Chemosensory function recovery in COVID-19 patients: A cross-sectional study.
To determine whether subjects who have recovered from COVID-19 smell and taste disturbance perform similarly to their COVID-naïve baseline, on gold-standard smell and taste tests. Prospective cross-sectional study. University of Miami Department of Otolaryngology in Miami, FL between September 2021, and August 2022. Those previously COVID-19 positive composed the experimental group, those who reported being COVID-naïve composed the control group. Mean total score for the UPSIT Smell Test, and the Burghart Taste Strip test were the primary outcome measures. 70 adult subjects (35 former COVID-positive, 35 COVID-naïve) were enrolled, with 21 females and 14 males in each group. 87 % of all subjects were white and were almost distributed evenly between Hispanic and non-Hispanic. Mean UPSIT total score for the experimental group was 30.6 (95 % CI 28.9-32.3), mean UPSIT total score for the control group was 31.2 (95 % CI 29.7-32.8). Mean Burghart total score for the experimental group was 11.3 (95 % CI 10.6-12.0), mean Burghart total score for the control group was 10.7 (95 % CI 9.7-11.8). These showed a significant overlap of the 95 % CI of the mean total score between the control group and the experimental group, suggesting no significant difference between the two groups. These results suggest that COVID-19 patients who experience smell and taste disturbance and recover, regain sensory ability similar to their pre-COVID ability. Further study is needed to validate these findings, but the results are promising in the long-term recovery of COVID-19.


The effects of stride length and stride frequency on trunk coordination in human walking.
In speeding-up normal walking, relative phase between horizontal thorax and pelvis rotations changes from more in-phase (synchronous) to more out-of-phase. In pathology (stroke, Parkinson's disease, low-back pain, pregnancy-related pelvic girdle pain), this often fails to happen. Even in healthy gait, however, these phenomena remain poorly understood. Thorax-pelvis relative phase may increase with either stride length, or stride frequency. Sixteen healthy male subjects walked on a treadmill at 0.5m/s, 1.0m/s, or 1.5m/s, with small, normal, or large steps. Increasing stride length (with lower frequency) led to larger spinal rotations, larger thorax-pelvis relative phase, and lower pelvis-leg relative phase, while the thorax continued to counterrotate with respect to the leg. With small steps, speeding-up hardly affected thorax-pelvis relative phase, and spinal amplitudes remained low. From a certain walking speed onwards, pelvis rotations start to contribute to stride length, and thus to speed (the "pelvic step"). This phenomenon appears to be driven, and the present study suggests, at least for higher speeds, that also thoracic counterrotations are driven, and not determined by the passive dynamics of the system. For patients, several strategies may exist to avoid large thorax-pelvis relative phase, and the concomitant large rotations of the spine: walking slowly, walking with small steps, adapting the timing of thorax rotations to that of the pelvis, or refraining from adapting the timing of pelvis rotations to the movements of the leg.


Leukocyte depletion of cellular blood components.
Clinical studies have indicated that the use of leukocyte-reduced cellular blood components produced in the laboratory may prevent febrile reactions and delay or prevent alloimmunization to HLA antigens and refractoriness to platelet transfusion. Additional investigations regarding the effects of the use of leukocyte-reduced blood components were reported during the past year. A recent study in patients with hematologic malignancy that employed the commonly used bedside leukocyte-reduction filters failed to confirm a decrease in the rate of alloimmunization, except in a subgroup of patients with acute myelogenous leukemia. Another major multicenter trial confirmed the effectiveness of leukocyte-reduced blood components in the prevention of cytomegalovirus infection. The effect of allogeneic leukocytes in transfused blood on immune function in patients undergoing colorectal surgery continues to receive attention. Whereas one study failed to demonstrate an adverse effect of standard blood components on disease recurrence or survival, a second study demonstrated a marginally significant decrease in infectious complications in patients who received only leukocyte-reduced blood. Increasingly efficient leukocyte-reduction filters have been developed for cellular blood components, many of which are best suited for laboratory filtration of unstored blood. Laboratory studies indicate that prestorage leukocyte-reduction of cellular blood components does not impair erythrocyte or platelet function and will not increase the incidence of microbial contamination of blood. New methods that employ flow cytometry should enable improved quality control of blood components rendered leukocyte-reduced by the newer, more efficient filters. Finally, a cost-benefit analysis suggests that the appropriate use of leukocyte-reduction filters for acute leukemia patients may reduce the cost of health care to these patients.


Cyclone '78 in Sri Lanka--the mental health trail.
A longitudinal study of psychological disturbance in the affected population in Sri Lanka after the cyclone disaster of 1978 was carried out. The post-cyclonic stress identified among the rural communities after their return to the same destroyed environment was studied. Symptoms tended to be early or delayed in appearance. The degree of unpreparedness is postulated as the causes of the former. Group cohesiveness and feelings of community tended to delay the manifestation of symptoms. Realization of losses, family needs, and continued habitation in damaged homes acted as reminders and reinforcers. Morbidity continued to affect over half the population one year later. Early intervention within community settings after such disasters is recommended.


Missing Concepts in De Novo Pulp Regeneration.
Regenerative endodontics has gained much attention in the past decade because it offers an alternative approach in treating endodontically involved teeth. Instead of filling the canal space with artificial materials, it attempts to fill the canal with vital tissues. The objective of regeneration is to regain the tissue and restore its function to the original state. In terms of pulp regeneration, a clinical protocol that intends to reestablish pulp/dentin tissues in the canal space has been developed--termed revitalization or revascularization. Histologic studies from animal and human teeth receiving revitalization have shown that pulp regeneration is difficult to achieve. In tissue engineering, there are 2 approaches to regeneration tissues: cell based and cell free. The former involves transplanting exogenous cells into the host, and the latter does not. Revitalization belongs to the latter approach. A number of crucial concepts have not been well discussed, noted, or understood in the field of regenerative endodontics in terms of pulp/dentin regeneration: (1) critical size defect of dentin and pulp, (2) cell lineage commitment to odontoblasts, (3) regeneration vs. repair, and (4) hurdles of cell-based pulp regeneration for clinical applications. This review article elaborates on these missing concepts and analyzes them at their cellular and molecular levels, which will in part explain why the non-cell-based revitalization procedure is difficult to establish pulp/dentin regeneration. Although the cell-based approach has been proven to regenerate pulp/dentin, such an approach will face barriers--with the key hurdle being the shortage of the current good manufacturing practice facilities, discussed herein.


The Epstein-Barr virus receptor is distinct from the C3 receptor.
Polyvalent serum directed against C3 receptors was employed in an attempt to block Epstein-Barr virus (EBV) binding to virus receptor-containing cell lines. The serum eliminated 90% of virus binding to Daudi and BJAB, lines which express only the C3d receptor. Raji and Ramos cells, which express the C3d, C3b and C3bi receptors, still adsorbed 70% of their virus capacity in the presence of excess antiserum. These effects were independent of the virus strain. In the light of previous reports, these data imply that, although the two receptors, EBV and C3d, are closely associated, the binding sites of EBV and complement are distinct. Additionally, an unusual EBV substrain-specific receptor found on U698 and P3HR-1/ASNP lines was shown to be independent of complement receptors.


Development of chemotactic smart scaffold for use in tissue regeneration.
Regenerative medicine aims to obviate the need for autologous grafting through the use of bioengineered constructs that combine stem cells, growth factors, and biocompatible vehicles. Human mesenchymal stem cells and vascular endothelial growth factor (VEGF) have both shown promise for use in this context, the former because of their pluripotent capacity and the latter because of its chemotactic activity. The authors harnessed the regenerative potential of human mesenchymal stem cells and VEGF to develop a chemotactic scaffold for use in tissue engineering. Human mesenchymal stem cells were transduced with human VEGF via lentivirus particles to secrete VEGF. The chemotactic activity of the VEGF-transduced stem cells was evaluated via a trans-well assay. Migration through semipermeable membranes was significantly greater in chambers filled with medium conditioned by VEGF-transduced cells. VEGF-transduced cells were then seeded on apatite-coated poly(lactic-co-glycolic acid) scaffolds, thereby creating the Smart Scaffold. To determine in vivo angiogenesis, the Smart Scaffolds were implanted into subcutaneous pockets in the backs of nude mice. Significantly larger numbers of capillaries were observed in the Smart Scaffold compared with control implants on immunohistologic studies. For the chemotactic in vivo study, human mesenchymal stem cells tagged with a fluorescent dye (1,1-dioctadecyl-3,3,3,3-tetramethylindotricarbocyanine iodide) were injected intravenously via tail vein after the subcutaneous implantation of the Smart Scaffolds. In vivo fluorescent imaging revealed that fluorescent dye-tagged human mesenchymal stem cells successfully accumulated within the Smart Scaffolds. These observations suggest that VEGF may play a vital role in the design of clinically relevant tissue regeneration graft substitutes through its angiogenic effects and ability to chemoattract mesenchymal stem cells.


Diarrhoea as a symptom.
Diarrhoea is a common symptom in all communities and in both general and hospital practice. Diarrhoeal diseases, particularly of infectious aetiology, are a huge health problem world-wide, causing much morbidity and mortality, especially amongst children. Although the symptom is almost universally understood, the definition of diarrhoea is difficult because of the wide variation in the bowel habits of normal individuals. Diarrhoea is, perhaps, best described as a change in bowel habit from normal with an increase in stool volume and/or fluidity with or without an increase in stool frequency. The disorders causing diarrhoea are many and various, but most episodes of diarrhoea are mild and self-limiting. However, all cases of chronic diarrhoea and all severe cases of acute diarrhoea require investigation after the initial clinical assessment. Investigation must be logical and structured and can be divided into three stages: the initial work-up (sigmoidoscopy, stool examination, screening blood tests), anatomical and functional assessment of the gastrointestinal tract, and further investigation of the difficult case (osmotic or secretory diarrhoea?, hormone levels, tests for laxative abuse, perfusion studies, laparotomy, etc.) Most cases are diagnosed after clinical assessment or the initial work-up. In the remainder, there are usually clues to the diagnosis or to the area of the gastrointestinal tract which needs to be investigated. Only a small number of cases require extensive investigation including the third stage of work-up. Analysis of the symptom of diarrhoea requires all the attributes of the good physician: wide clinical experience, careful history and examination, diagnostic and therapeutic acumen, a sound understanding of normal and abnormal physiology, skill and experience in selecting the appropriate investigations and interpreting their results, meticulous attention to detail and finally, a caring and sympathetic attitude to the patient.


Apolipoprotein E Genotypes, Age, Race, and Cognitive Decline in a Population Sample.
To examine the effects of age and race on the association of apolipoprotein E (APOE) genotypes with cognitive decline in a population sample. Longitudinal study of 18 years' duration. Biracial urban US population sample. There were a total of 5807 participants, 60% African American (AA) and 40% European American (EA). A composite cognitive function based on individual tests of episodic memory, perceptual speed, and the Mini-Mental State Examination. The frequencies of APOE ε2/ε3 (14% vs 12%), ε2/ε4 (4% vs 2%), ε3/ε4 (29% vs 22%), and ε4/ε4 (4% vs 2%) genotypes were higher among AAs than EAs. After adjusting for demographic factors, the rate of decline in global cognition was twice as high among participants with the APOE ε4/ε4 genotype compared to participants with the APOE ε3/ε3 genotype (0.097 vs 0.048 SD units [SDUs] per year; P < .0001). This doubling was not different between AAs (0.091 vs 0.045 SDUs per year) and EAs (0.118 vs 0.059 SDUs per year) (Pinteraction = .63). The APOE ε3/ε4 genotype was associated with a higher rate of decline with age (Pinteraction = .021), while the APOE ε2/ε4 genotype (Pinteraction = .016) and the APOE ε2/ε3 genotype (Pinteraction = .043) were associated with a lower rate of decline with higher age. The APOE ε2/ε2 genotype was associated with a lower rate of decline in episodic memory, while the APOE ε2/ε4 was associated with a higher rate of decline in episodic memory and perceptual speed. The association of the APOE genotypes with cognitive decline was not different between AAs and EAs. However, individuals with different APOE genotypes showed a lower or a higher rate of decline with age. J Am Geriatr Soc 67:734-740, 2019.


Microdeletions are a general feature of adult and adolescent acute lymphoblastic leukemia: Unexpected similarities with pediatric disease.
We present here a genome-wide map of abnormalities found in diagnostic samples from 45 adults and adolescents with acute lymphoblastic leukemia (ALL). A 500K SNP array analysis uncovered frequent genetic abnormalities, with cryptic deletions constituting half of the detected changes, implying that microdeletions are a characteristic feature of this malignancy. Importantly, the pattern of deletions resembled that recently reported in pediatric ALL, suggesting that adult, adolescent, and childhood cases may be more similar on the genetic level than previously thought. Thus, 70% of the cases displayed deletion of one or more of the CDKN2A, PAX5, IKZF1, ETV6, RB1, and EBF1 genes. Furthermore, several genes not previously implicated in the pathogenesis of ALL were identified as possible recurrent targets of deletion. In total, the SNP array analysis identified 367 genetic abnormalities not corresponding to known copy number polymorphisms, with all but two cases (96%) displaying at least one cryptic change. The resolution level of this SNP array study is the highest used to date to investigate a malignant hematologic disorder. Our findings provide insights into the leukemogenic process and may be clinically important in adult and adolescent ALL. Most importantly, we report that microdeletions of key genes appear to be a common, characteristic feature of ALL that is shared among different clinical, morphological, and cytogenetic subgroups.


Support of public-private partnerships in health promotion and conflicts of interest.
Public-private partnerships (PPPs) are considered key elements in the development of effective health promotion. However, there is little research to back the enthusiasm for these partnerships. Our objective was to describe the diversity of visions on PPPs and to assess the links between the authors and corporations engaged in such ventures. We reviewed the scientific literature through PubMed in order to select all articles that expressed a position or recommendation on governments and industries engaging in PPPs for health promotion. We included any opinion paper that considered agreements between governments and corporations to develop health promotion. Papers that dealt with healthcare provision or clinical preventive services and those related to tobacco industries were excluded. We classified the articles according to the authors' position regarding PPPs: strongly agree, agree, neutral, disagree and strongly disagree. We related the type of recommendation to authors' features such as institution and conflicts of interest. We also recorded whether the recommendations were based on previous assessments. Of 46 papers analysed, 21 articles (45.6%) stated that PPPs are helpful in promoting health, 1 was neutral and 24 (52.1%) were against such collaborations. 26 papers (57%) set out conditions to assure positive outcomes of the partnerships. Evidence for or against PPPs was mentioned in 11 papers that were critical or neutral (44%) but not in any of those that advocated collaboration. Where conflicts were declared (26 papers), absence of conflicts was more frequent in critics than in supporters (86% vs 17%). Although there is a lack of evidence to support PPPs for health promotion, many authors endorse this approach. The prevalence of ideas encouraging PPPs can affect the intellectual environment and influence policy decisions. Public health researchers and professionals must make a contribution in properly framing the PPP issue.


Medication for older people--aspects of rational therapy from the general practitioner's point of view.
This paper discusses GP perspectives on the principles underlying rational pharmacotherapy for older people. The rising use of prescription medicine forces the GP to balance the benefit of evidence group-based appropriate drug use against the problems arising when medication is given to older people and to consider different approaches when evaluating evidence of risk and benefit for the individual. Old people are facing a considerable risk of adverse drug reactions and recent initiatives, including the Continuous Medical Educational Efforts Programme, address issues of inappropriate prescribing practices. The authors recommend and present tools enabling the GP to focus on 'the core prescribing situation'. The logistics to optimise medication including compliance, the use of modern IT and better collaboration and communication between primary and secondary care are discussed. The authors state that a number of pharmacological regimens for older people are outperformed by non-pharmacological treatment alternatives involving competent individualised counselling and public provision of easy (transportation) possibilities for joining centres offering staff and equipment for physical and social activity (including basal aids for hearing and sight).


Tumor microenvironment and progression.
Tumor blood vessels are heterogeneous, of at least six distinct types, are induced primarily by vascular endothelial growth factor-A (VEGF-A), and provide a potentially useful therapeutic target. Breast cancer is characterized by changes in the microenvironment that result in altered tensional homeostasis. Also, breast cancers arise as the result of epigenetic as well as genetic changes. Tumor blood vessel pericytes result, in part, from bone marrow precursor cells, and VEGF is a negative regulator of glioblastoma tumor cell invasion.


Discovery of active enhancers through bidirectional expression of short transcripts.
Long-range regulatory elements, such as enhancers, exert substantial control over tissue-specific gene expression patterns. Genome-wide discovery of functional enhancers in different cell types is important for our understanding of genome function as well as human disease etiology. In this study, we developed an in silico approach to model the previously reported phenomenon of transcriptional pausing, accompanied by divergent transcription, at active promoters. We then used this model for large-scale prediction of non-promoter-associated bidirectional expression of short transcripts. Our predictions were significantly enriched for DNase hypersensitive sites, histone H3 lysine 27 acetylation (H3K27ac), and other chromatin marks associated with active rather than poised or repressed enhancers. We also detected modest bidirectional expression at binding sites of the CCCTC-factor (CTCF) genome-wide, particularly those that overlap H3K27ac. Our findings indicate that the signature of bidirectional expression of short transcripts, learned from promoter-proximal transcriptional pausing, can be used to predict active long-range regulatory elements genome-wide, likely due in part to specific association of RNA polymerase with enhancer regions.


Inhibition of the cAMP pathway decreases early long-term potentiation at CA1 hippocampal synapses.
Long-term potentiation (LTP) has several different phases, and there is general agreement that the late phase of LTP requires the activation of adenylyl cyclase (AC) and cAMP-dependent protein kinase (PKA). In contrast, several studies indicate that the early LTP is not affected by interfering with the cAMP pathway. We have further tested the role of the cAMP pathway in early LTP using several types of inhibitors. Bath application of the PKA inhibitor H89 suppressed the early LTP induced by a single tetanus. Similarly, the LTP induced by a pairing protocol was decreased by postsynaptic intracellular perfusion of the peptide PKA inhibitor PKI(6-22) amide. The decrease of LTP produced by these inhibitors was evident immediately after induction. These results indicate that PKA is important in early LTP, that its locus of action is postsynaptic, and that it does not act merely by enhancing the depolarization required for LTP induction. The failure of some other inhibitors of the cAMP pathway to affect the early phase of LTP might be attributable to the saturation of some step in the cAMP pathway during a tetanus. In agreement with this hypothesis we found that application of the AC inhibitor SQ 22536 by itself did not affect the early phase of LTP, but did produce a reduction if the cAMP pathway was already attenuated by the PKA inhibitor H89. Our analysis of the results of genetic modifications of the cAMP pathway, especially the work on AC knock-outs, indicates that the genetic data are generally consistent with the pharmacological results showing the importance of this pathway in early LTP.


The yeast repeated element sigma contains a hormone-inducible promoter.
A genomic clone (lambda ScG7) from Saccharomyces cerevisiae encoded a 650-nucleotide poly(A)-containing [poly(A)+] RNA that was about 50 times more abundant in MATa cells that had been exposed to the peptide pheromone alpha-factor than in untreated cells. This RNA was transcribed from a cluster of repetitive sequences: both intact and truncated delta and sigma elements adjacent to a tRNATrp gene. Strand-specific probes indicated that this RNA initiated within an intact sigma element and contained sigma sequences at its 5' end. MATa cells produced two other prominent poly(A)+ RNAs (500 and 5,300 bases) in response to alpha-factor that were homologous to the same strand of sigma but transcribed from other locations in the genome. Induction of the sigma-related transcripts was rapid, was not blocked by inhibition of protein synthesis, required a functional receptor (STE2 gene product), and hence appeared to be a primary response to pheromone. Pulse-labeling confirmed that accumulation of sigma RNA following alpha-factor administration was accounted for by an increase in its rate of transcription. The sigma RNAs also were induced in MAT alpha cells that had been treated with a-factor, but were not present at significant levels in MATa/MAT alpha diploids. In MATa cells transformed with a plasmid in which the lambda ScG7 sigma element was inserted just upstream of a gene coding for the intracellular form of invertase (SUC2) lacking its own promoter, a new poly(A)+ RNA (2.2 kilobases) appeared in response to alpha-factor that hybridized to both sigma and SUC2 probes, and intracellular invertase activity was elevated about 10-fold within 30 min. Primer extension showed that transcription from the hybrid gene initiated exclusively within the sigma sequence (117 nucleotides from the 3' end of the element).


Fourier transform holography using a quasimonochromatic incoherent source.
Fourier transform hologram of an object is recorded using a quasimonochromatic incoherent source. The object lies in the far field of the incoherent source and is illuminated in partially coherent light. The hologram is constituted by a large number of elementary holograms, each one reconstructing only a small region of the object. The hologram as a whole reconstructs the complete object. The bias problem encountered in incoherent holography is partly resolved though at the expense of resolution.


[Access to the pediatric ambulatory service at a university hospital].
In Brazil, one can verify an imbalance between the increase in the need for health care and its supply. The consolidation of the National Health System which recommends universality and equity in care, makes this issue important in the field of health service evaluation. Two pediatric services in a university hospital, one general and the other specialized are studied and compared in terms of their clients' access. Questionnaires were applied to 221 users of the general pediatrics outpatient departments of one of the specialties with a view to studying and comparing socioeconomic and several other variables related to the access to these and other health services. A high level of difficulty in the users' locomotion from local health services to the hospital was noted. Of the patients attended, 40% did not receive any kind of care before their arrival and were dependent exclusively on State-run health services. The clients of the specialty were different as regards several variables when compared to the users of the general outpatients' department. The fact that they are at a better socioeconomic level and are less dependent on State-run services brings out the social inequalities involved. Socioeconomic conditions, as well as organizational aspects of the service, are seen to be both causes and consequences of social inequality verified.


Multihierarchical interactive task planning: application to mobile robotics.
To date, no solution has been proposed to human-machine interactive task planning that deals simultaneously with two important issues: 1) the capability of processing large amounts of information in planning (as it is needed in any real application) and 2) being efficient in human-machine communication (a proper set of symbols for human-machine interaction may not be suitable for efficient automatic planning and vice versa). In this paper, we formalize a symbolic model of the environment to solve these issues in a natural form through a human-inspired mechanism that structures knowledge in multiple hierarchies. Planning with a hierarchical model may be efficient even in cases where the lack of hierarchical information would make it intractable. However, in addition, our multihierarchical model is able to use the symbols that are most familiar to each human user for interaction, thus achieving efficiency in human-machine communication without compromising the task-planning performance. We formalize here a general interactive task-planning process which is then particularized to be applied to a mobile robotic application. The suitability of our approach has been demonstrated with examples and experiments.


[Statistical approach to psychosomatic headaches].
Three groups of patients were compared statistically: 79 with the diagnosis psychosomatic headache' (in the strict sense of the term), 450 others whose headache was part of another disorder (termed symptomatic headache'), and 850 patients free from headache symptoms. The following characteristics were found for the group with psychosomatic headache: More psychosomatic diseases in the family, usually the eldest in birth rank, usually living in towns, married, two children, intellectual level above average, overweight, ego-strength with compulsive features, tendency towards oral abuse of different kinds, few other psychosomatic complaints (contrary to the group with symptomatic headache). In the discussion the Authors try to demonstrate the defensive function of this selective somatisation.


[Incorporation of phi80 phage into unusual chromosome sites and isolation of a specialized transducing bacteriophage].
The mutant strain KS713 of Escherichia coli K-12 deleted for the normal insertion site and secondary preferable one was obtained. The insertion frequency of phage phi80 into the double deletion strain is reduced about 30-fold with respect to integration into the strain H47 with deletion of the primary phi80 attachment site and about 500-fold relative to integration into wild type Escherichia coli. Analysis of the rare abnormal lysogens of KS 713 strain indicates that there are secondary sites on the chromosome, which are utilized for prophage attachment if insertion at preferable secondary att80-II site is eliminated too. The insertion of phi80 phage into the bfe locus was obtained by the appropriate selection technique. Induced prophage excision from the bfe site was rather efficient and lysates contained phi80 phage particles that could specificically transduce the argH+ gene. Upon transduction into a recipient strain carrying recA, heterogenotes harbouring both the wild-type and the mutant argH genes were isolated. These heterogenotes were used for producing high-frequency transducing lysates.


Trisomy 21--incidence and outcomes in the first year, in Ireland today.
Incidence of Trisomy 21 in Ireland, 1:546 live births, is the highest in Europe. This project aimed to define the incidence of T21 amongst liveborn infants at Cork University Maternity Hospital (CUMH), and to describe neonatal outcomes and progress in their first year. Infants were identified from Social Work department records. A retrospective review of the neonatal inpatient database, outpatient letters and medical charts was performed. Forty three infants with T21 were born in CUMH in 2010 and 2011. Incidence of T21 was 1:411. Antenatal diagnosis was uncommon at 14% (6). 34 (79%) were admitted to the neonatal unit. Co-morbidities included congenital heart disease 22 (51%) and duodenal atresia 2 (5%). Thirty four were followed-up in CUMH outpatient department. Of these, 34 (100%) had thyroid function testing, 29 (85%) ophthalmology and audiology referral, and 7 (21%) were referred for hip review. Mortality rate was 9% (4). Readmission to hospital in the first year of life was 42% (18).


Health effects following 9/11: implications for occupational health nurses.
The attacks on the World Trade Center in 2001 resulted in hazardous environmental exposures of enormous magnitude, bringing about persistent respiratory and psychological problems among survivors. Approximately 40,000 men and women worked at Ground Zero, the former site of the World Trade Center in New York City, and at the Staten Island landfill, the main wreckage depository, in the days, weeks, and months following 9/11. First responders such as firefighters and police, construction workers, and utility and public sector workers were involved. These individuals were at high risk for injury, respiratory complications, and psychological distress from the traumatic event. This article highlights the controversy surrounding 9/11 research and reports, identifies populations at high risk for exposure, and examines the health effects. Occupational health nurses should not only be empowered to provide the best care for workers affiliated with 9/11, but also contribute to research to protect worker health in future disaster responses.


Long-term work retention after treatment for cancer: a systematic review and meta-analysis.
Almost half of people diagnosed with cancer are working age. Survivors have increased risk of unemployment, but little is known about long-term work retention. This systematic review and meta-analysis assessed work retention and associated factors in long-term cancer survivors. We searched Medline/Pubmed, Embase, PsychINFO, and CINAHL for studies published 01/01/2000-08/01/2019 reporting work retention in adult cancer survivors ≥ 2 years post-diagnosis. Survivors had to be in paid work at diagnosis. Pooled prevalence of long-term work retention was estimated. Factors associated with work retention from multivariate analysis were synthesized. Twenty-nine articles, reporting 21 studies/datasets including 14,207 cancer survivors, were eligible. Work retention was assessed 2-14 years post-diagnosis. Fourteen studies were cross-sectional, five were prospective, and two contained both cross-sectional and prospective elements. No studies were scored as high quality. The pooled estimate of prevalence of long-term work retention in cancer survivors working at diagnosis was 0.73 (95%CI 0.69-0.77). The proportion working at 2-2.9 years was 0.72; at 3-3.9 years 0.80; at 4-4.9 years 0.75; at 5-5.9 years 0.74; and 6+ years 0.65. Pooled estimates did not differ by cancer site, geographical area, or study design. Seven studies assessed prognostic factors for work retention: older age, receiving chemotherapy, negative health outcomes, and lack of work adjustments were associated with not working. Almost three-quarters of long-term cancer survivors working at diagnosis retain work. These findings are pertinent for guidelines on cancer survivorship care. Professionals could focus support on survivors most likely to have poor long-term work outcomes.


The Impact Of Succinate Dehydrogenase Gene (SDH) Mutations In Renal Cell Carcinoma (RCC): A Systematic Review.
Renal cell cancer (RCC) syndrome is linked to Krebs cycle compartments and their coding genes' alterations like succinate dehydrogenase genes (SDHx). Here we present a systematic review of the SDH genes' mutations and their impact on both RCC diagnosis and prognosis. This systematic review includes any study in which tissue samples of RCC are considered in correlation with the SDHx mutations, microsatellite instability (MSI), and protein expression. For this purpose, a systematic search of MEDLINE (PubMed), Scopus, Embase, and Web of Science databases was conducted and finally 5384 articles were recruited. All studies' content was checked to find the related ones which were 145 articles, which with data extraction were limited to nineteen. The final selected nineteen studies investigating the SDHx role in RCC tumor genesis were included, among which fifteen were mutation analysis, three were just SDHx protein expression, and two were MSI and mutation analysis studies. A total of 432 RCC patients were reported by SDH mutations, and 64 patients with MSI and SDH expression change were reported in 514 surgically resected renal epithelial tumors. The most common mutation was the single nucleotide variant rs772551056 (c.137G>A) of SDHB. For SDHC, c.380A>G presented in 48 RCC patients, and for SDHA a novel germline mutation c.2T>C: p.M1T in an occasional case of gastrointestinal stromal tumor intricate with RCC. RCC as an aggressive type of kidney cancer needs some biomarkers to be diagnosed exactly. It was shown recently that the succinate dehydrogenase gene variations can provide this diagnostic and prognostic biomarker. For this purpose, SDHB rs772551056 associated with its protein expression alterations can be taken into account. It is possible that a novel mutation of SDHA (c.2T>C: p.M1T) can provide evidence of GIST associated with RCC as well.


Partial experience with the arc of the sun is sufficient for all-day sun compass orientation in homing pigeons, Columba livia.
The ability of animals to learn to use the sun for orientation has been explored in numerous species. In birds, there is conflicting evidence about the experience needed for sun compass orientation to develop. The prevailing hypothesis is that birds need entire daytime exposure to the arc of the sun to use the sun as an orientation cue. However, there is also some evidence indicating that, even with limited exposure to the arc of the sun, birds, like insects, can use the sun to orient at any time of day. We re-examine this issue in a study of compass orientation in a cue-controlled arena. Two groups of young homing pigeons received different exposure to the sun. The control group experienced the sun throughout the day; the experimental group experienced only the apparent descent of the sun. After 8 weeks of sun exposure, we trained both groups in the afternoon to find food in a specific compass direction in an outdoor arena that provided a view of the sun but not landmarks. We then tested the pigeons in the morning for their ability to use the morning sun as an orientation cue. The control group and the experimental group, which was exposed to the morning sun for the first time, succeeded in orienting in the training direction during test 1. The orientation of the experimental group was no different from that of the control group, although the experimental first trial directional response latencies were greater than the control latencies. Subsequently, we continued training both groups in the afternoon and then tested the pigeons during the morning under complete cloud cover. Both groups displayed random directional responses under cloud cover, indicating that the observed orientation was based on the visibility of the sun. The data indicate that pigeons with limited exposure to the arc of the sun can, like insects, use the sun for orientation at any time of day.


Electrosorption of pectin onto casein micelles.
Pectin, a polysaccharide derived from plant cells of fruit, is commonly used as stabilizer in acidified milk drinks. To gain a better understanding of the way that pectin stabilizes these drinks, we studied the adsorption and layer thickness of pectin on casein micelles in skim milk dispersions. Dynamic light scattering was used to measure the layer thickness of adsorbed pectin onto casein micelles in situ during acidification. The results indicate that the adsorption of pectin onto casein micelles is multilayered and takes place at and below pH 5.0. Renneting, i.e., cleaving-off kappa-casein from the casein micelles, did not alter the adsorption pH. It did, however, show that pectin arrests the rennet-induced flocculation of casein micelles below pH 5.0. From the findings we concluded the attachment of pectin onto casein micelles is driven by electrosorption. Adsorption measurements confirmed the multilayered nature of the adsorption of pectin onto casein micelles. Both the adsorbed amount and the layer thickness increased with decreasing pH in the relevant range 3.5-5.0. The phase behavior of a casein micelles/pectin mixture was determined and could be explained in terms of thermodynamic incompatibility being relevant above pH 5.0 and adsorption, leading to either stabilization and bridging, being relevant below pH 5.0. The results confirm that electrosorption is the driving force for the adsorption of pectin onto casein micelles.


Ultrasonographic measurement of the vascular wall thickness and intima-media thickness in patients with Behçet's disease with symptoms or signs of vascular involvement: A cross-sectional study.
This study aims to measure and compare bilateral carotid intima-media thickness (CIMT), bilateral jugular, common femoral, and main portal vein wall thicknesses (VWTs) in Behçet's disease (BD) patients with and without vascular involvement to obtain a cut-off value for vascular complications and determine their relationship with disease activity. Sixty-three BD patients (41 males, 22 females; median age: 38.0 years; min 20 - max 71 years) and 30 healthy control subjects (14 males, 16 females; median age: 40.3 years; min 21 - max 60 years) were included in this cross-sectional study between February and March 2020. According to imaging findings, BD patients were divided into two groups as those with and without vascular complications. Disease duration, medical treatment and BD manifestations of patients were questioned. Disease activity was evaluated using the Behçet's Disease Current Activity Form (BDCAF) and the Behçet's Syndrome Activity Scale (BSAS). Two radiologists blinded to the diagnosis of BD used ultrasound to measure VWT and CIMT. Receiver operating characteristics were assessed to obtain sensitivity and specificity values for each VWT and CIMT. The groups were similar in terms of age, sex, and body mass index (p>0.05). There was a significant difference between the BD groups when the BDCAF and BSAS scores were compared, while there was no difference between them in terms of disease duration and medical treatment (p>0.05). All VWTs and CIMTs were significantly higher in patients with BD compared to healthy controls (p<0.05). There was no significant difference between the BD groups in terms of CIMT, jugular and common femoral VWTs (p>0.05). But portal VWT was significantly higher in patients with vascular involvement (p<0.05). A cut-off value of ≥1.35 mm yielded a sensitivity of 79.2% and a specificity of 82.4% for the diagnosis of vascular involvement with the highest Youden's index (area under the curve, 0.869; 95% confidence interval, 0.783 to 0.956). Portal VWT has high sensitivity and specificity for the screening of vascular involvement in patients with BD.


The correlation between lipid volume in the target lesion, measured by integrated backscatter intravascular ultrasound, and post-procedural myocardial infarction in patients with elective stent implantation.
The aim of this study was to perform quantitative analysis of the plaques of target lesions by integrated backscatter intravascular ultrasound (IB-IVUS) and to investigate the association between these data and the risk of post-procedural myocardial injury after stenting. One hundred and fourteen consecutive patients who received elective stent implantations following IB-IVUS analysis were enrolled. The volume of each plaque component (lipid, fibrous, and calcified) was calculated for the target lesion. Creatine kinase-MB (CK-MB) and troponin-T (TnT) were also evaluated 18 h after procedure. We defined a post-procedural TnT level higher than three times the normal limit as a post-procedural myocardial injury. Lipid, fibrous, and calcified volumes were greater in patients with myocardial injury than in those without myocardial injury. Lipid and fibrous volumes correlated with post-procedural cardiac biomarkers, and the lipid volume fraction (lipid volume/total plaque volume) also correlated with post-procedural TnT and CK-MB. The fibrous volume fraction for plaques was found to be inversely correlated with post-procedural TnT and CK-MB. Hence, lipid volume and volume fraction were concluded to be independent predictors of post-procedural myocardial injury. A larger plaque volume and lipid-rich plaque may be indicative of embolic events after stent implantation, resulting in myocardial injury.


Mifepristone inhibits proliferation, migration and invasion of HUUA cells and promotes its apoptosis by regulation of FAK and PI3K/AKT signaling pathway.
The aim was to investigate mifepristone effects on endometrial carcinoma and the related mechanism. HHUA cells were treated with DMEM containing different concentrations of mifepristone. HHUA cells treated with 100 μmol/L mifepristone were named the Mifepristone group. HHUA cells co-transfected with pcDNA3.1-PI3K and pcDNA3.1-AKT overexpression vectors were treated with 100 μmol/L mifepristone and named the Mifepristone + PI3K/AKT group. mRNA expression was detected by quantitative reverse transcription PCR. Protein expression was performed by Western blot. Cell proliferation was conducted by MTT assay. Wound-healing assay was conducted. Transwell was used to detect cells migration and invasion. Apoptosis detection was performed by flow cytometry. Mifepristone inhibited HHUA cells proliferation in a dose-dependent manner. Compared with HHUA cells treated with 0 μmol/L mifepristone, HHUA cells treated by 50-100 μmol/L mifepristone had a lower wound-healing rate, a greater number of migrating and invasive cells (P<0.01), as well as a higher percentage of apoptotic cells and Caspase-3 expression (P<0.01). When HHUA cells were treated with 50-100 μmol/L of mifepristone, FAK, p-FAK, p-PI3K and p-AKT relative expression was all significantly lower than HHUA cells treated with 0 μmol/L of mifepristone (P<0.01). Compared with the Mifepristone group, HHUA cells of the Mifepristone + PI3K/AKT group had a lower cell growth inhibition rate and percentage of apoptotic cells (P<0.01). Mifepristone inhibited HUUA cells proliferation, migration and invasion and promoted its apoptosis by regulation of FAK and PI3K/AKT signaling pathway.


Effects of modifying gonadotrophin-releasing hormone input before and after the oestrogen-induced LH surge in ovariectomized ewes with hypothalamo-pituitary disconnection.
The patterns of gonadotrophin-releasing hormone (GnRH) input to the pituitary gland that affect the expression of a positive-feedback event by oestrogen on LH secretion were investigated in ovariectomized ewes with hypothalamo-pituitary disconnection (HPD). In experiment 1, ovariectomized HPD ewes were given hourly i.v. pulses of 250 ng GnRH and an i.m. injection of 50 micrograms oestradiol benzoate (OB). The ewes were given a bolus pulse of 2.25 micrograms GnRH 16 h after injection of OB, followed by half-hourly pulses of 250 ng GnRH for 14 h (treatment A). The LH surge response was significantly (P less than 0.05) greater in these ewes compared with that in ewes given a continuous infusion of GnRH (250 ng/h) after the OB injection, followed by a continuous infusion of 500 ng GnRH/h after the bolus pulse of GnRH (treatment B). When no GnRH was administered after the OB injection, except for the bolus pulse of GnRH (treatment C), the surge response was significantly (P less than 0.05) reduced compared with that in treatment A, and was reduced compared with treatment B. These data suggest that GnRH pulses are important in the generation of the OB-induced LH surge, but that a baseline secretory component can prime the pituitary to some extent. In experiment 2, a doubling of the continuous infusion dose of GnRH used in treatment B to 500 ng/h before the bolus pulse of GnRH and to 1 micrograms/h afterwards (treatment D) gave a similar response compared with treatment A, suggesting that if the baseline input of GnRH is of sufficient magnitude, it can overcome the lack of pulsatile input. In experiment 3, halving the GnRH pulse amplitude used in treatment A from 250 to 125 ng (treatment E) did not reduce the LH surge response, implying that when the GnRH input is in a pulsatile mode, the amplitude of GnRH pulses is less important than the pulsatile nature per se. In experiment 4, removal of GnRH input after the bolus pulse of GnRH (treatment F) significantly (P less than 0.05) reduced the surge response compared with when pulses were maintained (treatment A), indicating that GnRH input is still required once the LH surge has been initiated. Collectively, these experiments show that several forms of GnRH delivery, both pulsatile and baseline, can result in the full expression of a positive-feedback response in ovariectomized ewes treated with oestrogen.


Reversible Control of Protein Corona Formation on Gold Nanoparticles Using Host-Guest Interactions.
When nanoparticles (NPs) are exposed to biological media, proteins are adsorbed, forming a so-called protein corona (PC). This cloud of protein aggregates hampers the targeting and transport capabilities of the NPs, thereby compromising their biomedical applications. Therefore, there is a high interest in the development of technologies that allow control over PC formation, as this would provide a handle to manipulate NPs in biological fluids. We present a strategy that enables the reversible disruption of the PC using external stimuli, thereby allowing a precise regulation of NP cellular uptake. The approach, demonstrated for gold nanoparticles (AuNPs), is based on a biorthogonal, supramolecular host-guest interactions between an anionic dye bound to the AuNP surface and a positively charged macromolecular cage. This supramolecular complex effectively behaves as a zwitterionic NP ligand, which is able not only to prevent PC formation but also to disrupt a previously formed hard corona. With this supramolecular stimulus, the cellular internalization of AuNPs can be enhanced by up to 30-fold in some cases, and even NP cellular uptake in phagocytic cells can be regulated. Additionally, we demonstrate that the conditional cell uptake of purposely designed gold nanorods can be used to selectively enhance photothermal cell death.


Electrocorticography reveals spatiotemporal neuronal activation patterns of verbal fluency in patients with epilepsy.
Verbal fluency is commonly used to evaluate cognitive dysfunction in a variety of neuropsychiatric diseases, yet the neurobiology underlying performance of this task is incompletely understood. Electrocorticography (ECoG) provides a unique opportunity to investigate temporal activation patterns during cognitive tasks with high spatial and temporal precision. We used ECoG to study high gamma activity (HGA) patterns in patients undergoing presurgical evaluation for intractable epilepsy as they completed an overt, free-recall verbal fluency task. We examined regions demonstrating changes in HGA during specific timeframes relative to speech onset. Early pre-speech high gamma activity was present in left frontal regions during letter fluency and in bifrontal regions during category fluency. During timeframes typically associated with word planning, a distributed network was engaged including left inferior frontal, orbitofrontal and posterior temporal regions. Peri-Rolandic activation was observed during speech onset, and there was post-speech activation in the bilateral posterior superior temporal regions. Based on these observations in the context of prior studies, we propose a model of neocortical activity patterns underlying verbal fluency.


[Mild cervix dysplasia: does diagnostic biopsy have a "therapeutic" effect?].
The aim of the study was, to evaluate the possible curative effect of punch biopsy on low grade cervical intraepithelial dysplasia (CIN I) as indicated by the literature. After a three-month interval, 115 women with PAP-smears indicating CIN I were subsequently controlled by cytologic cervical smears. Additional colposcopically directed punch biopsies were taken in 26 patients at the first examination. The remission rate was similar in patients with or without punch biopsy (54% to 49%), as well as the progression rate (8% to 7%). In addition we performed in-situ hybridisation in all biopsy specimens for the detection of human papillomavirus (HPV)-DNA. On comparing the progression and remission rate of women with HPV-positive and HPV-negative dysplastic tissue, we found no difference between these two groups. Punch biopsy does not seem to have a therapeutic effect either in HPV positive or HPV negative CIN I.


Intraspecific variation in sexual isolation in the jewel wasp Nasonia.
Divergence in mate recognition systems can lead to reproductive isolation. In this study, we investigate patterns of intraspecific variation that contribute to premating isolation within and between two haplodiploid species, Nasonia vitripennis and N. longicornis. In a broad-scale survey of 17 North American isofemale lines encompassing the two species, we report strong asymmetric sexual isolation between species and a dramatic level of intraspecific variation for mate discrimination between species. A general lack of incipient speciation was found, with the exception of low levels of interpopulational sexual isolation within N. vitripennis. Regression analysis shows that the degree of intraspecific variation for within-species mating frequency is not associated with the degree for between-species mating frequency. Reinforcement or reproductive character displacement may be involved in some of the variation in interspecies premating isolation.


Theoretical and empirical arguments in relation to elective lymph node dissection for melanoma.
Nearly a century of clinical inquiry has failed to incontrovertibly resolve the question of whether elective lymph node dissection is therapeutically beneficial in the management of clinically localized melanoma. The controversy has been renewed by a recent interim update from the Intergroup Melanoma Surgical Program, sponsored by the National Cancer Institute, which has indicated a small survival benefit in a narrowly defined subgroup of patients with primary melanoma. That report stimulated this review of the data, which are presented in the historical context that originally prompted the Intergroup study. Case selection bias has intractably hindered firm conclusions from the numerous nonrandomized studies of elective lymphadenectomy. The two original randomized trials that were executed during the 1970s failed to uncover any significant effect of the procedure on survival. Definitive conclusions from the recent Intergroup report are limited by the likelihood that the observed therapeutic benefits are a chance occurrence resulting from uncorrected multiple subgroup comparisons. It remains uncertain whether elective lymphadenectomy can be therapeutically beneficial in the management of melanoma. Nevertheless, it is clear that the procedure, or preferably sentinel lymphatic mapping with selective lymphadenectomy, can provide clinically relevant prognostic information, as well as the staging data requisite to adjuvant interferon alfa-2b therapy or enrollment into other adjunctive trials for patients at high risk of clinical relapse.


Mivacurium in infants and children.
Mivacurium is the only available short-acting nondepolarizing muscle relaxant in clinical use. It is a bis-quaternary benzylisoquinolinium ester hydrolysed by plasma-cholinesterase into inactive compounds. The ED50 and ED95 in children are about 50 micrograms.kg-1 and 90 micrograms.kg-1 respectively. In infants, they have a tendency to be lower. A standard intubating dose of 0.25 mg.kg-1 causes complete neuromuscular depression in 1.5-2 min, recovery to 5% in 6-10 min, and complete recovery in 15-20 min. The recent tendency is to use 0.3 mg.kg-1 to obtain better intubating conditions with slight prolongation of effect. Since the recovery profile of mivacurium is independent of the dose and duration, it is most suitable for administration by continuous infusion. The infusion requirement in children is 10-16 micrograms.kg-1 min-1, which is about twice that of adults. Cutaneous flushes from histamine release are commonly seen with the larger doses of mivacurium; however, the associated hypotensive effects are minimal and counteracted by the tracheal intubation. The duration of action of mivacurium is prolonged in patients with cholinesterase deficiency. Mivacurium's neuromuscular effects can be satisfactorily antagonized by edrophonium or neostigmine.


Effect of infrared temperature on thermoregulatory behaviour in suckling piglets.
The objective of this study was to investigate the effect of infrared (IR) temperature on thermoregulatory behaviour in suckling piglets in the first 3 weeks after farrowing. A total of 10 piglets from each of the 16 litters were exposed to recommended IR temperature conditions at 1, 2 and 3 weeks of age, with a mild offset (4°C) in IR temperature during the first experiment and a more challenging offset (8°C) during the second experiment. Digital photos were taken when all piglets had settled in the creep area, and the lying posture and huddling behaviour were analysed. A lying posture score and a huddling score was calculated by multiplying the number of piglets in each category with a given value for each category, based on different lying postures and different degrees of huddling behaviour. With a 4°C change in IR temperature, the piglets tended to alter their lying posture, while an 8°C change had a significant effect on lying posture (P < 0.01). A change in IR temperature of 4°C had no effect on the degree of huddling. The huddling score decreased significantly with 8°C change in IR temperature (P < 0.05). Postural changes, rather than changes in degree of huddling were the preferred thermoregulatory strategy for suckling piglets.


Off-label psychopharmacologic prescribing for children: history supports close clinical monitoring.
The review presents pediatric adverse drug events from a historical perspective and focuses on selected safety issues associated with off-label use of medications for the psychiatric treatment of youth. Clinical monitoring procedures for major psychotropic drug classes are reviewed. Prior studies suggest that systematic treatment monitoring is warranted so as to both minimize risk of unexpected adverse events and exposures to ineffective treatments. Clinical trials to establish the efficacy and safety of drugs currently being used off-label in the pediatric population are needed. In the meantime, clinicians should consider the existing evidence-base for these drugs and institute close clinical monitoring.


Calreticulin Regulates SARS-CoV-2 Spike Protein Turnover and Modulates SARS-CoV-2 Infectivity.
Cardiovascular complications are major clinical hallmarks of acute and post-acute coronavirus disease 2019 (COVID-19). However, the mechanistic details of SARS-CoV-2 infectivity of endothelial cells remain largely unknown. Here, we demonstrate that the receptor binding domain (RBD) of the SARS-CoV-2 spike (S) protein shares a similarity with the proline-rich binding ena/VASP homology (EVH1) domain and identified the endoplasmic reticulum (ER) resident calreticulin (CALR) as an S-RBD interacting protein. Our biochemical analysis showed that CALR, via its proline-rich (P) domain, interacts with S-RBD and modulates proteostasis of the S protein. Treatment of cells with the proteasomal inhibitor bortezomib increased the expression of the S protein independent of CALR, whereas the lysosomal/autophagy inhibitor bafilomycin 1A, which interferes with the acidification of lysosome, selectively augmented the S protein levels in a CALR-dependent manner. More importantly, the shRNA-mediated knockdown of CALR increased SARS-CoV-2 infection and impaired calcium homeostasis of human endothelial cells. This study provides new insight into the infectivity of SARS-CoV-2, calcium hemostasis, and the role of CALR in the ER-lysosome-dependent proteolysis of the spike protein, which could be associated with cardiovascular complications in COVID-19 patients.


Cytology of metastatic renal medullary carcinoma in pleural effusion: a study of two cases.
Renal medullary carcinoma (RMC) is a rare and aggressive malignant epithelial neoplasm of the kidney. It almost exclusively affects children and young adults with a sickle cell trait or sickle cell disease. The majority of RMC patients present with widely disseminated disease at the time of diagnosis. Herein, we report two cases of young African-American patients with history of sickle cell trait, hematuria and renal mass, who present with malignant right pleural effusions. The cytology of pleural effusion reveals predominantly clusters and individual tumor cells. The tumor cells show high nuclear to cytoplasmic (NC) ratios and large nuclei with nuclear pleomorphism, nuclear grooves, and prominent single or multiple nucleoli. The cytoplasm is dense with a vacuolated and two-tone appearance. Surgical specimens of renal mass and lymph node show features of RMC. Metastatic RMC to the serous cavity is rare and may present a diagnostic dilemma since it may mimic a poorly differentiated adenocarcinoma or other high-grade malignant neoplasms. RMC should be considered in the differential diagnosis in young patients with a renal mass, particularly in those with history of sickle cell trait or sickle cell disease.


[Pharmacological action on the thrombocyte link in hemostasis in the treatment of ischemic heart disease].
The expediency of using agents inhibiting the functional property of blood platelets for the treatment and prevention of thrombus formation in the system of arteries is substantiated theoretically and by the findings of experimental and clinical study. Data are cited on the clinical use of acetylsalicylic acid, dipyridamole, clofibrat, and also of such preparations as pyridinol carbamate, nonachlasine, pentoxyphylline, cetedil, heparin, streptokinase and anti-vitamins K for the treatment of patients with ischemic heart disease. The correlations of the clinical effect and the influence of these drugs on various aspects of the functional blood platelet activity is analysed.


A Visible-Light-Sensitive Caged Serotonin.
Serotonin, or 5-hydroxytryptamine (5HT), is an important neurotransmitter in the nervous system of both vertebrates and invertebrates. Deficits in 5HT signaling are responsible for many disabling psychiatric conditions, and its molecular machinery is the target of many pharmaceuticals. We present a new 5HT phototrigger, the compound [Ru(bpy)2(PMe3)(5HT)]2+, where PMe3 is trimethylphosphine. As with other ruthenium-bipyridyl based caged compounds, [Ru(bpy)2(PMe3)(5HT)]2+ presents activity in the visible region of the spectrum. We characterize and discuss the photochemical properties of the caged compound, and demonstrate its use by modulating the excitability of mouse prefrontal principal neurons.


Exposure treatments for focal phobias. A review.
The effectiveness of in vivo exposure is evaluated in a comprehensive review of outcome studies on phobia treatments. A strictly data-based analysis focuses on issues of analog vs clinical research, methodological quality of designs, utilization of generalized measures, and maintenance of therapeutic change. In vivo exposure appears to be an effective treatment, both short- and long-term, and some decision rules for the clinical application are provided. However, from a researcher's point of view many methodological weaknesses (such as frequent lack of follow-up; unrealistic behavioral measures; and the utilization of unnecessarily complicated, and at times confusing, designs) are noted. A considerable consensus on the major procedural variables and on positive overall outcome justifies the clinical utility of the procedure. Detailed suggestions for further treatment comparisons are outlined, and a cautionary note on the potential of such a data-based review are added.


Progress on methods of gene detection in preimplantation embryos.
The advent of the polymerase chain reaction (PCR) and the development of fluorescence in situ hybridization (FISH) have had a tremendous impact on preimplantation genetic diagnosis (PGD). While PCR is a powerful tool in detecting genetic diseases or molecular markers affecting quantitative trait loci, the main use of FISH is screening for chromosomal aberrations. This presentation reviews the recent progress in preimplantation genetic diagnosis with an emphasis on bovine embryos. In particular the importance of biopsy size and strategies to avoid PCR contamination are discussed. Alternative DNA amplification and detection methods as well as methods to meet the challenge of multiple locus detection for marker assisted selection are presented.


Coexpression of stromelysin-3 and insulin-like growth factor II in tumors of ectodermal, mesodermal, and endodermal origin: indicator of a fetal cell phenotype.
Stromelysin-3 (ST-3) is thought to play an important role in invasion and tumor progression. We have analyzed ST-3 expression in fibroblasts with defined topographical relations to breast cancers. We demonstrate that these fibroblasts exhibit the same distinctive pattern of messenger ribonucleic acid (mRNA) expression that we have previously shown for insulin-like growth factor II (IGF-II). Tumor-derived fibroblasts and skin fibroblasts produce abundant ST-3 mRNA. Fibroblasts from normal breast stroma distant from the malignant tumor in the same patient express considerably less ST-3 mRNA. When we analyzed ST-3 and IGF-II gene expression in sarcomas, we found a similar pattern of coexpression. Immunohistochemical analysis of IGF-II and ST-3 protein expression in sarcomas and breast tumors confirmed the mRNA data. ST-3 mRNA expression was also seen in most colon cancer cell lines, again matching reports of IGF-II gene expression. As the two proteins are known to play an important role during fetal growth and development, their coexpression in fibroblasts from malignant tumors of ectodermal (breast cancer) and mesodermal (sarcoma) origin and in epithelial cells of endodermal origin (colon cancer) implies a more primitive cellular phenotype. The regained ability to express such developmentally regulated proteins might, therefore, be a more general marker indicating a fetal-type phenotype of cells in a malignant tumor.


Recent Advances in Stroke Prevention in Patients with Atrial Fibrillation and End-Stage Renal Disease.
Chronic kidney disease (CKD) is associated with a high prevalence of atrial fibrillation (AF), but in this population the risk/benefit ratio of anticoagulant therapy with vitamin K antagonists (VKA) for thromboprophylaxis is uncertain. In end-stage renal disease (ESRD) patients undergoing hemodialysis, VKA seem less effective in stroke prevention than in the general population, with an increased risk of major bleeding. Recently, novel oral anticoagulant agents (NOACs) have proven to be effective for stroke prevention in AF and have demonstrated an improved safety profile compared to VKA. Limited data from post hoc analyses of controlled clinical trials suggest the safe and effective use of NOACs in patients with moderate renal impairment (i.e., estimated glomerular filtration rate, eGFR, between 30 and 50 mL/min). The question still remains whether NOACs can be used in patients with an eGFR <30 mL/min, since there are no studies addressing this subject. In fact, patients with CKD stage 4 and 5 were excluded from controlled clinical trials on anticoagulation therapy for stroke prevention in AF. Left atrial appendage (LAA) occlusion represents a nonpharmacological alternative for stroke prevention in patients with AF who are difficult to manage medically. Preliminary data indicate a similar efficacy and safety profile in patients with CKD compared to patients with normal renal function. Stroke prevention in patients with ESRD and AF represents a clinical challenge with poor evidence. LAA occlusion may become the standard of care for stroke prevention in patients with ESRD and AF.


X-Ray Visualization of Intraductal Ethanol-Based Ablative Treatment for Prevention of Breast Cancer in Rat Models.
There are still a limited number of primary interventions for prevention of breast cancer. For women at a high risk of developing breast cancer, the most effective intervention is prophylactic mastectomy. This is a drastic surgical procedure in which the mammary epithelial cells that can give rise to breast cancer are completely removed along with the surrounding tissue. The goal of this protocol is to demonstrate the feasibility of a minimally invasive intraductal procedure that could become a new primary intervention for breast cancer prevention. This local procedure would preferentially ablate mammary epithelial cells before they can become malignant. Intraductal methods to deliver solutions directly to these epithelial cells in rodent models of breast cancer have been developed at Michigan State University and elsewhere. The rat mammary gland consists of a single ductal tree that has a simpler and more linear architecture compared to the human breast. However, chemically induced rat models of breast cancer offer valuable tools for proof-of-concept studies of new preventive interventions and scalability from mouse models to humans. Here, a procedure for intraductal delivery of an ethanol-based ablative solution containing tantalum oxide nanoparticles as X-ray contrast agent and ethyl cellulose as gelling agent into the rat mammary ductal tree is described. Delivery of aqueous reagents (e.g., cytotoxic compounds, siRNAs, AdCre) by intraductal injection has been described previously in mouse and rat models. This protocol description emphasizes methodological changes and steps that pertain uniquely to delivering an ablative solution, formulation consideration to minimize local and systemic side effects of the ablative solution, and X-ray imaging for in vivo assessment of ductal tree filling. Fluoroscopy and micro-CT techniques enable to determine the success of ablative solution delivery and the extent of ductal tree filling thanks to compatibility with the tantalum-containing contrast agent.


Case report: false aneurysm due to synovial sarcoma.
On the basis of a false aneurysm of the radial artery caused by a synovial sarcoma, the behavior and histology of this fairly rare tumor are discussed. There are no reports in the literature which record such a rapidly developing synovial sarcoma as that observed in the patient described here.


Leishmania major encodes an unusual peroxidase that is a close homologue of plant ascorbate peroxidase: a novel role of the transmembrane domain.
Haem-containing enzymes (peroxidase and catalase) are widely distributed among prokaryotes and eukaryotes and play a vital role in H2O2 detoxification. But, to date, no haem-containing enzymatic defence against toxic H2O2 has been discovered in Leishmania species. We cloned, expressed and purified an unusual plant-like APX (ascorbate peroxidase) from Leishmania major (LmAPX) and characterized its catalytic parameters under steady-state conditions. Examination of its protein sequence indicated approx. 30-60% identity with other APXs. The N-terminal extension of LmAPX is characterized by a charged region followed by a stretch of 22 amino acids containing a transmembrane domain. To understand how the transmembrane domain influences the structure-function of LmAPX, we generated, purified and extensively characterized a variant that lacked the transmembrane domain. Eliminating the transmembrane domain had no impact on substrate-binding affinity but slowed down ascorbate oxidation and increased resistance to H2O2-dependent inactivation in the absence of electron donor by 480-fold. Spectral studies show that H2O2 can quickly oxidize the native enzyme to compound (II), which subsequently is reduced back to the native enzyme by an electron donor. In contrast, ascorbate-free transmembrane domain-containing enzyme did not react with H2O2, as revealed by the absence of compound (II) formation. Our findings suggest that the single copy LmAPX gene may play an important role in detoxification of H2O2 that is generated by endogenous processes and as a result of external influences such as the oxidative burst of infected host macrophages or during drug metabolism by Leishmania.


Sympathectomy alters bone architecture in adult growing rats.
Sympathetic nervous system (SNS) fibres and alpha- and beta-receptors are present in bone, indicating that the SNS may participate in bone metabolism. The importance of these observations is controversial because stimulation or inhibition of the SNS has had various effects upon both anabolic and catabolic activity in this tissue. In this study we evaluated the effects of pharmacological sympathectomy, using chronic treatment of maturing male rats with 40 mg of guanethidine/kg i.p., upon various parameters in bone. Double labelling with tetracycline injection was also performed 20 and 2 days before sacrifice. Bone mass, mineral content, density and histomorphometric characteristics in different skeletal regions were determined. Bone metabolic markers included urinary deoxypyridinoline and serum osteocalcin measurements. Guanethidine significantly reduced the accretion of lumbar vertebral bone and of mineral content and density, compared to controls. Femoral bone mineral content and density were also significantly reduced, compared to controls. Histomorphometric analyses indicated these effects were related to a reduction of cortical bone and mineral apposition rate at femoral diaphysials level. Both markers of bone metabolism were reduced in controls as they approached maturity. Guanethidine significantly decreased serum osteocalcin compared to controls, while urinary deoxypyridinoline was unchanged. These data indicate that guanethidine-induced sympathectomy caused a negative balance of bone metabolism, leading to decreased mass by regulating deposition rather than resorption during modeling and remodeling of bone.


Issues with reducing the rotavirus-associated mortality by vaccination in developing countries.
More than 65% of the global rotavirus deaths were estimated to occur in 11 countries in Asia and Africa, claiming 345,000 children less than 5 years of age in 2004. While efficacious rotavirus vaccines are at hand, inequity in health delivery system within and between these countries was found to be the major hurdle against achieving the goal of rotavirus vaccine. When the coverage of currently used vaccines was applied to a rotavirus vaccine, a maximum of 202,550 deaths would be averted. Even if the coverage reached 80%, there would remain 96,841 children dying because of rotavirus diarrhea in these 11 countries. Studies are therefore encouraged to develop comprehensive strategies to resolve inequity in health delivery system enabling the increase in the immunization coverage.


Sleep quantity and quality in elite youth soccer players: a pilot study.
This study examined the effect of early evening high-intensity training on the sleep of elite male youth soccer players (n = 12) using wrist actigraphy. High-intensity training (TRAIN) nights were compared with a home environment (HOME) condition, created by averaging sleep variables on the night before and after TRAIN nights. Additionally, after TRAIN athletes alternately used cold water immersion (TRAIN+CWI) or none, to assess whether cold water immersion (CWI) had any impact on sleep quality and quantity. Ratings of perceived exertion, fatigue and recovery were recorded after training. Actigraphy sleep measures were bedtime, wake time, sleep duration, sleep onset latency, sleep efficiency and wake after sleep onset. Self-rated scores of sleepiness at bedtime and wake, plus overall sleep quality were also recorded. Only fatigue ratings were higher in TRAIN compared to TRAIN+CWI at bedtime, there were no other differences in training data. Both TRAIN and TRAIN+CWI conditions had significant later (07:45 ± 1:09 h p < 0.01 and 07:34 ± 1:20 h p = 0.01) wake times than HOME (06:44 ± 0:41 h). The TRAIN condition had a significantly higher (7 ± 2; p < 0.01) rating of sleepiness at bedtime compared to HOME (6 ± 1), but no further differences were found in any of the sleep (actigraphy and self-reported) measures. Across all conditions, time spent asleep was ∼7:30 (±0:52) h:min and sleep efficiency was ∼89% (±6.1). In conclusion, early evening high-intensity training had no impact on subsequent sleep quality and quantity, nor was there any effect on sleep after performing CWI post-training.


Transformational leadership and personal values for managers in the new millennium.
Transformational leadership is best suited to the many demands that home health managers face daily. Transformational leaders who are driven by values that remain constant are better able to guide their agency. They are the ones able to make sound decisions now and have a vision for the future.


Polymicrobial Infections In Brain Tissue From Alzheimer's Disease Patients.
Several studies have advanced the idea that the etiology of Alzheimer's disease (AD) could be microbial in origin. In the present study, we tested the possibility that polymicrobial infections exist in tissue from the entorhinal cortex/hippocampus region of patients with AD using immunohistochemistry (confocal laser scanning microscopy) and highly sensitive (nested) PCR. We found no evidence for expression of early (ICP0) or late (ICP5) proteins of herpes simplex virus type 1 (HSV-1) in brain sections. A polyclonal antibody against Borrelia detected structures that appeared not related to spirochetes, but rather to fungi. These structures were not found with a monoclonal antibody. Also, Borrelia DNA was undetectable by nested PCR in the ten patients analyzed. By contrast, two independent Chlamydophila antibodies revealed several structures that resembled fungal cells and hyphae, and prokaryotic cells, but most probably were unrelated to Chlamydophila spp. Finally, several structures that could belong to fungi or prokaryotes were detected using peptidoglycan and Clostridium antibodies, and PCR analysis revealed the presence of several bacteria in frozen brain tissue from AD patients. Thus, our results show that polymicrobial infections consisting of fungi and bacteria can be revealed in brain tissue from AD patients.


ROS-mediated abiotic stress-induced programmed cell death in plants.
During the course of their ontogenesis plants are continuously exposed to a large variety of abiotic stress factors which can damage tissues and jeopardize the survival of the organism unless properly countered. While animals can simply escape and thus evade stressors, plants as sessile organisms have developed complex strategies to withstand them. When the intensity of a detrimental factor is high, one of the defense programs employed by plants is the induction of programmed cell death (PCD). This is an active, genetically controlled process which is initiated to isolate and remove damaged tissues thereby ensuring the survival of the organism. The mechanism of PCD induction usually includes an increase in the levels of reactive oxygen species (ROS) which are utilized as mediators of the stress signal. Abiotic stress-induced PCD is not only a process of fundamental biological importance, but also of considerable interest to agricultural practice as it has the potential to significantly influence crop yield. Therefore, numerous scientific enterprises have focused on elucidating the mechanisms leading to and controlling PCD in response to adverse conditions in plants. This knowledge may help develop novel strategies to obtain more resilient crop varieties with improved tolerance and enhanced productivity. The aim of the present review is to summarize the recent advances in research on ROS-induced PCD related to abiotic stress and the role of the organelles in the process.


MORPHOFUNCTIONAL EVALUATION IN DOME-SHAPED MACULA: A MICROPERIMETRY AND OPTICAL COHERENCE TOMOGRAPHY STUDY.
To investigate retinal sensitivity (Se) in dome-shaped macula (DSM) using microperimetry and to correlate functional findings to specific spectral domain optical coherence tomography features. Patients affected by DSM in at least 1 eye were consecutively enrolled in a prospective, cross-sectional study. All studied eyes performed best-corrected visual acuity measurement, microperimetry to assess Se and optical coherence tomography to investigate DSM pattern and to measure bulge height and retinal and choroidal thicknesses. Fifty-three eyes of 29 patients were studied. Dome-shaped macula was vertically oriented (V-DSM) in 23 (43.4%), symmetric (S-DSM) in 17 (32.1%), and horizontally oriented (H-DSM) in 13 eyes (24.5%). Foveal subretinal fluid was present in 29/53 (54.7%) cases; it correlated to the bulge height (P < 0.0001) and determined a reduction of Se (P < 0.0001) not of best-corrected visual acuity (P = 0.7105). Mean Se was 13.9 ± 3.2 dB. Microperimetry parameters did not differ among the different DSM patterns. However, Se was significantly impaired if foveal subretinal fluid was present in V-DSM and in S-DSM, but not in H-DSM (V-DSM: P < 0.0001; S-DSM: P = 0.0252; H-DSM: P = 0.5723). In H-DSM, inferior choroidal thickness was thicker in cases with foveal subretinal fluid compared with those without it (P = 0.0363). In DSM, Se evaluation better reflects the central functional impairment than best-corrected visual acuity, particularly when some optical coherence tomography features, such as foveal subretinal fluid and higher bulge height, are present.


Complications in humeral shaft fractures - non-union, iatrogenic radial nerve palsy, and postoperative infection: a systematic review and meta-analysis.
The aim of this systematic review and meta-analysis was to assess risk for iatrogenic radial nerve palsy (iRNP), non-union, and post-operative infection in humeral shaft fractures. A PubMed search including original articles comparing different treatments for humeral shaft fractures published since January 2000 was performed. Random effect models with relative risks (RR) and 95% CIs were calculated for treatment groups and outcomes. Of the 841 results, 43 studies were included in the meta-analysis (11 level II, 5 level III, 27 level IV). Twenty-seven compared intramedullary nailing (IM) with ORIF, nine conservative with operative treatment, four ORIF with minimally invasive plate osteosynthesis (MIPO), and three anterior/anterolateral with posterior approach. iRNP risk was higher for ORIF vs IM (18 studies; RR: 1.80; P = 0.047), ORIF vs MIPO (4 studies; RR: 5.60; P = 0.011), and posterior vs anterior/anterolateral approach (3 studies; RR: 2.68; P = 0.005). Non-union risk was lower for operative vs conservative therapy (six studies; RR: 0.37; P < 0.001), but not significantly different between ORIF and IM (21 studies; RR: 1.00; P = 0.997), or approaches (two studies; RR: 0.36; P = 0.369). Post-operative infection risk was higher for ORIF vs IM (14 studies; RR: 1.84; P = 0.004) but not different between approaches (2 studies; RR: 0.95; P = 0.960). Surgery appears to be the method of choice when aiming to secure bony union, albeit risk for iRNP has to be considered, particularly in case of ORIF vs IM or MIPO, and posterior approach. Due to the limited number of randomised studies, evidence on the best treatment option remains moderate, though.


Deregulation of the Akt pathway in human cancer.
Akt (protein kinase B) is a serine/threonine kinase which is a central regulator of widely divergent cellular processes including proliferation, differentiation, migration, survival and metabolism. Akt is activated by a variety of stimuli, through growth factor receptors, in phosphatidylinositol 3-kinase (PI3K)-dependent manner. Akt is also negatively regulated by the tumor suppressor phosphatase and tensin homolog deleted on chromosome 10 (PTEN). A disruption of normal Akt/PKB/PTEN signaling frequently occurs in many human cancers, which plays an important role in cancer development, progression and therapeutic resistance. Numerous studies have revealed the blockage of Akt signaling to result in apoptosis and growth inhibition of tumor cells. Therefore, this signaling pathway, including both upstream and downstream of Akt, has recently attracted considerable attention as a new target for effective cancer therapeutic strategies. In fact, many inhibitors of Akt pathway have been identified and clinical studies of some agents are ongoing. In this review, we describe Akt signaling pathway components and its cellular functions as well as the alterations in human cancers and the therapeutic approaches for targeting the Akt pathway in cancer.


Mini outbreak of Kaposi's varicelliform eruption in skin ward: a study of five cases.
Kaposis varicelliform eruption (KVE) represents widespread cutaneous herpes simplex virus (HSV) infection in patients with preexisting dermatoses. Occasionally, this infection can present as a nosocomial infection in skin wards, if adequate bed-spacing and barrier nursing methods are not followed. We are reporting five cases of KVE; four cases acquired the infection in a makeshift ward after admission of the first case in May 2005, due to the renovation work of the regular skin ward. The purpose of this study is to create clinical awareness about this uncommon dermatologic entity and to stress upon the importance of bed-spacing and barrier nursing in skin wards. Five cases of KVE, three females and two males with different primary dermatoses (pemphigus foliaceus--one, pemphigus vulgaris--two, paraneoplastic pemphigus--one and toxic epidemal necrolysis--one) were included in this study. Diagnosis was made clinically and supported with Tzanck smear and HSV serology. All the cases were treated with oral acyclovir. Four out of five cases of KVE recovered with treatment, one case of extensive pemphigus vulgaris with KVE succumbed to death. Mini outbreaks of KVE can occur in skin wards with inadequate bed-spacing and overcrowding of patients. Therefore adequate bed-spacing, barrier nursing and isolation of suspected cases are mandatory to prevent such life-threatening infections.


Comparison of Exponential and Biexponential Models of the Unimolecular Decomposition Probability for the Hinshelwood-Lindemann Mechanism.
The traditional understanding is that the Hinshelwood-Lindemann mechanism for thermal unimolecular reactions, and the resulting unimolecular rate constant versus temperature and collision frequency ω (i.e., pressure), requires the Rice-Ramsperger-Kassel-Marcus (RRKM) rate constant k(E) to represent the unimolecular reaction of the excited molecule versus energy. RRKM theory assumes an exponential N(t)/N(0) population for the excited molecule versus time, with decay given by RRKM microcanonical k(E), and agreement between experimental and Hinshelwood-Lindemann thermal kinetics is then deemed to identify the unimolecular reactant as a RRKM molecule. However, recent calculations of the Hinshelwood-Lindemann rate constant kuni(ω,E) has brought this assumption into question. It was found that a biexponential N(t)/N(0), for intrinsic non-RRKM dynamics, gives a Hinshelwood-Lindemann kuni(ω,E) curve very similar to that of RRKM theory, which assumes exponential dynamics. The RRKM kuni(ω,E) curve was brought into agreement with the biexponential kuni(ω,E) by multiplying ω in the RRKM expression for kuni(ω,E) by an energy transfer efficiency factor βc. Such scaling is often done in fitting Hinshelwood-Lindemann-RRKM thermal kinetics to experiment. This agreement between the RRKM and non-RRKM curves for kuni(ω,E) was only obtained previously by scaling and fitting. In the work presented here, it is shown that if ω in the RRKM kuni(ω,E) is scaled by a βc factor there is analytic agreement with the non-RRKM kuni(ω,E). The expression for the value of βc is derived.


Molecular clonality analysis of esophageal adenocarcinoma by multiregion sequencing of tumor samples.
Intratumor heterogeneity has been demonstrated in several cancer types, following a model of branched evolution. It is unknown to which extent intratumor heterogeneity is applicable to esophageal adenocarcinoma. Therefore the aim of this study was to characterise intratumor heterogeneity in esophageal adenocarcinoma. Multiregional targeted sequencing of four commonly altered genes was performed on 19 tumor regions collected from five esophageal adenocarcinomas. Alterations were classified as homogeneous or heterogeneous based on mutational and loss of heterozygosity analysis. Identical TP53 mutations and homogeneously loss of heterozygosity of the TP53 locus were identified in all separated tumor regions in each of five adenocarcinomas, and in the corresponding Barrett's esophagus and tumor positive lymph node of one primary tumor. Loss of heterozygosity of the P16 locus was homogeneous among all tumor regions in four adenocarcinomas, and an identical pattern of loss of heterozygosity was present in the Barrett's esophagus. Loss of heterozygosity of the SMAD4 and APC loci was observed in a heterogeneous pattern. Known driver alterations, such as TP53 and P16 are homogeneously present within each adenocarcinoma, and therefore occur early during carcinogenesis and subsequently clonally expand throughout the entire tumor. However, loss of heterozygosity of the SMAD4 and APC loci shows a heterogeneous pattern, indicating intratumor heterogeneity of esophageal adenocarcinoma.


Control of sex development.
The process of sexual differentiation is central for reproduction of almost all metazoan, and therefore, for maintenance of practically all multicellular organisms. In sex development, we can distinguish two different processes, sex determination, that is the developmental decision that directs the undifferentiated embryo into a sexually dimorphic individual. In mammals, sex determination equals gonadal development. The second process known as sex differentiation takes place once the sex determination decision has been made through factors produced by the gonads that determine the development of the phenotypic sex. Most of the knowledge on the factors involved in sexual development came from animal models and from studies of cases in whom the genetic or the gonadal sex does not match the phenotypical sex, that is, patients affected by disorders of sex development (DSDs). Generally speaking, factors influencing sex determination are transcriptional regulators, whereas factors important for sex differentiation are secreted hormones and their receptors. This review focuses on these factors and whenever possible, references regarding the 'prismatic' clinical cases are given.


PSO-based multiobjective optimization with dynamic population size and adaptive local archives.
Recently, various multiobjective particle swarm optimization (MOPSO) algorithms have been developed to efficiently and effectively solve multiobjective optimization problems. However, the existing MOPSO designs generally adopt a notion to "estimate" a fixed population size sufficiently to explore the search space without incurring excessive computational complexity. To address the issue, this paper proposes the integration of a dynamic population strategy within the multiple-swarm MOPSO. The proposed algorithm is named dynamic population multiple-swarm MOPSO. An additional feature, adaptive local archives, is designed to improve the diversity within each swarm. Performance metrics and benchmark test functions are used to examine the performance of the proposed algorithm compared with that of five selected MOPSOs and two selected multiobjective evolutionary algorithms. In addition, the computational cost of the proposed algorithm is quantified and compared with that of the selected MOPSOs. The proposed algorithm shows competitive results with improved diversity and convergence and demands less computational cost.


Unlocking patients with mental disorders who were in restraints at home: a national follow-up study of China's new public mental health initiatives.
In 2005, China implemented a demonstration program known as "686" to scale-up nation-wide basic mental health services designed to improve access to evidence-based care and to promote human rights for people with severe mental disorders. As part of the 686 Program, teams "unlocked" and provided continuous mental health care to people with severe mental disorders who were found in restraints and largely untreated in their family homes. We implemented a nation-wide two-stage follow-up study to measure the effectiveness and sustainability of the "unlocking and treatment" intervention and its impact on the well-being of patients' families. 266 patients unlocked from 2005 in "686" demonstration sites across China were recruited in Stage One of the study in 2009. In 2012, 230 of the 266 cases were re-interviewed (the Stage Two study). Outcome measures included the patient medication adherence and social functioning, family burden ratings, and relocking rate. We utilized pre-post tests to analyze the changes over time following the unlocking efforts. 96% of patients were diagnosed with schizophrenia. Prior to unlocking, their total time locked ranged from two weeks to 28 years, with 32% having been locked multiple times. The number of persons regularly taking medicines increased from one person at the time of unlocking to 74% in 2009 and 76% in 2012. Pre-post tests showed sustained improvement in patient social functioning and significant reductions in family burden. Over 92% of patients remained free of restraints in 2012. Practice-based evidence from our study suggests an important model for protecting the human rights of people with mental disorders and keeping them free of restraints can be achieved by providing accessible, community based mental health services with continuity of care. China's "686" Program can inform similar efforts in low-resource settings where community locking of patients is practiced.


Global assessment of C-reactive protein and health-related outcomes: an umbrella review of evidence from observational studies and Mendelian randomization studies.
C-reactive protein (CRP) has been studied extensively for association with a large number of non-infectious diseases and outcomes. We aimed to evaluate the breadth and validity of associations between CRP and non-infectious, chronic health outcomes and biomarkers. We conducted an umbrella review of systematic reviews and meta-analyses and a systematic review of Mendelian randomization (MR) studies. PubMed, Scopus, and Cochrane Database of Systematic Reviews were systematically searched from inception up to March 2019. Meta-analyses of observational studies and MR studies examining associations between CRP and health outcomes were identified, excluding studies on the diagnostic value of CRP for infections. We found 113 meta-analytic comparisons of observational studies and 196 MR analyses, covering a wide range of outcomes. The overwhelming majority of the meta-analyses of observational studies reported a nominally statistically significant result (95/113, 84.1%); however, the majority of the meta-analyses displayed substantial heterogeneity (47.8%), small study effects (39.8%) or excess significance (41.6%). Only two outcomes, cardiovascular mortality and venous thromboembolism, showed convincing evidence of association with CRP levels. When examining the MR literature, we found MR studies for 53/113 outcomes examined in the observational study meta-analyses but substantial support for a causal association with CRP was not observed for any phenotype. Despite the striking amount of research on CRP, convincing evidence for associations and causal effects is remarkably limited.


Collective Behavior of Chiral Active Matter: Pattern Formation and Enhanced Flocking.
We generalize the Vicsek model to describe the collective behavior of polar circle swimmers with local alignment interactions. While the phase transition leading to collective motion in 2D (flocking) occurs at the same interaction to noise ratio as for linear swimmers, as we show, circular motion enhances the polarization in the ordered phase (enhanced flocking) and induces secondary instabilities leading to structure formation. Slow rotations promote macroscopic droplets with late time sizes proportional to the system size (indicating phase separation) whereas fast rotations generate patterns consisting of phase synchronized microflocks with a controllable characteristic size proportional to the average single-particle swimming radius. Our results defy the viewpoint that monofrequent rotations form a vapid extension of the Vicsek model and establish a generic route to pattern formation in chiral active matter with possible applications for understanding and designing rotating microflocks.


An atypical case of cutaneous leishmaniasis caused by Leishmania infantum in Portugal.
Leishmaniasis is a parasitic disease caused by an intracellular protozoan that belongs to the genus Leishmania and is transmitted by a phlebotomine sandfly. In Southwest Europe, including Portugal, cutaneous leishmaniasis is considered a rare disease of unknown or underestimated prevalence. Leishmania infantum is the only species identified as responsible for the autochthonous cases.We report the case of a 66-year-old man with an erythematous, painless plaque on the mid face region, accompanied by nasal obstruction with 9 months of evolution. The initial diagnoses were: lymphoma, subcutaneous mycosis, Wegener's granulomatosis, and lupus vulgaris. The diagnosis of leishmaniasis was based on histopathology findings and identification of L. infantum by DNA based methods. Blood cultures, abdominal ultrasound and myelogram ruled out systemic involvement. The patient was treated with intravenous meglumine antimoniate (20 mg per kg/day) for four weeks, without major side effects.We emphasize the importance of this case because human cutaneous leishmaniasis has rarely been diagnosed in Portugal and some cases are atypical, such as the situation herein described.


Werner protein recruits DNA polymerase delta to the nucleolus.
Werner syndrome is a Mendelian disorder of man that produces a number of manifestations resembling human aging. This disorder is caused by inactivation of the wrn gene, a member of the RecQ family of DNA helicases. The helicase and exonuclease activities of the Werner protein (WRN) suggest that it functions in DNA transactions, but the physiological function of WRN remains elusive. We present several lines of evidence that WRN interacts specifically with the p50 subunit of polymerase delta, the major DNA polymerase required for chromosomal DNA replication. P50, identified by yeast two-hybrid screening, interacts physically with the C terminus of WRN. Native WRN protein coimmunoprecipitates with p50 in a cellular fraction enriched in nucleolar proteins, and this immunocomplex also includes p125, the catalytic subunit of polymerase delta. In subcellular localization studies of cells transfected with WRN, p50 and p125 redistribute to the nucleolus and colocalize with WRN. These results suggest that one of the functions of WRN protein is to directly modify DNA replication via its interaction with p50 and abet dynamic relocalization of the DNA polymerase delta complexes within the nucleus.


[An aniline method of determining glucose in biological fluids].
A simple method for glucose measurements in biologic fluids has been developed, making use of aniline chromogen. Using this method, one may do without carcinogenic ortho-toluidine and work with less concentrated (and less acid) acetic acid solutions. Introduction of the aniline method of glucose measurement will help improve the working conditions of laboratory assistants at laboratories employing the ortho-toluidine method at present.