. Thereby, defined properties of the individual fragmentation pattern generated by the specified modes could be observed. Furthermore, the compatibility of the varying PSD and CID (MS/MS) data with database search derived identification using two public accessible search algorithms has been evaluated. The peptide sequence tag information obtained by PSD and high energy CID enabled in the majority of cases an unambiguous identification. In contrast, part of the data obtained by low energy CID were not assignable using similar search parameters and therefore no clear results were obtainable. The knowledge of the properties of available MALDI-based fragmentation techniques presents an important factor for data interpretation using public accessible search algorithms and moreover for the identification of two-dimensional gel separated proteins.


Breastfeeding, dummy use, and adult intelligence.
Several studies show that children who were breastfed as babies gain higher scores on intelligence tests than those who were bottlefed. Although these findings suggest that breastfeeding in early life may promote cognitive development, their interpretation is complicated by the current association between breastfeeding and higher social class. We investigated the relation between method of feeding in infancy and adult intelligence in a setting where breastfeeding was not linked with socioeconomic advantage. We followed up 994 men and women, born between 1920 and 1930 in Hertfordshire, UK, for whom information on infant feeding had been recorded by health visitors. Intelligence was measured by the AH4 IQ test, taken on a computer. Factors significantly linked with IQ were investigated by multivariate analysis. Study participants who had been exclusively breastfed gained slightly higher scores on the IQ test than those who had been exclusively bottlefed, or fed with both breast and bottle. IQ was lower in participants who had used a dummy (pacifier) in infancy, in those whose fathers were in manual occupations at the time of their birth, and in those whose mothers were young at the time they were born. Scores on the IQ test fell as the number of older siblings increased. In multivariate analysis, after adjustment for the effect of all other variables, no association was found between adult intelligence and method of feeding. Dummy use in infancy, number of older siblings, maternal age at birth of the participant, and father's occupational class remained independent predictors of adult intelligence. The mechanisms that link type of feeding in early life with later intelligence may have more to do with the child's social environment that with the nutritional qualities of the milk.


NF-kappaB/I-kappaB pathway during ischemia reperfusion injury of rat liver.
To determine the role of the NF-kappaB/I-kappaB pathway during ischemia reperfusion (I/R) injury to rat liver. A group of rats underwent partial hepatic ischemia and reperfusion. The left and median lobe of the liver was subjected to ischemia for 90 minutes followed by reperfusion for previously specified periods. NF-kappaB activity was analyzed by electrophoretic mobility shift assay (EMSA). The protein level of I-kappaB was assessed using Western blot analysis. A semiquantitative reverse transcriptase polymerase chain reaction was used to analyze TNF-alpha and ICAM-1 mRNA levels. During liver I/R injury, NF-kappaB activation was induced in a time-dependent fashion. NF-kappaB was activated within 1 hour and 2 hours after the initiation of reperfusion and decreased afer 4 hours. The I-kappaB protein level was decreased in the cytoplasm after 2 hours, and the messenger RNA expression of TNF-alpha and ICAM-1 were increased simultaneously. The data suggest that I-kappaB protein was degraded during hepatic I/R injury, NF kappaB was released and bound to special sequence in the promoters of budget genes, which regulated the expression of TNF-alpha and ICAM-1 mRNA. This provides evidence that the NF-kappaB/I-kappaB pathway plays an important modulating role in the expression of proinflammatory genes relevant to the development of ischemia reperfusion injury.


[Ca2+/H+-exchange mechanisms in myometrial plasmalemma cells].
Transport of 45Ca2+ into vesicules of hog myometrium plasmolemma under dissipation conditions of opposite-directed transmembrane gradient of protons (delta pH) was investigated. When studying some time regularities of the process, H+ dissipation was determined to have little effect on the initial velocity Vo (18 and 25 nmol Ca2+/1 mg of protein per 1 min at delta pH = 0 and delta pH = 1.5, respectively) and the time of semiaccumulation of cation (1.1 and 2.1 min). Estimation of Ca2+ accumulation concentrational dependence in the vesicules in Vo (30 s) revealed that Ca2+ input into vesicules was limited by binding the cation with carboxyl residues of Ca2+ channel external part. This effect is a consequence of the absence of Ca(2+)-transport systems in the vesicules on the background of quick filling of the intervesicular space by the cation as well as discrimination of Ca2+ sorption process by the vesicules inner surface under operating in the Vo regime. The value K0.5 = 0.5 microM for Ca2+ obtained conforms to physiological meaning of the imagined Kd, Ca2+ binding with four glutamate residues of Ca2+ channel external part. Dissipation of the artificial delta pH = 1.5 on the vesicular membrane leads to increasing the affinity for Ca2+ (to 0.1 microM at constant value of Vmax (40 nmol Ca2+/1 mg of protein per 1 min). We have also demonstrated irreversibility of the process tested and substrate specificity. The results obtained permit to suppose that delta pH dissipation provides for some conformational changes of the channel structure resulting in increasing Ca2+ affinity for the transporting system as well as increases the membrane permeability for the cation. The latter means the interrelation of two most important signal molecules such as Ca2+ and H+ in the cell is capable to occur on the level on Ca2+ separate channels.


The Role of Diffusion-Weighted Magnetic Resonance Imaging in the Differentiation of Head and Neck Masses.
The purpose of this study was to evaluate the value of diffusion-weighted MRI (DW-MRI) in differentiating benign and malignant head and neck masses by comparing their apparent diffusion coefficient (ADC) values. The study included 32 patients with a neck mass >1 cm in diameter who were examined with echo planar DW-MRI. Two different diffusion gradients (b values of b = 0 and b = 1000 s/mm²) were applied. DWI and ADC maps of 32 neck masses in 32 patients were obtained. Mean ADC values of benign and malignant neck lesions were measured and compared statistically. A total of 15 (46.9%) malignant masses and 17 (53.1%) benign masses were determined. Of all the neck masses, the ADC value of cystic masses was the highest and that of lymphomas was the lowest. The mean ADC values of benign and malignant neck masses were 1.57 × 10-3 mm²/s and 0.90 × 10-3 mm²/s, respectively. The difference between mean ADC values of benign and malignant neck masses was significant (p < 0.01). Diffusion-weighted MRI with ADC measurements can be useful in the differential diagnosis of neck masses.


Clinical Efficacy of Diet Intervention Combined with Bismuth Potassium Citrate in Helicobacter pylori-Related Chronic Atrophic Gastritis.
To investigate the clinical impact of dietary intervention in combination with bismuth potassium citrate in the management of chronic atrophic gastritis (CAG) caused by Helicobacter pylori. From April 2019 to October 2022, 160 patients with newly identified Helicobacter pylori-related CAG were treated at our facility. They were split into two groups at random: the bismuth potassium citrate medication group (n = 80) and the diet intervention + bismuth potassium citrate experimental groups (n = 80). The bismuth potassium citrate treatment group was given bismuth potassium citrate capsule treatment only, and the diet intervention + bismuth potassium citrate treatment group was given diet intervention based on bismuth potassium citrate capsule. The diet intervention score, symptom score, and pathological score of the two groups were observed at baseline and after treatment, and the relationship between dietary intervention and symptoms and pathology of Helicobacter pylori-related CAG was analyzed. During the baseline period, there was no discernible difference in the diet intervention score, symptom score, or pathology score between the two groups (P > .05); after the diet intervention combination treatment, the diet intervention score, diet intervention + bismuth potassium citrate experimental groups symptom score, and pathology score were considerably lower than those in the bismuth potassium citrate treated group (P < .05). Dietary intervention combined with bismuth potassium citrate exhibited more effective treatment than bismuth potassium citrate-only treatment in Helicobacter pylori-related CAG, which hinted us proper diet has a positive impact on improving the therapeutic efficacy of bismuth potassium citrate.


Analysis of costs and benefits of the Gambian Eye Care Program.
To estimate the net benefit of the Gambian Eye Care Program (GECP) using a limited definition of benefits from a societal perspective. The number of cases of blindness avoided was modeled using population projections, population-based blindness survey estimates from 1986 and 1996, and reported blindness-related mortality differences. Benefits were measured as lifetime productivity gains that resulted from the cases of blindness avoided between the surveys. Costs included all contributions to GECP between the surveys. In 1996, 1658 fewer individuals were blind than would have been without GECP. The present value of costs was 1.28 US million dollars (1995 dollars). Although the net benefit between the blindness surveys was negative, the net lifetime benefit was 1.01 US million dollars (1995 dollars), yielding an internal rate of return of 10%. In the primary sensitivity analysis, assuming similar benefits to Senegalese citizens, who accounted for 30% of patients, the internal rate of return was 19%. Upper bound sensitivity analyses result in internal rates of return higher than 20%. In one sub-Saharan African country with avoidable blindness due to cataract and eye infections, the internal rate of return of a national eye care program was substantial when using a limited definition of benefit.


Seriously ill patients' discussions of preparation and life completion: an intervention to assist with transition at the end of life.
Patients approaching the end of life not only face challenges to physical well-being but also threats to emotional and spiritual integrity. Yet, identifying appropriate, effective, and brief interventions to address those concerns has proven elusive. We developed an intervention based on life review and emotional disclosure literatures and conducted a pilot study to determine feasibility and acceptability. This article presents qualitative intervention responses. We conducted a three-armed randomized control trial to evaluate the effects of preparation and life completion discussion on health outcomes in patients with advanced serious illness. Hospice-eligible subjects were randomly assigned to one of three groups: (1) intervention (life completion discussion intervention), (2) attention control (relaxation meditation), and control (no intervention). Subjects in the intervention arm met with a facilitator three times. Session 1 focused on life story, Session 2 on forgiveness, and Session 3, on heritage and legacy. Eighteen subjects participated in the pilot intervention interviews. Subjects from a range of socioeconomic backgrounds completed the intervention with equal facility. Results from Session 1 demonstrate narrative responses participants gave as they reconnected with previous life roles, values, and accomplishments. The second session illustrated reflections of choices one might have made differently and exploration of forgiveness offered and sought. Content from the first and second sessions laid the foundation for discussing Session 3's lessons learned and heritage and legacy. Responses are summarized to assist clinicians in anticipating life review content that may improve overall quality of life at the end of life. Discussions of life completion may improve important health outcomes for patients at the end of life. This intervention may provide a brief, standardized, and transportable means for improving the quality of life of patients with advanced serious illness.


A multilocus variable number tandem repeat analysis assay provides high discrimination for genotyping Leptospira santarosai strains.
Considering the prevalence of Leptospira santarosai infections in the Americas and the scarce information about the species, we aimed to apply a multilocus variable number tandem repeat (VNTR) analysis (MLVA) for the molecular typing of L. santarosai isolates from various sources. Amplification of three VNTR loci selected from L. santarosai genome sequences resulted in a wide range of sizes for the amplified products amongst the 21 L. santarosai strains analysed. This suggested a variation in tandem repeat copy numbers in the VNTR loci. secY sequencing also showed a high nucleotide diversity, confirming the MLVA data. In conclusion, this novel MLVA provided a high level of discrimination between L. santarosai isolates, and this new typing tool could be used to investigate leptospirosis in regions where L. santarosai predominates.


[The functional characteristics of the immune system, of lipid peroxidation and of the endogenous antioxidant system in miners working in deep coal mines].
A study was made of the condition of the immune status and lipid peroxidation in 77 essentially healthy underground miners of a coal mine that showed a decline in cellular as well as humoral links of immunity and increase in amounts of circulating immune complexes. Moreover, the miners exhibited a rise in conjugated dienes, malonic dialdehyde, and catalase. The workers were divided into groups depending on how difficult were jobs they were assigned to. A relatedness was found out of enhancement of processes of lipid peroxidation and activity of antienzymatic defence to strenuousness of work performed.


Local health department factors associated with performance in the successful implementation of community-based strategies: a mixed-methods approach.
We examined which local health department (LHD)-level factors contributed to successful implementation of policy, systems, and environmental change strategies in Minnesota. We used a retrospective mixed-methods design to evaluate the relationship between the Statewide Health Improvement Plan (SHIP) grant initiative and key predictor variables (2009-2011). We obtained quantitative capacity data for 91 cities and counties in Minnesota; in addition, we conducted 15 key informant interviews to examine factors that facilitated and acted as barriers to LHD performance. Grantee performance was distributed as follows: exceeds expectations (29.7%), meets expectations (55.0%), and is approaching expectations (15.3%). Organizational quality improvement (QI) maturity was strongly positively associated with grantee performance on SHIP. Organizations with high QI maturity, effective leadership, efficient decision-making, and successful regional or cross-jurisdictional partnerships were more likely to be rated as exceeding expectations. This study successfully translated practice-based research findings into tangible outcomes, including new system-level performance measures for local public health and recommendations for shaping the statewide initiative examined in this study. The approach taken in this study to systematically monitor communications, dissemination, and translation may be a model for others.


Effects of Nano-Graphene Oxide on Testis, Epididymis and Fertility of Wistar Rats.
Nanoscale graphene oxide (NGO) has great potential in biomedicine by the virtue of its facile functionalization and tunable characteristics. Toxicity assessments have therefore become essential prior to its biomedical applications. This study examined the effects of NGO exposure on male reproductive function of adult Wistar rats. Rats were exposed intraperitoneally to three increasing doses, namely low-dose (0.4 mg/kg BW), mid-dose (2.0 mg/kg BW) and high-dose (10.0 mg/kg BW) of NGO. Repeated exposure of NGO for 15 and 30 days resulted in decreased epididymal sperm counts and elevated sperm abnormalities. Percentage of motile sperms was also significantly reduced due to the exposure. Activities of SOD, GPx and malondialdehyde concentration in the testes increased in a dose-specific manner. Results of the study demonstrated that high-dose of NGO resulted in considerable histological damage to testicular tissue which included atrophy of seminiferous tubules with reduction in germinal epithelium, germ cell loss and vacuolization. Low and mid-doses of NGO were not associated with sperm dysfunction or testis damage. Withdrawal of treatment for 30 days demonstrated significant recovery potential. Histology of epididymis and male fertility potential were not affected due to the NGO exposure. These findings are important for assessment of the risk involved in manufacturing, use and processing of the graphene oxide-based materials towards male reproductive function.


Future Directions for Hypothermia following Severe Traumatic Brian Injury.
Traumatic brain injury (TBI) is a serious health care problem on both individual and public health levels. As a major cause of death and disability in the United States, it is associated with a significant economic and public health burden. Although the evidence to support the use of induced hypothermia on neurologic outcome after cardiac arrest is well established, its use in treating TBI remains controversial. Hypothermia has the potential to mitigate some of the destructive processes that occur as part of secondary brain injury after TBI. Hypothermia can be helpful in lowering intracranial pressure, for example, but its influence on functional outcome is unclear. There is insufficient evidence to support the broad use of prophylactic hypothermia for neuroprotection after TBI. Investigators are beginning to more carefully select patients for temperature modulating therapies, in a more personalized approach. Examples include targeting immunomodulation and scaling hypothermia to achieve metabolic targets. This review will summarize the clinical evidence for the use of hypothermia to limit secondary brain injury following acute TBI.


The visual contour in depth.
We asked subjects to match points on the surface of a smooth three-dimensional (3-D) shape with points on the surface of another object that was geometrically identical to the first object but was placed in a different pose, was differently textured, and was differently shaded. In all cases, the fiducial point was on the rim of one of the objects (i.e., the boundary of the visible region of the surface), whereas the matching point was well within the silhouette of the other object. This allowed us to draw (preliminary) conclusions concerning the way monocular human observers are able to handle the neighborhood of the rim, where the local slant assumes arbitrarily high values. All experiments were done in real space with real objects (no computer-simulated scenes), the points being indicated with laser beam illumination. The subject was given control over the direction of the laser beams and was thus able to perform the task by adjustment from the vantage position. We studied both consistency (whether the subject's judgments were invariant against changes of relative pose) and veridicality (whether the depth of the visual contour as calculated from the settings agreed with the true distance as measured by mechanical means). Subjects caught much of the 3-D structure of the contour but did deviate appreciably and apparently idiosyncratically from the true geometry.


Compounding pharmacies: who is in charge?
Compounding pharmacies play an increasing and increasingly important role in our healthcare system, but recent media attention has exposed limited regulatory control over these organizations at the same time their role is expanding. Compounding pharmacies are not regulated in the same manner as pharmaceutical companies and are governed largely by Chapter <797>, a monograph on the pharmaceutical compounding of sterile products, issued but not enforced by the U.S. Pharmacopeial Convention. Not all states require adherence to Chapter <797>, and those that do may choose not to enforce it stringently. Furthermore, Chapter <797> is not a strong standard--for example, it does not require documentation of drug lot numbers or cross-references for patient identification. Thus, there have long been many potential quality issues associated with compounding pharmacies. As these compounding pharmacies provide important products and services, better regulation is urgently needed. Moreover, clinicians should be better aware that some injectable products they use may have been prepared by a compounding pharmacy.


Dissociating haptic feedback from physical assistance does not improve motor performance.
In robots for motor rehabilitation and sports training, haptic assistance typically provides both mechanical guidance and task-relevant information. With the natural human tendency to minimise metabolic cost, mechanical guidance may however prevent efficient short term learning and retention. In this work, we explore the effect of providing haptic feedback to the not active hand during a tracking task. We test four types of haptic feedback: task- or error-related information, no information and irrelevant information. The results show that feedback provided to the hand not carrying out the tracking task did not improve task performance. However, irrelevant information to the task worsened performance, and negatively influenced the participants' perception of helpfulness, assistance, likability and predictability.


Third- and second-harmonic generation microscopy of individual metal nanocones using cylindrical vector beams.
We demonstrate third- (THG) and second-harmonic generation (SHG) microscopy of individual silver nanocones using tightly focused cylindrical vector beams (CVBs). Although THG is expected to be a weaker process than SHG, the yield for THG with radial polarization was higher than for SHG. We also found an excellent correlation between the imaging properties of THG and SHG, suggesting that both are governed by the same overall features of the individual nanocone. We also found that the transverse spatial resolution of THG with CVBs, particularly RP, exceeds that of SHG. Our work establishes the potential of THG microscopy with CVBs for structure-sensitive imaging of three-dimensional (3D) metal nano-objects.


Persistent primitive trigeminal artery: a review.
The trigeminal artery is the largest of the fetal carotid-basilar anastomotic arteries, and it persists for the longest embryonic period. The artery usually involutes after the development of the posterior communicating artery. The exact causes of persistence of this primitive vessel into adulthood are not completely clear. Angiographic and anatomical descriptions of the various persistent trigeminal artery (PTA) configurations and their relation to the remainder of the cerebrovascular tree and the other surrounding structures have been reported. Persistent trigeminal artery can be associated with many other vascular anomalies and disorders including aneurysms, arteriovenous malformations and carotid-cavernous fistulae. A thorough understanding of the anatomical and angiographic features of this persistent embryonic arterial channel is of utmost importance when making therapeutic decisions and embarking on surgical or endovascular intervention for any pertinent pathological condition. We review the embryology, angiographic features, microsurgical anatomy and associated vascular anomalies and disorders of the persistent trigeminal artery.


Hemochromatosis gene mutations may affect the survival of patients with myelodysplastic syndrome.
The recent availability of potent oral iron chelators is renewing an interest in the assessment of the possible impact of HFE genetics in MDS. Thirty six newly diagnosed patients with MDS were studied for parameters of iron metabolism in addition to C282Y and H63D mutations of the HFE gene. Mutations were present in 11 out of 36 patients (31%), which were not different from our general population and were equally distributed among MDS subtypes. Mutated patients had higher ferritin levels (P = 0.039) and lower TIBC (P = 0.018). Ferritin was found to be higher for the untransfused mutated patients (P = 0.017), but not for transfusion-dependent patients in whom ferritin levels correlated significantly with the number of blood units received (P = 0.04). There was no difference in the number of blood units received between the mutated and wild type patients. A new observation made was that the mutated patients had a lower overall survival in addition to a poorer leukemia free survival (LFS) (P = 0.004 and P = 0.003, respectively). The HFE gene mutations are not more frequent in MDS patients. Iron overload in mutated patients was higher but there was no correlation found using supportive therapy for anemia. The effect of mutations on survival could be mediated by changes in iron metabolism. The HFE genotype may predict MDS prognosis and there is a need for further studies. It remains a challenging question if HFE mutated MDS patients should be considered for potent iron chelation therapy.


Ovarian carcinoma initially presenting as metastatic axillary lymphadenopathy.
Ovarian carcinoma usually presents at advanced stage due to diffuse intraabdominal disease. Presenting signs and symptoms often relate to the degree of intraabdominal spread. It is rare to have distant lymph node metastases, in conjunction with minimal intraabdominal disease, at initial presentation. A 78-year-old woman was noted to have an enlarged axillary lymph node on a routine, screening mammogram. Biopsy revealed metastatic adenocarcinoma, consistent with primary breast cancer. Physical examination, diagnostic mammogram, and magnetic resonance imaging of the breasts were normal. A pelvic computed tomography scan revealed a 7-cm complex, right adnexal mass. At exploratory laparotomy, there was minimal intraabdominal tumor burden; only a 6-cm right ovarian tumor and a single 1.0-cm nodule adherent to the bladder peritoneum were found. After optimal cytoreductive surgery, she received tamoxifen for presumed metastatic breast cancer. One year later, recurrent disease developed in the pelvis. After reexploration and excision of all gross pelvic disease, a revised diagnosis of recurrent ovarian cancer was made, and therapy was changed to carboplatin and paclitaxel chemotherapy. The patient is currently without evidence of disease. Ovarian carcinoma usually presents with signs and symptoms related to the tumor burden within the peritoneal cavity. The finding of isolated, distant metastatic lymphadenopathy with minimal intraabdominal disease is very unusual. Immunohistochemical tumor markers can help determine the origin of a metastatic adenocarcinoma when the clinical presentation is atypical.


Newer insights on the mechanism of heparin-induced thrombocytopenia.
Heparin-induced thrombocytopenia (HIT) type II is a complex clinical syndrome. It is an immune reaction to heparin in which the formation of antibodies targeted against the heparin-platelet factor 4 complex results in platelet activation. Platelet activation plays a central role in HIT; however, platelet activation does not occur as an isolated physiologic response. To elucidate further the mechanism of thrombogenesis in HIT, we undertook studies to determine the effect of heparin antibodies on endothelial cells, leukocytes, and the inflammatory state. We summarize our previous and new findings. For endothelial cells: Antiheparin antibodies bind to and directly activate microvascular endothelial cells, whereas binding to and activating macrovascular endothelial cells requires preactivation by platelets or tumor necrosis factor alpha (TNFalpha). Increased circulating levels of hemostatic activation factors as observed with thrombosis, particularly soluble P-selectin, plasminogen activator inhibitor type 1 (PAI-1), tissue factor, and thrombomodulin, were associated with endothelial cell activation and were also found in the blood circulation of patients with HIT. For the inflammatory state: Neutrophils and monocytes (but not lymphocytes) bind to and form complexes with platelets in the presence of HIT antibodies. Activated monocytes bind to endothelial cells and produce a procoagulant state. Patients with HIT have an increased level of cytokines in their blood circulation. For HIT antibodies: Only heparin fractions larger than 5 kd interacted with HIT antibodies, explaining why low-molecular-weight heparin (LMWH) usually does not generate antibodies. HIT antibodies are heterogeneous in structure, affinity, and specificity. These data suggest that, in addition to the platelet component, several other mechanisms are associated with the pathophysiology of HIT. These include an inflammatory state, endothelial cell remodeling, and the known procoagulant state. Differences between patients in the levels of the inflammatory markers may relate to various stages of the inflammatory/procoagulant state that exists in patients with HIT. The variations within the HIT antibodies may influence their ability to activate platelets, endothelial cells, and leukocytes, and thus contribute further to the variations in the pathogenicity of HIT.


Chemical eye injuries: presentation and management difficulties.
To review the pattern of presentation and management difficulty of patients with ocular chemical bums. Retrospective study of all patients with ocular burns seen over 8-year period (March 1998-April 2006) in the eye clinic as well as the plastic and reconstructive surgery unit of our hospital. Case files were retrieved and relevant information extracted and analyzed. There were a total of 23 patients (n=33 eyes) seen in the period under review consisting of 19 males and 4 females. The age ranged from 6-52 years with mean age of 31.87years. The chemical injuries were accidental in 73.9% of the cases and of these 76.5% were work related. The remaining 26.1% resulting from assault were bilateral and led to blindness in all the patients. Main injurious agents were acid and alkali. Major cause of chemical injury was work related; although blindness and disability occurred more in the cases of assault. Occupational health issues need a revisit, preparedness of health institutions to take adequate care of people with ocular burns is presently poor.


The Marulu Strategy 2008-2012: overcoming Fetal Alcohol Spectrum Disorder (FASD) in the Fitzroy Valley.
Aboriginal leaders concerned about high rates of Fetal Alcohol Spectrum Disorder (FASD) in the Fitzroy Valley, remote north-western Australia, introduced restrictions on access to take-away full-strength alcohol. Following this, Aboriginal leaders engaged strategic partners in a broader strategy to address FASD in the region. The aim of this study was to develop and implement a community-led, researcher-supported, FASD strategy. A review of literature focusing on community-led FASD strategies identified key components that informed the Marulu FASD strategy. These included strategy ownership, leadership, and governance by participating communities, and a research framework. Community meetings and workshops led to the development of The Marulu FASD Strategy (2008). Feasibility and community consent to conduct a FASD prevalence study (the Lililwan Project) was confirmed, and implementation was progressed (2010-2013). Concurrent FASD prevention activities were conducted. In 2012, the Marulu FASD Unit was established within a local Aboriginal organisation to sustain and coordinate ongoing strategy activities. Community control of public health initiatives can be achieved when Aboriginal communities prioritise issues of significant concern, and engage strategic partners to overcome them. Implications for public health: The Marulu Strategy forms a template for action to address FASD and other public health issues in Aboriginal communities in Australia and internationally.


Higher efficiency of the liver phosphorylative system in diabetic Goto-Kakizaki (GK) rats.
Liver mitochondrial bioenergetics of Goto-Kakizaki (GK) rats (a model of non-insulin dependent diabetes mellitus) reveals a Delta Psi upon energization with succinate significantly increased relatively to control animals. The repolarization rate following ADP phosphorylation is also significantly increased in GK mitochondria in parallel with increased ATPase activity. The increase in the repolarization rate and ATPase activity is presumably related to an improved efficiency of F(0)F(1)-ATPase, either from a better phosphorylative energy coupling or as a consequence of an enlarged number of catalytic units. Titrations with oligomycin indicate that diabetic GK liver mitochondria require excess oligomycin pulses to completely abolish phosphorylation, relative to control mitochondria. Therefore, accepting that the number of operational ATP synthase units is inversely proportional to the amount of added oligomycin, it is concluded that liver mitochondria of diabetic GK rats are provided with extra catalytic units relative to control mitochondria of normal rats. Other tissues (kidney, brain and skeletal muscle) were evaluated for the same bioenergetic parameters, confirming that this feature is exclusive to liver from diabetic GK rats.


Health financing and insurance reform in Morocco.
The government of Morocco approved two reforms in 2005 to expand health insurance coverage. The first is a payroll-based mandatory health insurance plan for public- and formal private-sector employees to extend coverage from the current 16 percent of the population to 30 percent. The second creates a publicly financed fund to cover services for the poor. Both reforms aim to improve access to high-quality care and reduce disparities in access and financing between income groups and between rural and urban dwellers. In this paper we analyze these reforms: the pre-reform debate, benefits covered, financing, administration, and oversight. We also examine prospects and future challenges for implementing the reforms.


Controlling Lanthanide Exchange in Triple-Stranded Helicates: A Way to Optimize Molecular Light-Upconversion.
The kinetic lability of hexadentate gallium-based tripods is sufficient to ensure thermodynamic self-assembly of luminescent heterodimetallic [GaLn(L3)3 ]6+ helicates on the hour time scale, where Ln is a trivalent 4f-block cation. The inertness is, however, large enough for preserving the triple-helical structure when [GaLn(L3)3 ]6+ is exposed to lanthanide exchange. The connection of a second gallium-based tripod further slows down the exchange processes to such an extent that spectroscopically active [CrErCr(L4)3 ]9+ can be diluted into closed-shell [GaYGa(L4)3 ]9+ matrices without metal scrambling. This feature is exploited for pushing molecular-based energy-transfer upconversion (ETU) at room temperature.


Structural analysis of the chicken BRCA2 gene facilitates identification of functional domains and disease causing mutations.
Carriers of mutations in the BRCA2 gene have a high risk of developing breast and other cancers. The BRCA2 gene, which is located on human chromosome 13, encodes a very large protein of only poorly understood function. To define regions of sequence conservation and highlight potentially functionally important domains, we have cloned and characterized the chicken BRCA2 gene, the first non-mammalian BRCA2 gene to be described. The gene is organized similarly to the human BRCA2 gene, but is more compact and is localized to the subtelomeric region of chicken chromosome 1q, within a region that contains other genes from human chromosome 13. The chicken BRCA2 gene encodes a protein of 3399 amino acids, which is poorly conserved with mammalian BRCA2 proteins, having only 37% amino acid identity overall with human BRCA2. However, certain domains are much more highly conserved, indicating functional significance. We describe genes with some of these conserved domains in organisms as diverse as intracellular parasites, mosquitoes and plants. The evolutionarily divergent chicken BRCA2 sequence may also be useful in assigning the large number of sequence variants that have been described in the human BRCA2 gene which are of unknown significance in disease causation.


Optimizing rapid aiming behaviour: Movement kinematics depend on the cost of corrective modifications.
Recent studies have shown that the initial impulse associated with goal-directed aiming movements typically brings the limb to a position short of the target. This is because target overshooting is associated with greater temporal and energy costs than target undershooting. Presumably these costs can be expected to vary not only with the muscular forces required to move the limb, but also the gravitational forces inherent in the aiming task. In this study we examined the degree to which primary movement endpoint distributions depend on the direction of the movement with respect to gravity. We hypothesized that the magnitude of an undershoot bias would be greatest for downward movements because target overshooting necessitates a time and energy consuming movement reversal against gravity. Participants completed rapid aiming movements toward targets located above and below, as well as proximal and distal to a central home position. Movements were made both with and without additional mass attached to the limb. Although movement time did not vary with experimental condition, primary movement endpoint distributions were consistent with our predictions. Specifically, both greater undershooting and greater endpoint variability was associated with downward aiming movements. As well, a greater proportion of the overall movement time was spent in the corrective phase of the movement. These results are consistent with models of energy minimization that posit an inherent efficiency of control and hold that movements are organized to minimize movement time and energy expenditure and maximize mechanical advantages.


Patient-reported acute GI symptoms in locally advanced cervical cancer patients correlate with rectal dose.
To investigate relationships between patient-reported acute gastro-intestinal symptoms in a locally advanced cervical cancer (LACC) prospective cohort and clinical and dosimetric parameters, while also taking spatial dose into account. A total of 103 patients was included, receiving radiotherapy based on a plan-library-based plan-of-the-day protocol, combined either with concurrent chemotherapy or with neo-adjuvant chemotherapy and concomitant hyperthermia. Toxicity endpoints were extracted from questionnaires sent out weekly during treatment and regularly in the acute phase after treatment. Endpoints were defined for symptoms concerning obstipation, diarrhea, fecal leakage, bowel cramps and rectal bleeding. Dose surface maps were constructed for the rectum. Clinical parameters and dosimetric parameters of the bowel bag and rectum were collected for all patients. The use of concomitant chemotherapy and an increase in Planning Target Volume (PTV) resulted in a significant increase in reported diarrhea. The dose-volume parameters V5Gy-V25Gy of the rectum were found to be significant, unlike dose-volume parameters of the bowel bag. Additionally, a significantly higher dose to the inferior part of the rectum was found for patients reporting diarrhea. No significance was reached for fecal leakage and bowel cramps. The significance of results for patients reporting diarrhea symptoms found for PTV volume indicates a potential benefit for a plan-of-the-day protocol. Additionally, the results suggest that a reduction of inferior rectum dose could decrease patient-reported diarrhea symptoms, while the administration of concomitant chemotherapy appears to lead to radiosensitizing effects that increase these symptoms.


An analysis of patient safety incident reports describing injuries to staff working in critical care in the North West of England between 2009 and 2013.
Critical care environments are potentially high-risk areas for staff harm due to procedural demand and increased incidence of delirium/dependence. The principal types of harm and temporal trends have not yet been quantified. Retrospective analysis of a multicentre dataset prospectively collected over a five-year period. All patient safety incidents reported to a regional network project were analysed; those recorded as staff harm were extracted, quantified and assessed by thematic analysis to identify key areas of harm, temporal trends and incident rates. Staff harm accounted for 7% of all reported patient safety incidents over the study period. Incident rates remained static, ranging annually from 2.6 to 3.7 episodes/1000 patient days. Assaults on staff accounted for the highest proportional contribution on thematic analysis, which was a consistent annual finding. Sharps injuries and manual handling incidents were also notable contributions. Temporal trends for each theme remained static over the study period implying limited reduction in staff harm despite implementation of national guidance and local initiatives. Staff harm is a consistent issue for those working in critical care. Assaults on staff appear to be the highest contributor on thematic analysis. These data imply significant reduction in harm can still be achieved and can be used to design and implement interventional measures.


Synthetic osmotic dilators in the induction of labour-An international multicentre observational study.
To evaluate the effects of synthetic osmotic dilators (Dilapan-S/ Dilasoft) in women who required induction of labour in a large prospective multicentre international observational study. Primary outcomes were duration of Dilapan-S/Dilasoft insertion (hours), total induction - delivery interval (hours) and the rate of vaginal deliveries within 24 h (%). Secondary outcomes were the number of dilators inserted, Bishop score increase after extraction of Dilapan-S/Dilasoft, complications during induction (uterine contractions, uterine tachysystole and hyperstimulation, effect on the fetus) and post induction (infections and neonatal outcomes), agents / procedures used for subsequent induction of labour, immediate rate of spontaneous labours following cervical ripening period, rate of spontaneous vaginal deliveries, rate of instrumental vaginal deliveries and caesarean sections. Total of 543 women were recruited across 11 study sites, of which, 444 women were eligible for analysis. With Dilapan-S/Dilasoft use of <12 h (n = 188) the overall vaginal delivery rate was 76.6% with 45.7% of these births occurring within 24 h, 66% within 36 h and 75.5% within 48 h from insertion of Dilapan-S/Dilasoft. The mean insertion-delivery interval for this group was 24.3(±10.4) hours. With Dilapan-S/Dilasoft use of >12 h (n = 256), the overall vaginal delivery rate was 64.8%, with 16% of these births occurring within 24 h, 48.4% within 36 h and 54.7% within 48 h from insertion of Dilapan-S/Dilasoft. The mean insertion-delivery interval for this group was 39.1(±29.2) hours. The mean gain in the Bishops score was +3.6(±2.3). The mean number of Dilapan-S/Dilasoft dilators used was 3.8 (±1.1). The overall rate of caesarean section was 30.1%. The overall complication rate was low including infection risk. No adverse neonatal outcome was attributable to the use of Dilapan-S/Dilasoft. Dilapan-S/Dilasoft are safe and effective methods for cervical ripening. Their use is associated with low maternal and neonatal complication rates. Future research should aim at level I clinical trials comparing Dilapan-S to other mechanical or pharmacological cervical ripening agents. https://clinicaltrials.gov/ct2/show/NCT02318173.


Selective interaction of lansoprazole and astemizole with tau polymers: potential new clinical use in diagnosis of Alzheimer's disease.
We describe the interactions of two benzimidazole derivatives, astemizole (AST) and lansoprazole (LNS), with anomalous aggregates of tau protein (neurofibrillary tangles). Interestingly, these compounds, with important medical applications in the treatment of allergies and gastrointestinal disorders respectively, specifically bind to aggregated variants of tau protein and to paired helical filaments isolated from brains of Alzheimer's disease (AD) patients. These ligands appear to be a powerful tool to tag brain-isolated tau-aggregates and heparin-induced polymers of recombinant tau. The interactions of AST and LNS with tau aggregates were assessed by classical radioligand assays, surface plasmon resonance, and bioinformatic approaches. The affinity of AST and LNS for tau aggregates was comparatively higher than that for amyloid-beta polymers according to our data. This is relevant since senile plaques are also abundant but are not pathognomonic in AD patients. Immunochemical studies on paired helical filaments from brains of AD patients and surface plasmon resonance studies confirm these findings. The capacity of these drugs to penetrate the blood-brain barrier was evaluated: i) in vitro by parallel artificial membrane permeability assay followed by experimental Log P determinations; and ii) in vivo by pharmacokinetic studies comparing distribution profiles in blood and brain of mice using HPLC/UV. Importantly, our studies indicate that the brain/blood concentration ratios for these compounds were suitable for their use as PET radiotracers. Since neurofibrillary tangles are positively correlated with cognitive impairment, we concluded that LNS and AST have a great potential in PET neuroimaing for in vivo early detection of AD and in reducing the formation of neurofibrillary tangles.


Pharmacologic and nonpharmacologic therapies for stroke prevention in nonvalvular atrial fibrillation.
Thromboembolism is the crucial cause of ischemic stroke in patients with atrial fibrillation (AF). Anticoagulation therapy with vitamin K antagonists, such as warfarin, have been proven to be effective for stroke prevention in AF. Nonetheless, the use of warfarin may be limited due to increased risk of bleeding, the potential interaction with multiple foods and drugs, and the need for routine coagulation monitoring. Over the last decade anticoagulants, such as dabigatran and rivaroxaban, have been developed and have shown superiority compared to warfarin for preventing stroke in patients with nonvalvular AF in large randomized trials. In addition, on account of the risk of thrombus formation in the left atrial appendage (LAA), many nonpharmacologic approaches have been developed to reduce stroke risk in patients with AF who are not candidates for anticoagulant therapy. Surgical, epicardial, and endovascular techniques for LAA closure are being investigated currently. Both novel pharmacotherapy and nonpharmacologic approaches for stroke prevention will be detailed in this review.


The use of restricted mean survival time to estimate the treatment effect in randomized clinical trials when the proportional hazards assumption is in doubt.
In most randomized clinical trials (RCTs) with a right-censored time-to-event outcome, the hazard ratio is taken as an appropriate measure of the effectiveness of a new treatment compared with a standard-of-care or control treatment. However, it has long been known that the hazard ratio is valid only under the proportional hazards (PH) assumption. This assumption is formally checked only rarely. Some recent trials, particularly the IPASS trial in lung cancer and the ICON7 trial in ovarian cancer, have alerted researchers to the possibility of gross non-PH, raising the critical question of how such data should be analyzed. Here, we propose the use of the restricted mean survival time at a prespecified, fixed time point as a useful general measure to report the difference between two survival curves. We describe different methods of estimating it and we illustrate its application to three RCTs in cancer. The examples are graded from a trial in kidney cancer in which there is no evidence of non-PH, to IPASS, where the opposite is clearly the case. We propose a simple, general scheme for the analysis of data from such RCTs. Key elements of our approach are Andersen's method of 'pseudo-observations,' which is based on the Kaplan-Meier estimate of the survival function, and Royston and Parmar's class of flexible parametric survival models, which may be used for analyzing data in the presence or in the absence of PH of the treatment effect.


Abolition of prescription copayments in Wales: an observational study on dispensing rates.
To assess effects of abolition of prescription copayments in Wales on rates of dispensing. General practice-level monthly dispensing data were compared before/after abolition between Wales and North East (NE) England where the charge was retained. Data for 14 medicines that had most items dispensed subject to charge before abolition were similarly compared with NE England. For those with over-the-counter substitutes, wholesale sales to pharmacies were examined. A survey examined local initiatives, which might differentially affect dispensing between the two areas. Total dispensing rates (items/1000 patients) increased significantly in both areas but significantly less so in Wales (difference = -19.7, P = 0.024, 95% confidence interval [CI] = -36.7 to -2.6). For the 14 selected medicines, combined dispensing rates increased significantly in both areas but significantly more in Wales (difference = 27.51, P < 0.0001, 95% CI = 23.66-31.35). There was much variation for individual drugs, but categories tended to show this same trend except for antibiotics, where rates increased in Wales but decreased in NE England. The survey revealed few local initiatives that could explain these differences. Sales of over-the-counter substitutes did not explain the changes in dispensing. The Welsh policy was associated with a modest increase in dispensing rates relative to NE England for the 14 medicines with the highest number of items dispensed subject to charge before abolition. Although factors besides the copayment may have influenced these observations, the smaller relative increase in total dispensing rates in Wales suggests that the overall impact of abolition was minimal.


Lasting treatment effects in a postmarketing surveillance study of prolonged-release melatonin.
Surveillance studies are useful to evaluate how a new medicinal product performs in everyday treatment and how the patient who takes it feels and functions, thereby determining the benefit/risk ratio of the drug under real-life conditions. Prolonged-release melatonin (PRM; Circadin) was approved in Europe for the management of primary insomnia patients age 55 years or older suffering from poor quality of sleep. With traditional hypnotics (e.g. benzodiazepine-receptor agonists), there are concerns about rebound insomnia and/or withdrawal symptoms. We report data from a postmarketing surveillance study in Germany on the effects of 3 weeks of treatment with PRM on sleep in patients with insomnia during treatment and at early (1-2 days) and late (around 2 weeks) withdrawal. In total, 653 patients (597 evaluable) were recruited at 204 sites (mean age 62.7 years, 68% previously treated with hypnotics, 65% women). With PRM treatment, the mean sleep quality (on a scale of 1-5 on which 1 is very good and 5 is very bad) improved from 4.2 to 2.6 and morning alertness improved from 4.0 to 2.5. The improvements persisted over the post-treatment observation period. Rebound insomnia, defined as a one-point deterioration in sleep quality below baseline values, was found in 3.2% (early withdrawal) and 2.0% (late withdrawal). Most of the patients (77%) who used traditional hypnotics before PRM treatment had stopped using them and only 5.6% of naive patients started such drugs after PRM discontinuation. PRM was well tolerated during treatment and the most frequently reported adverse events were nausea (10 patients, 1.5%), dizziness, restlessness and headache (five patients each, <1%). There were no serious adverse events and no adverse events were reported after discontinuation. The persisting treatment effect and very low rebound rate suggest a beneficial role of sleep-wake cycle stabilization with PRM in the treatment of insomnia.


Effects of cellular acidification on ADH-induced intramembrane particle aggregates.
8-Bromoadenosine 3',5'-cyclic monophosphate [an analogue of adenosine 3',5'-cyclic monophosphate (cAMP), the intracellular mediator for antidiuretic hormone (ADH) action] induces, in frog urinary bladder, an increase in water permeability that is rapidly and reversibly inhibited by cellular acidification. The effect of CO2 bubbling on the simultaneously observed intramembranous particle aggregates, which probably represent water channels, depended on the time that elapsed after changing medium pH: 3 min of CO2 bubbling depressed the water flux by 70%, whereas the membrane surface occupied by the aggregates remained unchanged. On the contrary, after 9-15 min of CO2 bubbling, both the water flux and the surface area occupied by the aggregates were strongly reduced. These results can be interpreted by accepting two post-cAMP levels of action for cellular acidification: 1) the channels themselves that, as previously suggested by ADH experiments at low temperature, would shift their structure from an "open" to a "closed" state, and 2) the mechanism that controlled the aggregates' plug in and removal.


[Quality assurance of Doppler sonographic procedures--educational concepts of medical programs].
The example of diagnostic ultrasound, particularly the one of Doppler sonography, demonstrate how programmes of postgraduate training and on measures for quality assurance including documentation must be integrated to a common concept. The introduction of sonography as a group of novel non-invasive techniques offers the opportunity to re-consider existing concepts of postgraduate training.


[Optimization of cardiovascular function by peptide bio-regulators].
Effects of peptide bioregulators (thymaline, epithalamine, cortexine) on systemic hemodynamics in cardiovascular and cerebrovascular affections were studied. Assessment of functional stability and quality of cardiovascular system regulation was made according to methodological principles of automatic regulation theory. Peptide bioregulators showed high effectiveness in the above patients who markedly improved their hemodynamic parameters.


Modification of avoidance responding by amphetamine and dopamine receptor antagonists.
This study was designed to investigate the effects of preferential D1 (SCH 23390) and D2 (haloperidol) dopamine (DA) receptor antagonists and their interaction with low-dose (1 mg kg) D-amphetamine during the acquisition of two-way shuttle avoidance in rats. In the course of training, the dissociation of drug effects on response latencies was observed. Haloperidol (0.05 mg/kg) caused significant reduction in the frequency of short-latency avoidance responses that was only partially compensated by concomitant amphetamine administration. In contrast, SCH 2339 (0.025 mg/kg) did not affect the frequency of short-latency responses but lowered probability of avoidances emitted toward the end of 5 s interval between the onsets of conditoned and unconditioned stimuli (CS-UCS interval). Amphetamine compensated for this impairment by increasing frequency of short-latency avoidances well above the control level. These results argue for different nature of short- and long-latency avoidance responses, and suggest involvement of DA D2 receptors in the process of response initiation facilitated by amphetamine. Interestingly, a profound behavioral breakdown was observed under higher dose of SCH 23390 (0.05 mg/kg), but only when applied together with amphetamine. The latter result seems to confirm the notion that behavioral output of dopaminergic transmission may depend more on the balance between D1 and D2 receptors than on the independent modulation of particular receptor system.


High-Throughput 3D Ensemble Characterization of Individual Core-Shell Nanoparticles with X-ray Free Electron Laser Single-Particle Imaging.
The structures as building blocks for designing functional nanomaterials have fueled the development of versatile nanoprobes to understand local structures of noncrystalline specimens. Progress in analyzing structures of individual specimens with atomic scale accuracy has been notable recently. In most cases, however, only a limited number of specimens are inspected lacking statistics to represent the systems with structural inhomogeneity. Here, by employing single-particle imaging with X-ray free electron lasers and algorithms for multiple-model 3D imaging, we succeeded in investigating several thousand specimens in a couple of hours and identified intrinsic heterogeneities with 3D structures. Quantitative analysis has unveiled 3D morphology, facet indices, and elastic strain. The 3D elastic energy distribution is further corroborated by molecular dynamics simulations to gain mechanical insight at the atomic level. This work establishes a route to high-throughput characterization of individual specimens in large ensembles, hence overcoming statistical deficiency while providing quantitative information at the nanoscale.


Dissecting the recruitment and self-organization of αSMA-positive fibroblasts in the foreign body response.
The foreign body response (FBR) is a clinically relevant issue that can cause malfunction of implanted medical devices by fibrotic encapsulation. Whereas inflammatory aspects of the FBR have been established, underlying fibroblast-dependent mechanisms remain unclear. We here combine multiphoton microscopy with ad hoc reporter mice expressing α-smooth muscle actin (αSMA) protein to determine the locoregional fibroblast dynamics, activation, and fibrotic encapsulation of polymeric materials. Fibroblasts invaded as individual cells and established a multicellular network, which transited to a two-compartment fibrotic response displaying an αSMA cold external capsule and a long-lasting, inner αSMA hot environment. The recruitment of fibroblasts and extent of fibrosis were only incompletely inhibited after depletion of macrophages, implicating coexistence of macrophage-dependent and macrophage-independent mediators. Furthermore, neither altering material type or porosity modulated αSMA+ cell recruitment and distribution. This identifies fibroblast activation and network formation toward a two-compartment FBR as a conserved, self-organizing process partially independent of macrophages.


Screening of transcriptionally regulated genes following iron chelation in human astrocytoma cells.
Deferoxamine is an effective iron chelator and a potential therapeutic agent for use in minimizing free radical-mediated injury following trauma. Iron chelation may also be an effective means of limiting tumor growth by decreasing bioavailable iron. Deferoxamine can modulate gene expression through manipulation of intracellular iron levels; specifically at the posttranscription level by changing the activity of iron regulatory proteins (IRPs). The effect of iron chelation on the transcription of genes is still unclear, but iron-binding sites on DNA have been reported. Here we investigate the influence of deferoxamine on gene transcription. Two-directional (forward and backward) suppression subtraction hybridization (SSH) was performed on human astrocytoma cells (SW1088) cultured in either standard media or treated for 48 hours with deferoxamine. To restrict the number of false-positive clones, reverse Northern blotting was used to further verify the differentially expressed cDNA clones. Positive clones were sequenced and the mRNAs were re-examined on Northern blots for changes in expression over time of deferoxamine exposure. The results of these analyses have identified both novel and known genes whose expression is influenced by iron chelation. The known genes include a group related to energy production and a group related to protease function. These results provide examples of genes not previously known to be directly influenced by iron availability, and as such may be potential targets for iron chelation therapy.


Development and validation of a multiplex UHPLC-MS/MS assay with stable isotopic internal standards for the monitoring of the plasma concentrations of the antiretroviral drugs bictegravir, cabotegravir, doravirine, and rilpivirine in people living with HIV.
The widespread use of highly active antiretroviral treatments has dramatically changed the prognosis of people living with HIV (PLWH). However, such treatments have to be taken lifelong raising issues regarding the maintenance of both therapeutic effectiveness and long-term tolerability. Recently approved or investigational antiretroviral drugs present considerable advantages, allowing once daily oral dosage along with activity against resistant variants (eg, bictegravir and doravirine) and also parenteral intramuscular administration that facilitates treatment adherence (eg, long-acting injectable formulations such as cabotegravir and rilpivirine). Still, there remains a risk of insufficient or exaggerated circulating exposure due to absorption issues, abnormal elimination, drug-drug interactions, and others. In this context, a multiplex ultra-high performance liquid chromatography coupled to tandem mass spectrometry (UHPLC-MS/MS) bioassay has been developed for the monitoring of plasma levels of bictegravir, cabotegravir, doravirine, and rilpivirine in PLWH. A simple and convenient protein precipitation was performed followed by direct injection of the supernatant into the UHPLC-MS/MS system. The four analytes were eluted in less than 3 minutes using a reversed-phase chromatography method coupled with triple quadrupole mass spectrometry detection. This bioassay was fully validated following international guidelines and achieved good performances in terms of trueness (94.7%-107.5%), repeatability (2.6%-11%), and intermediate precision (3.0%-11.2%) over the clinically relevant concentration ranges (from 30 to 9000 ng/mL for bictegravir, cabotegravir, and doravirine and from 10 to 1800 ng/mL for rilpivirine). This sensitive, accurate, and rapid UHPLC-MS/MS assay is currently applied in our laboratory for routine therapeutic drug monitoring of the oral drugs bictegravir and doravirine and is also intended to be applied for the monitoring of cabotegravir/rilpivirine levels in plasma from PLWH receiving once monthly or every 2-month intramuscular injection of these long-acting antiretroviral drugs.


Effect of Medicaid eligibility category on racial disparities in the use of psychotropic medications among youths.
This study sought to determine the degree to which Medicaid eligibility categories modify disparities between black and white youths in the prevalence of psychotropic medication. Computerized claims for 189,486 youths aged two to 19 years who were continuously enrolled in a mid-Atlantic state Medicaid program for the year 2000 were analyzed to determine population-based annual prevalence of psychotropic medication by race or ethnicity and by whether the youths were eligible for Medicaid for reasons of family income, disability, or foster care placement. Logistic regression was used to assess the interaction of eligibility category and race. The mean annual prevalence of psychotropic medication for the population was 9.9 percent. The prevalence was 2.17 times higher for white youths than for black youths (16.5 percent compared with 7.6 percent). However, within eligibility categories, the white-to-black disparity was 3.8 among youths who were eligible for Medicaid because their family income was below the federal poverty level and 3.2 for youths enrolled in the State Children's Health Insurance Program. Medicaid eligibility categories had a profound impact on the racial disparity associated with the prevalence of psychotropic medications for youths. Eligibility category should be taken into account when ascertaining the role of access, undertreatment, and culture in disparities in mental health treatment.


Succesful [Successful] endovascular repair of an abdominal mycotic aneurysm. A case report.
A 73-year-old man was admitted to the emergency department presenting with cramping pain in the left iliac fossa that had persisted for ten days, with diarrhoea and dysuria. A recent onset of high fever had urged him to the hospital. A routine blood sample showed a leukocytosis of 11.9 x 10(3)/mm(3) and an elevated CRP of 16 mg/dl. Haemocultures and a urine sample were taken. A colonoscopy and ultrasound showed no abnormalities. The urine culture contained salmonella enteritidis. On day 5 a CT scan of the abdomen was performed. This showed a saccular aneurysm of the abdominal aorta, approximately 2 cm in length, with clear signs of a contained rupture. An urgent EVAR procedure was performed. An Excluder bifurcation-endoprosthesis was placed under antibiotic coverage. Control CT scan showed a thrombosis of the aneurysm and a type II endoleakage. The endoleakage spontaneously resolved within 3 months. The patient was kept on antibiotics (levofloxacine) for 4 months. We suggest that the use of an endoprosthesis could be a good and safe alternative for the repair of infrarenal mycotic aorta aneurysm.


A novel role for high-mobility group a proteins in cellular senescence and heterochromatin formation.
Cellular senescence is a stable state of proliferative arrest that provides a barrier to malignant transformation and contributes to the antitumor activity of certain chemotherapies. Senescent cells can accumulate senescence-associated heterochromatic foci (SAHFs), which may provide a chromatin buffer that prevents activation of proliferation-associated genes by mitogenic transcription factors. Surprisingly, we show that the High-Mobility Group A (HMGA) proteins, which can promote tumorigenesis, accumulate on the chromatin of senescent fibroblasts and are essential structural components of SAHFs. HMGA proteins cooperate with the p16(INK4a) tumor suppressor to promote SAHF formation and proliferative arrest and stabilize senescence by contributing to the repression of proliferation-associated genes. These antiproliferative activities are canceled by coexpression of the HDM2 and CDK4 oncogenes, which are often coamplified with HMGA2 in human cancers. Our results identify a component of the senescence machinery that contributes to heterochromatin formation and imply that HMGA proteins also act in tumor suppressor networks.


A Preliminary Validation of the Polish Version of the Comprehensive Intellectual Humility Scale (CIHS).
In the last few years, empirical research on intellectual humility has grown notably, involving the elaboration of promising measures that provide a different outlook on the construct. Although all of them offer valid, theoretically sound, and meaningful contributions, we selected the 22-item Comprehensive Intellectual Humility Scale (CIHS) by Krumrei-Mancuso and Rouse for validation. The rationale for choosing this questionnaire for Polish validation stands in its multidimensional nature, which enables the study of various nuances of this psychological concept. The research was carried out with the participation of 260 adults (Study 1) and 210 adults (Study 2). The respondents completed a Polish translation of the original version of the CIHS, the Gratitude Questionnaire-Six Item Form (GQ-6), the General Self-Efficacy Scale (GSES), and the Positive Orientation Scale (P-Scale). The findings obtained in both studies support the four-factor model of the CIHS with the higher order factor. The good fit indices of the CFA and MGCFA show the psychometric solidity of the 22-item structure of the Polish version of the CIHS. With respect to convergent validity, the validation study (Study 2) confirmed that gratitude, self-efficacy, and positive orientation are significant correlates of the CIHS. Since intellectual humility is still a little-known psychological construct, both as a concept and as a possible antecedent or consequence, it would be worth examining it in the future with other variables of an intraindividual and interindividual nature.


The Proteome of Biologically Active Membrane Vesicles from Piscirickettsia salmonis LF-89 Type Strain Identifies Plasmid-Encoded Putative Toxins.
Piscirickettsia salmonis is the predominant bacterial pathogen affecting the Chilean salmonid industry. This bacterium is the etiological agent of piscirickettsiosis, a significant fish disease. Membrane vesicles (MVs) released by P. salmonis deliver several virulence factors to host cells. To improve on existing knowledge for the pathogenicity-associated functions of P. salmonis MVs, we studied the proteome of purified MVs from the P. salmonis LF-89 type strain using multidimensional protein identification technology. Initially, the cytotoxicity of different MV concentration purified from P. salmonis LF-89 was confirmed in an in vivo adult zebrafish infection model. The cumulative mortality of zebrafish injected with MVs showed a dose-dependent pattern. Analyses identified 452 proteins of different subcellular origins; most of them were associated with the cytoplasmic compartment and were mainly related to key functions for pathogen survival. Interestingly, previously unidentified putative virulence-related proteins were identified in P. salmonis MVs, such as outer membrane porin F and hemolysin. Additionally, five amino acid sequences corresponding to the Bordetella pertussis toxin subunit 1 and two amino acid sequences corresponding to the heat-labile enterotoxin alpha chain of Escherichia coli were located in the P. salmonis MV proteome. Curiously, these putative toxins were located in a plasmid region of P. salmonis LF-89. Based on the identified proteins, we propose that the protein composition of P. salmonis LF-89 MVs could reflect total protein characteristics of this P. salmonis type strain.


Gray-level grouping (GLG): an automatic method for optimized image contrast enhancement--Part II: the variations.
This is Part II of the paper, "Gray-Level Grouping (GLG): an Automatic Method for Optimized Image Contrast Enhancement". Part I of this paper introduced a new automatic contrast enhancement technique: gray-level grouping (GLG). GLG is a general and powerful technique, which can be conveniently applied to a broad variety of low-contrast images and outperforms conventional contrast enhancement techniques. However, the basic GLG method still has limitations and cannot enhance certain classes of low-contrast images well, e.g., images with a noisy background. The basic GLG also cannot fulfill certain special application purposes, e.g., enhancing only part of an image which corresponds to a certain segment of the image histogram. In order to break through these limitations, this paper introduces an extension of the basic GLG algorithm, selective gray-level grouping (SGLG), which groups the histogram components in different segments of the grayscale using different criteria and, hence, is able to enhance different parts of the histogram to various extents. This paper also introduces two new preprocessing methods to eliminate background noise in noisy low-contrast images so that such images can be properly enhanced by the (S)GLG technique. The extension of (S)GLG to color images is also discussed in this paper. SGLG and its variations extend the capability of the basic GLG to a larger variety of low-contrast images, and can fulfill special application requirements. SGLG and its variations not only produce results superior to conventional contrast enhancement techniques, but are also fully automatic under most circumstances, and are applicable to a broad variety of images.


SNP discovery in Litopenaeus vannamei with a new computational pipeline.
Litopenaeus vannamei (Pacific white shrimp) have been farmed in the Americas for many years and are growing in popularity in Asia with the development of specific pathogen-free stocks. The full genomic sequence of this species might not be available in the near future, so other tools are needed to discover the location of polymorphic sites for quantitative trait loci mapping, association studies and subsequent marker-assisted selection. Currently, 25 937 L. vannamei expressed sequence tags (ESTs) are publicly available. These sequences were manually screened, masked for tandem repeats and inputted into CAP3 for clustering. The resulting 3532 contigs were analysed for possible single nucleotide polymorphisms (SNPs) with SNPIDENTIFIER, a newly developed computer program for predicting SNPs. SNPIDENTIFIER is designed for ESTs without accompanying chromatogram sequence quality information, and therefore it performs quality control checks on all data. SNPIDENTIFIER sets a threshold such that the sequences used have a poor quality nucleotide (N) frequency <0.1, and it trims off the first 10 bases of every sequence to ensure higher sequence quality. For a base to be predicted as an SNP, the minor nucleotide (allele) frequency must be >0.1, it must be observed at least four times and the 15 bases on either side must exactly match the consensus sequence. Using these conservative parameters, 504 SNPs were predicted from 141 contigs for L. vannamei. A small sample of 18 individuals from three lines have been sequenced to verify prediction results and 17 of 39 (44%) of the tested SNPs have been confirmed.


Sled-type motion on the nanometer scale: determination of dissipation and cohesive energies of c60.
The tribological properties of C(60) on the mesoscopic scale were investigated with a scanning force microscope, which allowed simultaneous measurements of normal and lateral forces under ultrahigh-vacuum conditions. Islands of C(60), deposited on NaCl(001), could be moved by the action of the probing tip in a controlled way. Different modes of motion, such as translation and rotation, were observed. An extremely small dissipation energy of about 0.25 millielectron volt per molecule and a cohesive energy of 1.5 electron volts were determined in these nanometer-scale experiments. The corresponding shear strength of 0.05 to 0.1 megapascal was smaller by one order of magnitude than typical values of boundary lubricants. For C(60) on graphite, disruption of the islands was observed and collective motion of the islands could not be achieved. These results could find use in the field of nanotechnology; for example, C(60) islands could be developed into a sled-type transport system on the nanometer scale.


Effect of Alcohol and Tobacco Smoke on Long-Term Memory and Cell Proliferation in the Hippocampus of Rats.
Alcohol is frequently used in combination with tobacco and few studies explore interactions between these two drugs of abuse. Here, we evaluated the effect of chronic alcohol administration and concomitant exposure to tobacco smoke on long-term memory and on cell proliferation in the hippocampus of rats. Forty male Wistar rats were assigned to four groups and treated with alcohol (2g/kg by gavage) and/or exposed to tobacco smoke (from six cigarettes, by inhalation) twice a day (at 9:00 AM and 2:00 PM) for 30 days. Long-term memory was evaluated in the inhibitory avoidance test and hippocampal cell proliferation was analyzed for bromodeoxyuridine immunohistochemistry. Our results showed that alcohol, tobacco smoke, or their combination improved the long-term memory evaluated by the memory index in rats. Moreover, alcohol and tobacco coadministration decreased bromodeoxyuridine-labeled cells by 60% when compared to the control group, while alcohol treatment decreased labeled cells by 40%. The tobacco group showed a nonsignificant 26% decrease in labeled cells compared to the control group. Chronic alcohol and tobacco coadministration improves the long-term memory in rats in the inhibitory avoidance test. However, coadministration decreases the cell proliferation in the hippocampus of rats, suggesting a deleterious effect by the combined use of these drugs of abuse.


Relationship of mitochondrial membrane potential to hemoglobin synthesis during Friend cell maturation.
Previous studies have shown that exposure to imidazole dissociates hemoglobin synthesis from other aspects of cell maturation in dimethylsulfoxide (DMSO)-treated mouse erythroleukemia (MEL) cells. In the present study, we have found that imidazole causes hyperpolarization of the mitochondrial membrane in MEL cells exposed to DMSO, in contrast to the depolarization observed with DMSO alone. Like the defect in hemoglobin synthesis, membrane hyperpolarization is reversible upon removal of imidazole and incubation of cells with DMSO alone. These correlations suggest that alterations in the electrostatic properties of the mitochondrial membrane, due directly or indirectly to the effects of imidazole, interfere with heme synthesis but not with other aspects of the maturation process in these developing erythroid cells.


Identifying and using 'core competencies' to help design and assess undergraduate neuroscience curricula.
There has been a growing emphasis on the use of core competencies to design and inform curricula. Based on our Faculty for Undergraduate Neuroscience workshop at Pomona we developed a set of neuroscience core competencies. Following the workshop, faculty members were asked to complete an online survey to determine which core competencies are considered most essential and the results are presented. Backward Design principles are then described and we discuss how core competencies, through a backward design process, can be used to design and assess an undergraduate neuroscience curriculum. Oberlin College is used as a case study to describe the use of core competencies to help develop learning objectives, activities, and assessment measures for an undergraduate neuroscience major.


Impaired pulmonary ventilation beyond pneumonia in COVID-19: A preliminary observation.
Coronavirus disease 2019 (COVID-19) may severely impair pulmonary function and cause hypoxia. However, the association of COVID-19 pneumonia on CT with impaired ventilation remains unexplained. This pilot study aims to demonstrate the relationship between the radiological findings on COVID-19 CT images and ventilation abnormalities simulated in a computational model linked to the patients' symptoms. Twenty-five patients with COVID-19 and four test-negative healthy controls who underwent a baseline non-enhanced CT scan: 7 dyspneic patients, 9 symptomatic patients without dyspnea, and 9 asymptomatic patients were included. A 2D U-Net-based CT segmentation software was used to quantify radiological futures of COVID-19 pneumonia. The CT image-based full-scale airway network (FAN) flow model was employed to assess regional lung ventilation. Functional and radiological features were compared across groups and correlated with the clinical symptoms. Heterogeneity in ventilation distribution and ventilation defects associated with the pneumonia and the patients' symptoms were assessed. Median percentage ventilation defects were 0.2% for healthy controls, 0.7% for asymptomatic patients, 1.2% for symptomatic patients without dyspnea, and 11.3% for dyspneic patients. The median of percentage pneumonia was 13.2% for dyspneic patients and 0% for the other groups. Ventilation defects preferentially affected the posterior lung and worsened with increasing pneumonia linearly (y = 0.91x + 0.99, R2 = 0.73) except for one of the nine dyspneic patients who had disproportionally large ventilation defects (7.8% of the entire lung) despite mild pneumonia (1.2%). The symptomatic and dyspneic patients showed significantly right-skewed ventilation distributions (symptomatic without dyspnea: 0.86 ± 0.61, dyspnea 0.91 ± 0.79) compared to the patients without symptom (0.45 ± 0.35). The ventilation defect analysis with the FAN model provided a comparable diagnostic accuracy to the percentage pneumonia in identifying dyspneic patients (area under the receiver operating characteristic curve, 0.94 versus 0.96). COVID-19 pneumonia segmentations from CT scans are accompanied by impaired pulmonary ventilation preferentially in dyspneic patients. Ventilation analysis with CT image-based computational modelling shows it is able to assess functional impairment in COVID-19 and potentially identify one of the aetiologies of hypoxia in patients with COVID-19 pneumonia.


Mouse models of Alzheimer's disease: insight into treatment.
Mice overexpressing mutant Alzheimer's disease (AD)-related proteins exhibit many of the neuropathological and behavioral features of the human disease. Transgenic animals have been created that express mutations in the amyloid precursor protein (APP), presenilin (PS)1, and PS2, and also animals expressing more than one of these mutations. For example, in APP mouse models, there are age-related accumulations of amyloid-beta (Abeta)-containing neuritic plaques in the hippocampus and cerebral cortex, activation of astrocytes and microglial cells in regions containing plaques, and degeneration of cholinergic nerve terminals in brain regions that eventually become plaque containing. Missing in the APP and PS mouse models are neurofibrillary tangles and robust neuronal loss in cerebral cortical and subcortical regions such as the basal forebrain cholinergic and locus coeruleus noradrenergic nuclei. Neurofibrillary tangles can be produced in mice expressing mutant tau protein, and the tangle formation is further enhanced in animals that also express mutant APP. Studies in APP mouse models indicate that, like AD, there are abnormalities in adult hippocampal neurogenesis. The animal models of AD have been used to develop and test treatments that reduce brain levels of the Abeta42 protein, neuritic plaque load and glial activation, and some have been found to restore learning and memory function. If such treatments can be shown to stop the neurodegenerative process and restore hippocampal neurogenesis, damaged brain circuits may be replaceable in patients with AD.


A qualitative assessment of the small group teaching at hawler college of medicine.
Although the medical schools in Iraq recently started to increasingly use the small group teaching approach, only little is known about the students' perceptions toward this approach. Therefore, the aim of this study was to assess small group teaching as a method of teaching at Hawler College of Medicine, from the students' perspectives. This study was a qualitative study which was based on six focus group discussions which involved a sample of students from the three last years at the Hawler College of Medicine. A topic guide was used to lead the discussions and it covered questions on the positive aspects and the problems of small group teaching in the college, in addition to recommendations for its improvement. The qualitative data analysis involved a content analysis, followed by a thematic analysis. The participants were generally happy with the application of the small group teaching approach and they recognized many positive aspects which were related to this experience, which included, increasing the focus on the study subjects, enhancing the student-teacher interaction, building a better student-teacher relationship, encouraging the students' attendance, providing a better opportunity to apply a student-centered learning, enhancing a more efficient use of time and assisting in a better understanding of the subjects. The main problems which were faced, included a poor infrastructure and teaching facilities, problems which were related to examinations and the mark distribution, an improper syllabus preparation and problems which were related to the teachers' commitments and performances. The main suggestions which were put forth to improve this system, included, changing the assessment system with the focus more on the end of the course assessment, the students' involvement in the curriculum design, improving the infrastructure and teaching facilities and a better organization and management of the system. The concept of the small group teaching approach was well received by the students and many positive aspects of this approach have been highlighted. However, this experience witnessed many problems and faced different challenges that need better preparation, organization of the resources and the orientation of students and teachers, for insuring its success.


Human chromosome 22.
The acrocentric chromosome 22, one of the shortest human chromosomes, carries about 52 000 kb of DNA. The short arm is made up essentially of heterochromatin and, as in other acrocentric chromosomes, it contains ribosomal RNA genes. Ten identified genes have been assigned to the long arm, of which four have already been cloned and documented (the cluster of lambda immunoglobulin genes, myoglobin, the proto-oncogene c-sis, bcr). In addition, about 10 anonymous DNA segments have been cloned from chromosome 22 specific DNA libraries. About a dozen diseases, including at least four different malignancies, are related to an inherited or acquired pathology of chromosome 22. They have been characterised at the phenotypic or chromosome level or both. In chronic myelogenous leukaemia, with the Ph1 chromosome, and Burkitt's lymphoma, with the t(8;22) variant translocation, the molecular pathology is being studied at the DNA level, bridging for the first time the gap between cytogenetics and molecular genetics.