Scarce resources, public health and professional care: the COVID-19 pandemic exacerbating bioethical conflicts - findings from global qualitative expert interviews.
Since spring 2020, the SARS-CoV-2 virus has spread worldwide, causing dramatic global consequences in terms of medical, care, economic, cultural and bioethical dimensions. Although the resulting conflicts initially appeared to be quite similar in most countries, a closer look reveals a country-specific intensification and differentiation of issues. Our study focused on understanding and highlighting bioethical conflicts that were triggered, exposed or intensified by the COVID-19 pandemic in low and middle-income countries (LMICs) and high-income countries (HICs). We conducted qualitative interviews with 39 ethics experts from 34 countries (Argentina, Australia, Austria, Brazil, Canada, Colombia, Denmark, Ecuador, Ethiopia, France, Germany, India, Italy, Israel, Japan, Kyrgyzstan, Mexico, Nigeria, Oman, Pakistan, Paraguay, Poland, Romania, Russia, Singapore, South Korea, Spain, Sweden, South Africa, Tunisia, Türkiye, United-Kingdom, United States of America, Zambia) from November 2020 to March 2021. We analysed the interviews using qualitative content analysis. The scale of the bioethical challenges between countries differed, as did coping strategies for meeting these challenges. Data analysis focused on: a) Resource scarcity in clinical contexts: Scarcity of medical resources led to the need to prioritize the care of some COVID-19 patients in clinical settings globally. Because this entails the postponement of treatment for other patients, the possibility of serious present or future harm to deprioritized patients was identified as a relevant issue. b) Health literacy: The pandemic demonstrated the significance of health literacy and its influence on the effective implementation of health measures. c) Inequality and vulnerable groups: The pandemic highlighted the context-sensitivity and intersectionality of the vulnerabilities of women and children in LMICs and the aged in HICs. d) Conflicts surrounding healthcare professionals: The COVID-19 outbreak underscored the tough working conditions for nurses and other health professionals, raising awareness of the need for reform. The pandemic exposed pre-existing structural problems in LMICs and HICs. Without neglecting individual contextual factors in the observed countries, we created a mosaic of different voices of experts in bioethics across the globe, drawing attention to the need for international solidarity in the context of a global crisis.


The effect of membrane biocompatibility on plasma beta 2-microglobulin levels in chronic hemodialysis patients.
Several studies have shown that patients who have been dialyzed with high-flux biocompatible membranes have a lower plasma level of beta 2-microglobulin and a lower incidence of amyloid disease compared with patients who have been dialyzed with low-flux bioincompatible membranes. However, because high-flux membranes are associated with significant dialytic removal of beta 2-microglobulin, the specific role of membrane biocompatibility in influencing the rate of increase of beta 2-microglobulin has not been previously determined. This study investigated the effect of biocompatibility on the rate of increase of plasma levels of beta 2-microglobulin in 159 new hemodialysis patients from 13 dialysis centers (ten centers affiliated with Dallas Nephrology Associates and three with Vanderbilt University Medical Center) by using two low-flux membranes with widely different biocompatibilities. These patients were prospectively randomized to be dialyzed with either a low-flux biocompatible membrane or a low-flux bioincompatible membrane. Plasma beta 2-microglobulin levels were measured at 0, 3, 6, 9, 12, and 18 months. Sixty-six patients completed the 18-month study. Plasma beta 2-microglobulin increased in all patients; however, the increase was not significantly different from baseline at any time point in the group that used the biocompatible membrane. In this group, beta 2-microglobulin increased from (mean +/- SD) 27.8 +/- 14.8 mg/L to 34.0 +/- 10.0 mg/L at 18 months (P = not significant), and the mean increase at 18 months was 2.6 +/- 14.7 mg/L. In contrast, the increase in plasma beta 2-microglobulin level in the bioincompatible membrane group became significant in Month 6 when the levels had increased from a baseline of 24.8 +/- 9.6 mg/L to 29.5 +/- 12.2 mg/L (P < 0.001); these increases continued to be significant until Month 18, when serum beta 2-microglobulin reached 36.8 +/- 13.9 mg/L with an average increase of 11.8 +/- 11.2 mg/L (P < 0.0001). The higher rate of plasma B2-microglobulin increase in the group that had been dialyzed with the bioincompatible membrane was also evident when only patients who had completed the study were analyzed. There were no significant differences in the actual level of beta 2-microglobulin or in residual renal function between the two groups during the 18 months of the study. It was concluded that over a period of 18 months, the use of biocompatible membranes, even in the low-flux configuration, is associated with a significantly slower increase in plasma beta 2-microglobulin, independent of the influence of residual renal function.


p53 protein expression status and recurrence in men treated with radiation and androgen suppression therapy for higher-risk prostate cancer: a prospective phase II Cancer and Leukemia Group B Study (CALGB 9682).
It has been hypothesized that abnormal p53 protein expression is associated with a worse prognosis after radiation (RT) and androgen suppression therapy (AST). This hypothesis was prospectively tested. Between May 1997 and April 2001, 180 men with clinical stage T1c-T3cN0M0 adenocarcinoma of the prostate were registered on a study evaluating whether the endorectal magnetic resonance imaging (eMRI)-defined change in tumor volume (TV) during neoadjuvant (n) AST was associated with prostate-specific antigen (PSA) outcome. Of these, 141 had sufficient tissue to perform immunohistochemical detection of the p53 protein expression status and 113 had complete eMRI information. Multivariable Cox regression analysis was used to assess whether p53 protein expression status predicted time to PSA failure adjusting for known prognostic factors. After a median follow-up of 6.9 years and adjusting for PSA level, Gleason score, clinical stage, and eMRI-defined TV change during nAST, men with abnormal compared with normal p53 expression were at increased risk of PSA failure (hazard ratio [HR]: 2.8; 95% confidence interval [CI]: 1.3-5.9; P = 0.008 for the 141; HR: 2.4; 95% CI: 1.1-5.4; P = 0.03 for the 113). Adjusted estimates of PSA failure were significantly higher (P = 0.03) in men with abnormal compared with normal p53 expression. At 5 years, these respective estimates were 33% and 18%. Maximizing local control and randomized trials evaluating the impact on survival of adding novel agents to maximal local therapy are warranted in men whose prostate cancer demonstrates abnormal p53 expression.


Milestones for Apheresis education.
Milestones represent the essential knowledge, skills, and attitudes required for the practice of a medical discipline. Defining these milestones for each medical specialty has become a focus for the American Council of Graduate Medical Education (ACGME). Practitioners of Apheresis Medicine come from a variety of medical specialties making it challenging to establish the essential educational milestones for all. The American Society for Apheresis (ASFA) has an interest in promoting standards of excellence for Apheresis Medicine. ASFA's Physician's Curriculum Content Committee is a group of physician educators in the field of Apheresis Medicine, both donor and therapeutic, from across the United States, who have met regularly for several years to discuss the appropriate educational milestones in Apheresis training. The committee members teach residents and fellows from Pathology, Transfusion Medicine, Hematology/Oncology, Nephrology and other specialties. In this document, we have outlined the basic set of Apheresis milestones required in the ACGME defined competency areas of Patient Care and Medical Knowledge. We have also recommended methods of evaluation and estimated the time necessary for the acquisition of these cognitive and behavioral elements.


Combinatorial Library Screening with Liposomes for Discovery of Membrane Active Peptides.
Membrane active peptides (MAPs) represent a class of short biomolecules that have shown great promise in facilitating intracellular delivery without disrupting cellular plasma membranes. Yet their clinical application has been stalled by numerous factors: off-target delivery, a requirement for high local concentration near cells of interest, degradation en route to the target site, and in the case of cell-penetrating peptides, eventual entrapment in endolysosomal compartments. The current method of deriving MAPs from naturally occurring proteins has restricted the discovery of new peptides that may overcome these limitations. Here, we describe a new branch of assays featuring high-throughput functional screening capable of discovering new peptides with tailored cell uptake and endosomal escape capabilities. The one-bead-one-compound (OBOC) combinatorial method is used to screen libraries containing millions of potential MAPs for binding to synthetic liposomes, which can be adapted to mimic various aspects of limiting membranes. By incorporating unnatural and d-amino acids in the library, in addition to varying buffer conditions and liposome compositions, we have identified several new highly potent MAPs that improve on current standards and introduce motifs that were previously unknown or considered unsuitable. Since small variations in pH and lipid composition can be controlled during screening, peptides discovered using this methodology could aid researchers building drug delivery platforms with unique requirements, such as targeted intracellular localization.


[Recurrent idiopathic hypertrophic pachymeningitis after surgery of chronic otitis media with cholesteatoma: a case report].
A 70-year-old woman visited our hospital because of a chronic headache four years ago. MRI demonstrated almost symmetrically thickened dura mater in the frontal and parietal regions. She was diagnosed with idiopathic hypertrophic pachymeningitis and received corticosteroid therapy. Corticosteroid therapy improved her clinical symptoms and thickening of the dura mater. She remained free of neurological symptoms after prednisolone was tapered to 5 mg/day. However, three years ago, she developed ear pain, otorrhea and hearing loss on the left side. She was diagnosed as having otitis media with cholesteatoma last year, and underwent mastoidectomy and tympanoplasty on the left side three months ago. After surgery, she recovered from the ear symptoms, but noticed a headache on the left side. Three months after the surgery, MRI demonstrated the recurrence of hypertrophic pachymeningitis in the frontal and parietal regions, particularly on the left side. Corticosteroid therapy again improved the headache and thickening of the dura mater. The finding that the patient recovered after corticosteroid therapy alone suggests that non-infectious inflammation played a major role in the pathogenesis. Chronic inflammation associated with otitis media with cholesteatoma or surgical invasiveness might induce the recurrence of idiopathic hypertrophic pachymeningitis.


Integrin αvβ3-Targeted [64Cu]CuS Nanoparticles for PET/CT Imaging and Photothermal Ablation Therapy.
Copper sulfide (CuS) nanoparticles have been considered one of the most clinical relevant nanosystems because of their straightforward chemistry, small particle size, low toxicity, and intrinsic theranostic characteristics. In our previous studies, radioactive [64Cu]CuS nanoparticles were successfully developed to be used as efficient radiotracers for positron emission tomography and for photothermal ablation therapy of cancer cells using near-infrared laser irradiation. However, the major challenge of CuS nanoparticles as a theranostic platform is the lack of a means for effective targeted delivery to the tumor site. To overcome this challenge, we designed and synthesized angiogenesis-targeting [64Cu]CuS nanoparticles, which are coupled with cyclic RGDfK peptide [c(RGDfK)] through polyethylene glycol (PEG) linkers using click chemistry. In assessing their tumor-targeting efficacy, we found that the tumor uptakes of [64Cu]CuS-PEG-c(RGDfK) nanoparticles at 24 h after intravenous injection were significantly greater (8.6% ± 1.4% injected dose/gram of tissue) than those of nontargeted [64Cu]CuS-PEG nanoparticles (4.3% ± 1.2% injected dose/gram of tissue, p < 0.05). Irradiation of tumors in mice administered [64Cu]CuS-PEG-c(RGDfK) nanoparticles induced 98.7% necrotic areas. In contrast, irradiation of tumors in mice administered nontargeted CuS-PEG nanoparticles induced 59% necrotic areas ( p < 0.05). The angiogenesis-targeting [64Cu]CuS nanoparticles may serve as a promising platform for image-guided ablation therapy with high efficacy and minimal side effects in future clinical translation of this novel class of multifunctional nanomaterials.


The role of prescriptive norms and knowledge in children's and adults' causal selection.
A widely discussed discovery has been the influence of norms on causal selection. Confronted with scenarios in which 2 agents contribute equally to an effect, adult participants tend to choose the agent who is violating a norm over an agent who is conforming to a norm as the cause of the outcome. To date, this effect has been established only in adult populations, so its developmental course is unknown. In 2 experiments, we investigated the influence of norm violations on causal selection in both 5-year-old children and adults. In particular, we focused on the role of mental state ascription and blame evaluation as potential mediating factors in this process. To this end, the knowledge status of the agent in question was varied such that she either was or was not aware of her norm transgression. Results revealed that children and adults assigned blame differently: Only adults were sensitive to the knowledge of the agent about norms as a mitigating factor. Crucially, however, despite its different sensitivity to knowledge ascription in children and adults, blame assignment in both age groups affected causal selection in the same ways. The relevance of these findings for alternative theories of causal selection is discussed.


Development, Validation, and Application of the Microbiology Concept Inventory.
If we are to teach effectively, tools are needed to measure student learning. A widely used method for quickly measuring student understanding of core concepts in a discipline is the concept inventory (CI). Using the American Society for Microbiology Curriculum Guidelines (ASMCG) for microbiology, faculty from 11 academic institutions created and validated a new microbiology concept inventory (MCI). The MCI was developed in three phases. In phase one, learning outcomes and fundamental statements from the ASMCG were used to create T/F questions coupled with open responses. In phase two, the 743 responses to MCI 1.0 were examined to find the most common misconceptions, which were used to create distractors for multiple-choice questions. MCI 2.0 was then administered to 1,043 students. The responses of these students were used to create MCI 3.0, a 23-question CI that measures students' understanding of all 27 fundamental statements. MCI 3.0 was found to be reliable, with a Cronbach's alpha score of 0.705 and Ferguson's delta of 0.97. Test item analysis demonstrated good validity and discriminatory power as judged by item difficulty, item discrimination, and point-biserial correlation coefficient. Comparison of pre- and posttest scores showed that microbiology students at 10 institutions showed an increase in understanding of concepts after instruction, except for questions probing metabolism (average normalized learning gain was 0.15). The MCI will enable quantitative analysis of student learning gains in understanding microbiology, help to identify misconceptions, and point toward areas where efforts should be made to develop teaching approaches to overcome them.


[Reactivity of the neuroglia in guinea pigs sensitized with Mycobacteria tuberculosis].
The changes in the glial cell reactivity depended on the phase and severity of the pathological process in the experimental allergic encephalomyelitis induced in guinea pigs by injection of Mycobacteria tuberculosis in a mixture of arlacel and vaselin. These reactivity changes measured by the method of inhibition of the glial cell migration in the tissue culture was specific of the nervous tissue antigens. The same changes in the reactivity could be induced in the tissue culture of the glial cells from the intact animals by the addition of sera or the lymph node cells from the actively sensitized guinea pigs. The present data did not allow to attribute the changes in the glial cell reactivity to the products of destruction of the nervous tissue only to the action of the humoral or the cell factors (elements) penetrating into the CNS from the blood vessels or the lymphatic tissue.


New developments in clinical oncology: the interdependence of bench and bedside.
Efforts to diminish the overall morbidity and mortality of malignancy have required a variety of strategies and a balanced national research agenda. The design of curative regimens against leukemia, lymphomas, testis cancer, and childhood malignancies is a tribute to the interactions between laboratory and clinical scientists. Laboratory models illustrated the importance of dose and the need for combinations to avoid the emergence of drug resistance in heterogeneous tumors. In addressing the incurability of common epithelial cancers in adults once disseminated, again laboratory models suggested that regimens which produced responses in advanced disease might be curative in patients with micro-metastases. Such proved to be the case in adjuvant therapy for breast cancer involving lymph nodes and for osteogenic sarcoma. Recent studies have extended this strategy to less advanced breast cancer and to locally advanced colon cancer. Lung cancer has required a different strategy. A coalition has developed to support the strongest possible public position against smoking. For the first time lung cancer incidence has leveled off in white males. Women and minorities continue to be a major target for smoking cessation programs. While large randomized trials are expensive (and to some scientists, unexciting), they are our most reliable means of detecting treatment differences of 10 to 15%. Because lung, breast, and colon cancer kill almost 250,000 Americans each year, such "small" differences represent thousands of Americans. There are also a number of interesting current studies that may impact in the longer term on the care of patients with cancer. Research of three different groups of investigators has recently converged. Over the past 3 decades several groups of basic laboratory investigators had been studying and cloning hematopoietic growth factors. Large randomized trials now confirm that myelosuppression after intensive chemotherapy can be substantially ameliorated, reducing infections and decreasing hospital days, risks, and costs. Another cohort of clinical pharmacologists and clinicians were studying bone marrow transplantation, developing combinations of agents that can be given at high dose to overcome resistance, albeit with considerable toxicity. Other groups in blood banks and those interested in the regulation of hematopoiesis recognized that early hematopoietic progenitor cells circulate in the peripheral blood. Their number were increased after certain chemotherapy regimens, by growth factors and most remarkably, with growth factors given after chemotherapy. Patients supported with peripheral blood progenitor cells reengraft both platelets and granulocytes more rapidly than those given marrow, in the time frame of recovery after standard doses of chemotherapy (i.e., 21 days).(ABSTRACT TRUNCATED AT 400 WORDS)


Heat shock triggers rapid protein phosphorylation in soybean seedings.
Heat shock arrests the synthesis of many cellular proteins and simultaneously initiates expression of a unique set of proteins, termed heat shock proteins. We have found that heat shock rapidly triggers phosphorylation of a set of proteins in soybean seedlings. Although the kinetics of phosphorylation and the heat shock response are similar, the major identified phosphorylation products do not comigrate with heat shock proteins on polyacrylamide gels. Cadmium, which is known to induce the heat shock response, stimulates phosphorylation of the same set of proteins. The rapidity of phosphorylation suggests that it may play a pivotal role in sensing and transducing elevated temperature stress in plants.


Identification of soil bacteria susceptible to TiO2 and ZnO nanoparticles.
Because soil is expected to be a major sink for engineered nanoparticles (ENPs) released to the environment, the effects of ENPs on soil processes and the organisms that carry them out should be understood. DNA-based fingerprinting analyses have shown that ENPs alter soil bacterial communities, but specific taxon changes remain unknown. We used bar-coded pyrosequencing to explore the responses of diverse bacterial taxa to two widely used ENPs, nano-TiO(2) and nano-ZnO, at various doses (0, 0.5, 1.0, and 2.0 mg g(-1) soil for TiO(2); 0.05, 0.1, and 0.5 mg g(-1) soil for ZnO) in incubated soil microcosms. These ENPs significantly altered the bacterial communities in a dose-dependent manner, with some taxa increasing as a proportion of the community, but more taxa decreasing, indicating that effects mostly reduced diversity. Some of the declining taxa are known to be associated with nitrogen fixation (Rhizobiales, Bradyrhizobiaceae, and Bradyrhizobium) and methane oxidation (Methylobacteriaceae), while some positively impacted taxa are known to be associated with the decomposition of recalcitrant organic pollutants (Sphingomonadaceae) and biopolymers including protein (Streptomycetaceae and Streptomyces), indicating potential consequences to ecosystem-scale processes. The latter was suggested by a positive correlation between protease activity and the relative abundance of Streptomycetaceae (R = 0.49, P = 0.000) and Streptomyces (R = 0.47, P = 0.000). Our results demonstrate that some metal oxide nanoparticles could affect soil bacterial communities and associated processes through effects on susceptible, narrow-function bacterial taxa.


Cost functions to estimate a posteriori probabilities in multiclass problems.
The problem of designing cost functions to estimate a posteriori probabilities in multiclass problems is addressed in this paper. We establish necessary and sufficient conditions that these costs must satisfy in one-class one-output networks whose outputs are consistent with probability laws. We focus our attention on a particular subset of the corresponding cost functions; those which verify two usually interesting properties: symmetry and separability (well-known cost functions, such as the quadratic cost or the cross entropy are particular cases in this subset). Finally, we present a universal stochastic gradient learning rule for single-layer networks, in the sense of minimizing a general version of these cost functions for a wide family of nonlinear activation functions.


Systemic sclerosis and lupus: points in an interferon-mediated continuum.
To investigate peripheral blood (PB) cell transcript profiles of systemic sclerosis (SSc) and its subtypes in direct comparison with systemic lupus erythematosus (SLE). We investigated PB cell samples from 74 SSc patients, 21 healthy controls, and 17 SLE patients using Illumina Human Ref-8 BeadChips and quantitative polymerase chain reaction confirmation. None of the study participants were receiving immunosuppressive agents other than low-dose steroids and hydroxychloroquine. In addition to conventional statistical and modular analysis, a composite score for the interferon (IFN)-inducible genes was calculated. Within the group of patients with SSc, the correlation of the IFN score with the serologic and clinical subtypes was investigated, as were single-nucleotide polymorphisms in a selected number of IFN pathway genes. Many of the most prominently overexpressed genes in SSc and SLE were IFN-inducible genes. Forty-three of 47 overexpressed IFN-inducible genes in SSc (91%) were similarly altered in SLE. The IFN score was highest in the SLE patients, followed by the SSc patients, and then the controls. The difference in IFN score among all 3 groups was statistically significant (P < 0.001 for all 3 comparisons). SSc and SLE PB cell samples showed striking parallels to our previously reported SSc skin transcripts in regard to the IFN-inducible gene expression pattern. In SSc, the presence of antitopoisomerase and anti-U1 RNP antibodies and lymphopenia correlated with the higher IFN scores (P = 0.005, P = 0.001, and P = 0.004, respectively); a missense mutation in IFNAR2 was significantly associated with the IFN score. SLE and SSc fit within the same spectrum of IFN-mediated diseases. A subset of SSc patients shows a "lupus-like" high IFN-inducible gene expression pattern that correlates with the presence of antitopoisomerase and anti-U1 RNP antibodies.


Regularizing active set method for retrieval of the atmospheric aerosol particle size distribution function.
The determination of the aerosol particle size distribution function by using the particle spectrum extinction equation is an ill-posed integral equation of the first kind [S. Twomey, J. Comput. Phys.18, 188 (1975);Y. F. Wang, Computational Methods for Inverse Problems and Their Applications (Higher Education Press, 2007)], since we are often faced with limited or insufficient observations in remote sensing and the observations are contaminated. To overcome the ill-posed nature of the problem, regularization techniques were developed. However, most of the literature focuses on the application of Phillips-Twomey regularization and its variants, which are unstable in several cases. As is known, the particle size distribution is always nonnegative, and we are often faced with incomplete data. Therefore, we study the active set method and propose a regularizing active set algorithm for ill-posed particle size distribution function retrieval and for enforcing nonnegativity in computation. Our numerical tests are based on synthetic data for theoretical simulations and the field data obtained with a CE 318 Sun photometer for the Po Yang lake region of Jiang Xi Province, China, and are performed to show the efficiency and feasibility of the proposed algorithms.


The Pathogenic Factors from Oral Streptococci for Systemic Diseases.
The oral cavity is suggested as the reservoir of bacterial infection, and the oral and pharyngeal biofilms formed by oral bacterial flora, which is comprised of over 700 microbial species, have been found to be associated with systemic conditions. Almost all oral microorganisms are non-pathogenic opportunistic commensals to maintain oral health condition and defend against pathogenic microorganisms. However, oral Streptococci, the first microorganisms to colonize oral surfaces and the dominant microorganisms in the human mouth, has recently gained attention as the pathogens of various systemic diseases, such as infective endocarditis, purulent infections, brain hemorrhage, intestinal inflammation, and autoimmune diseases, as well as bacteremia. As pathogenic factors from oral Streptococci, extracellular polymeric substances, toxins, proteins and nucleic acids as well as vesicles, which secrete these components outside of bacterial cells in biofilm, have been reported. Therefore, it is necessary to consider that the relevance of these pathogenic factors to systemic diseases and also vaccine candidates to protect infectious diseases caused by Streptococci. This review article focuses on the mechanistic links among pathogenic factors from oral Streptococci, inflammation, and systemic diseases to provide the current understanding of oral biofilm infections based on biofilm and widespread systemic diseases.


Evaluation of Vitamin D3 levels and dietary management in patients with papillary thyroid cancer.
Vitamin D (VitD) plays various roles, promotes musculoskeletal health, maintains parathyroid hormone levels and supports the immune processes. Vitamin D deficiency is common among cancer patients including thyroid cancer. Since some data indicate that preoperative VitD levels in cancer patients correlate with the further prognosis of the disease. Therefore, it is worthwhile to investigate this in the most common cancer of the thyroid gland, papillary thyroid cancer (PTC). The aim of this study was to evaluate serum VitD levels in patients with PTC concerning age, gender, body mass index (BMI), cancer stage, thyroid hormone levels, thyroglobulin concentration and the efficiency of VitD3 supplementation in these patients. Our cross-sectional study included 105 patients, and 34 healthy subjects in the control group. After 12 weeks of VitD3 supplementation (insufficient patients received1000IJ/day, deficient patients 2000IJ/day, severe deficient patient 5000IJ/day) along with the lifestyle and dietary management, the response was evaluated according to the personal characteristics, levels of VitD, free thyroxine (FT4), freetriiodothyronine (FT3) hormones and thyroglobulin (TG). The responders whose median age was 61-year-old, were mostly women (94%), with BMI below 23.7kg/m3, which indicates that most of the patients were normally nourished. 70% of patients were in the first stage of PTC, 76% had a vitamin D deficiency, while musculoskeletal disorders were present in 30% patients. VitD supplementation improved serum VitD status, FT3 discretely elevated and the TG levels significantly decreased in our PTC patients. It should be noted that VitD deficiency is presented in 70% of patients with PTC in our study sample. Dietary recommendation applied as lifestyle changes along with oral VitD3 supplementation, corrected VitD status to the recommended serum level. Although the data from our study is not sufficient to evaluate the VitD level as a prognostic factor for cancer, we have shown that it is necessary to examine its level along with an individual dietary approach for each patient with PTC.


Ryanodine receptor type III (Ry3R) identification in mouse parotid acini. Properties and modulation of [3H]ryanodine-binding sites.
Immunoblot analysis and [3H]ryanodine binding were used to characterize and identify ryanodine receptors (RyRs) in nonexcitable mouse parotid acini. Western analysis revealed ryanodine receptor type III (Ry3R) to be the only detectable isoform in parotid microsomal membranes. Binding of [3H]ryanodine to microsomal fractions was dependent on Ca2+, salt, pH, and temperature. At 23 degrees C, and in the presence of 0.5 M KCl and 100 microM Ca2+, [3H]ryanodine bound specifically to membranes with high affinity (Kd = 6 nM); maximum binding capacity (Bmax) was 275 fmol/mg protein. Mg2+ and ruthenium red inhibited [3H]ryanodine binding (IC50 = 1.4 mM and 0.5 microM, respectively). 4-Chloro-3-ethylphenol enhanced the binding of [3H]ryanodine 2.5-fold; whereas ATP and caffeine were much less efficacious toward activating Ry3R (56% and 18% maximal enhancement, respectively). Bastadin, a novel modulator of the 12-kDa FK506 binding protein.RyR complex, increased [3H]ryanodine binding 3-4-fold by enhancing Kd. The immunosuppressant FK506 enhanced [3H]ryanodine receptor occupancy at >100 microM and antagonized the action of bastadin, suggesting that an immunophilin modulates Ry3R in parotid acini. These results suggest that Ry3R may play an important role in Ca2+ homeostasis in mouse parotid acini.


Prohormone convertases 1 and 2 process ProPACAP and generate matured, bioactive PACAP38 and PACAP27 in transfected rat pituitary GH4C1 cells.
Pituitary adenylate cyclase-activating polypetide (PACAP) exists in two amidated forms, PACAP38 and PACAP27, which are expressed in the magnocellular and parvocellular neurons of the paraventricular nucleus (PVN) and the magnocellular neurons of the supraoptic nucleus (SON) of the hypothalamus. The prohormone convertases PC1 and PC2, subtilisin-like PCs of the Kex2 family, are expressed in neuroendocrine cells. Immunocytochemistry and in situ hybridization of PC1 and PC2 in the hypothalamus have shown that PC1 and PC2 are also present in the PVN and SON. Therefore, it is possible that the precursor of PACAP is processed by PC1 and/or PC2 in the hypothalamic nuclei and then converted to its mature forms. To test this hypothesis, rat pituitary GH4C1 cells were supertransfected with human PACAP cDNA and either rat PC1 or PC2 cDNA. The acid extracts of these cells were analyzed by reversed-phase HPLC for proPACAP, PACAP38 and/or PACAP27 radioimmunoassays using three antibodies with different recognition sites, and then bioassayed for the ability to stimulate adenylate cyclase. The cells transfected with PACAP cDNA alone yielded PACAP-like immunoreactivity (PACAP-li) corresponding to molecular weights between 15 and 20 kDa without PACAP bioactivity. Cotransfection of these cells with PC1 or PC2 generated PACAP-li, which coeluted with synthetic PACAP38 and PACAP27, respectively. Western blot also revealed 4.5- and 3.0-kDa PACAP-li bands, which correspond to the molecular weights of PACAP38 and PACAP27, respectively. The HPLC fractions containing PACAP-li, which were coeluted with synthetic PACAP38 and PACAP27, showed marked bioactivities. These findings suggest that the precursor of PACAP expressed in the PVN and SON of the hypothalamus could be efficiently processed by PC1 and PC2, and then converted to mature, bioactive PACAP38 and PACAP27.


Natriuretic peptides: an update on bioactivity, potential therapeutic use, and implication in cardiovascular diseases.
The natriuretic peptide system includes three known peptides: atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and C-type natriuretic peptide (CNP). They contribute to the regulation of cardiovascular homeostasis through diuretic, natriuretic, and vasodilatory properties. Among them, ANP has received particular attention because of its effects on blood pressure regulation and cardiac function. Although the potential for its therapeutic application in the treatment of hypertension and heart failure has been evaluated in several experimental and clinical investigations, no pharmacological approach directly targeted at modulation of ANP levels has ever reached the stage of being incorporated into clinical practice. Recently, ANP has also received attention as being a possible cardiovascular risk factor, particularly in the context of hypertension, stroke, obesity, and metabolic syndrome. Abnormalities in either peptide levels or peptide structure are thought to underlie its implied role in mediating cardiovascular diseases. Meanwhile, BNP has emerged as a relevant marker of left ventricular (LV) dysfunction and as a useful predictor of future outcome in patients with heart failure. This review deals with the major relevant findings related to the cardiovascular and metabolic effects of natriuretic peptides, to their potential therapeutic use, and to their role in mediating cardiovascular diseases.


Assessment of a psychiatric intervention at community level for people who inject drugs in a low-middle income country: the DRIVE-Mind cohort study in Hai Phong, Viet Nam.
Access to psychiatric care for people who inject drugs (PWID) is limited/absent and stigmatized in most low-middle-income countries (LMICs). Innovative interventions are needed. We aimed to describe and assess the impact of a community-based psychiatric intervention among PWID in Hai Phong, Vietnam. In a cohort study with one year psychiatric follow-up, PWID diagnosed with a psychotic disorder, a major depressive episode, or suicide risk, were recruited from the wider Drug-Related Infections in ViEtnam (DRIVE) project in the city of Hai Phong. The community-based psychiatric intervention included specialized follow-up (free consultations with psychiatrists, free medication, referral to mental health department for hospitalization when necessary) and support from community-based organisations (case management, harm reduction, administrative support, linkage to HIV care, methadone maintenance treatment and mental health support). The main outcome was reduction/remission of symptoms. Access to and retention in psychiatric care, quality-of-life and stigmatization were also measured pre and post-intervention. Among the 1212 participants screened from March to May 2019, 271 met the inclusion criteria, 233 (86.3%) accepted the intervention and 170 completed the follow-up (72.9%). At inclusion, 80.6% were diagnosed with current depression, 44.7% with psychotic disorder and 42.4% with suicide risk. After a one-year follow-up, these proportions dropped to 15.9%, 21.8%, and 22.9% respectively. Quality-of-life and perceived stigma related to mental health were also significantly improved, while drug use decreased only marginally. Community-based psychiatric interventions are both feasible and efficient in the Vietnamese context. Similar interventions should be implemented and evaluated in other, different LMICs. : This work was supported by grants from NIDA (US) (#DA041978) and ANRS (France) (#13353). The funding agencies had no role in designing the research, data analyses, or preparation of the report.


Direct Determination of the Phase Diagram of a Depletion-Mediated Colloidal System.
Depletion is one widely used potential to modulate colloidal interaction because it enables the production of a wide variety of crystalline and glassy phases of spherical and shape-tailored colloids. The attractive depletion potential gives rise to qualitatively new behavior. However, depletion-mediated phase behaviors have never been systematically investigated experimentally regarding pair potentials for aqueous suspensions. In this work, we implement three distinct phases of fluid, crystal, and glass by adjusting the concentrations of depletant and salt in the aqueous suspension of polystyrene particles. To define the phase boundary between the fluid and crystal, we calculate pair potential with a superposition of van der Waals, electrostatic, and depletion interactions. Two unknown parameters in the pair potential─the concentration of ionic impurities and the ratio of the molar concentration of depletant to osmolarity─are experimentally determined from sets of reflectance spectra. The interparticle spacing in the crystalline phase is extracted from the peak wavelength originating from Bragg diffraction, which corresponds to the interparticle separation at energy minimum in the pair potential. The boundary between the fluid and crystal is well defined with the depth of the energy well of 3kBT. By contrast, the onset of glass formation is better characterized by not the well depth but the assembly rate, which is estimated from the slope of the pair potential from force balance. Glasses are produced as the speed exceeds 300 μm/s. That is, crystals are produced by enthalpy gain overwhelming entropy loss, whereas glasses are kinetically produced due to fast jamming.


A hierarchical flower-like hollow alumina supported bimetallic AuPd nanoparticle catalyst for enhanced solvent-free ethylbenzene oxidation.
Currently, oxidation of alkylaromatics is considered as one of the most crucial chemical technologies to produce high added-value alcohols, ketones and carboxylic acids, due to its significant importance both in fine synthetic chemistry and in the academic field. In this work, a novel hierarchical marigold-like hollow alumina supported bimetallic AuPd nanoparticle catalyst was successfully fabricated and employed for highly efficient solvent-free ethylbenzene oxidation to produce acetophenone with the coexistence of both molecular oxygen and tert-butyl hydroperoxide as the oxidant and the initiator. The as-fabricated bimetallic AuPd nanocatalyst conferred a superior catalytic performance to the corresponding monometallic counterparts and commercial Al2O3 or solid Al2O3 microsphere supported AuPd ones, along with a high acetophenone selectivity of 88.2% at a conversion of 50.9% under mild reaction conditions (120 °C and oxygen pressure of 1.0 MPa), as well as an unprecedentedly high turnover frequency value of 46 768 h-1. Such exceptional efficiency of the catalyst was related to both the significant synergy between the Au-Pd atoms and strong metal-support interactions, and the unique hierarchical micro/nanostructure of the support being beneficial to the close contact of reactants with surface adsorption and reaction sites and easy product diffusion. Moreover, the present bimetallic AuPd catalyst was recyclable and stable. The developed approach is expected to offer exciting opportunities for designing other supported monometallic or bimetallic catalysts with various active components applied in heterogeneous catalysis.


Recurrence of Paget-Schroetter Syndrome: A Rare Case Report and Review of Literature.
Paget-Schroetter syndrome (PSS) is a primary upper extremity deep vein thrombosis (DVT) that occurs with no significant risk factors, mostly in a young and healthy patient. Treatment of this disease is discussed heavily in the literature and the optimal treatment method is still being debated. Here, we present a patient with PSS treated with balloon angioplasty, thrombolysis and treatment with an oral thrombin inhibitor (apixaban) who developed recurrence of PSS. A 38-year-old white male with no past medical history, presented to an urgent care center with sudden onset axillary pain and an axillary lump that was treated with outpatient antibiotics. Extensive deep venous thrombosis was diagnosed with computed tomography (CT) and ultrasound. He underwent percutaneous pharmacomechanical thrombectomy. Postprocedural angiogram showed significant improvement in the caliber of the axillary and subclavian veins where they crossed the first rib. He was discharged on apixaban and underwent removal of his first rib 1 month later. He returned 3 weeks later with recurrence of right arm pain and swelling. Repeat ultrasound showed thrombus in the right arm and venogram confirmed 80% stenosis at the subclavian vein as it enters the innominate vein. He was again treated with placement of a thrombolytic catheter and overnight thrombolysis of the central venous circulation on the right-side upper extremity balloon angioplasty of the subclavian vein, axillary vein, and basilic vein. He is disease-free for 6 months. Recurrence of PSS after surgical removal of rib, thrombectomy, thrombolysis while using apixaban is very rare. This is the first case to our knowledge presented with recurrent PSS treated with apixaban, early rib resection, balloon angioplasty and thrombectomy.


[The influence of smoking on clinical manifestation and composition of bronchoalveolar lavage in sarcoidosis].
Sarcoidosis is defined as an inflammatory systemic disease; the characteristic morphological feature is the noncaseating granuloma. Typical finding in bronchoalveolar lavage (BAL) is a lymphocytic alveolitis with an increased CD4/CD8-quotient. A higher frequency of sarcoidosis in non-smokers (NS) than in smokers (S) has been reported. The influence of inhalative smoking on demographical data, lung function and results of BAL in prospectively selected patients with sarcoidosis was investigated. 111 NS (Sarcoidosis stage I/II+III 48/63) and 44 S (23/21) were included in the study. 16 patients without provable pulmonary disease (9 NS, 7 S) served as controls. Patients with sarcoidosis ware less often S than NS (28 vs. 72%, p = 0,0001) Controls 44 vs. 56%, p = 0.6 [chi(2)]). Sarcoidosis S were younger than NS (40.4 +/- 11.9 vs. 45.6 +/- 14.7 years, p = 0.009). There were no differences in the IVC (in % predicted). There was a negative effect of smoking on the course of the IVC (% predicted) with incremental age, not seen in the non smoking group (S vs. NS: r = -0.54, p = 0.001 vs. r = -0.13, p = 0.22). In BAL of Sarcoidosis S there was a lower concentration of albumin than of NS (in mg/dl), S vs. NS: 9.5 +/- 5.9 vs. 14.5 +/- 13.4, p = 0.012 and a trend to a less intensive lymphocytic alveolitis (in % of BAL-cells, S vs. NS: 29.2 +/- 21.1 vs. 34.1 +/- 18.6, p = 0.099). Influences of the smoking on the populations of T-lymphocytes could not be seen. (CD4/CD8-ratio S vs. NS 10.0 +/- 11.4 vs. 7. 2 +/- 7.1, p = 0, 25). In conclusion patients with sarcoidosis were more often NS than S. S were younger than NS. A protective effect of smoking on the course of lung function in sarcoidosis could be excluded. In the BAL S demonstrated a lower content of albumin and a trend to a less pronounced lymphocytosis and therefore a less pronounced alveolitis than NS. Influences of smoking on the distribution of the lymphocytic populations were not seen.


Predicting the unpredictable: a new prediction model for operating room times using individual characteristics and the surgeon's estimate.
: Routine predictions made by surgeons or historical mean durations have only limited capacity to predict operating room (OR) time. The authors aimed to devise a prediction model using the surgeon's estimate and characteristics of the surgical team, the operation, and the patient. : Seventeen thousand four hundred twelve consecutive, elective operations from the general surgical department in an academic hospital were analyzed. The outcome was OR time, and the potential predictive factors were surgeon's estimate, number of planned procedures, number and experience of surgeons and anesthesiologists, patient's age and sex, number of previous hospital admissions, body mass index, and eight cardiovascular risk factors. Linear mixed modeling on the logarithm of the total OR time was performed. : Characteristics of the operation and the team had the largest predictive performance, whereas patient characteristics had a modest but distinct effect on OR time: operations were shorter for patients older than 60 yr, and higher body mass index was associated with longer OR times. The surgeon's estimate had an independent and substantial contribution to the prediction, and the final model explained 27% of the residual variation in log (OR time). Using the prediction model instead of the surgeon's prediction based on historical averages would reduce shorter-than-predicted and longer-than-predicted OR time by 2.8 and 6.6 min per case (a relative reduction of 12 and 25%, respectively), assessed on independent validation data. : Detailed information on the operative session, the team, and the patient substantially improves the prediction of OR times, but the surgeon's estimate remains important. The prediction model may be used in OR scheduling.


Arhodomonas sp. strain Seminole and its genetic potential to degrade aromatic compounds under high-salinity conditions.
Arhodomonas sp. strain Seminole was isolated from a crude oil-impacted brine soil and shown to degrade benzene, toluene, phenol, 4-hydroxybenzoic acid (4-HBA), protocatechuic acid (PCA), and phenylacetic acid (PAA) as the sole sources of carbon at high salinity. Seminole is a member of the genus Arhodomonas in the class Gammaproteobacteria, sharing 96% 16S rRNA gene sequence similarity with Arhodomonas aquaeolei HA-1. Analysis of the genome predicted a number of catabolic genes for the metabolism of benzene, toluene, 4-HBA, and PAA. The predicted pathways were corroborated by identification of enzymes present in the cytosolic proteomes of cells grown on aromatic compounds using liquid chromatography-mass spectrometry. Genome analysis predicted a cluster of 19 genes necessary for the breakdown of benzene or toluene to acetyl coenzyme A (acetyl-CoA) and pyruvate. Of these, 12 enzymes were identified in the proteome of toluene-grown cells compared to lactate-grown cells. Genomic analysis predicted 11 genes required for 4-HBA degradation to form the tricarboxylic acid (TCA) cycle intermediates. Of these, proteomic analysis of 4-HBA-grown cells identified 6 key enzymes involved in the 4-HBA degradation pathway. Similarly, 15 genes needed for the degradation of PAA to the TCA cycle intermediates were predicted. Of these, 9 enzymes of the PAA degradation pathway were identified only in PAA-grown cells and not in lactate-grown cells. Overall, we were able to reconstruct catabolic steps for the breakdown of a variety of aromatic compounds in an extreme halophile, strain Seminole. Such knowledge is important for understanding the role of Arhodomonas spp. in the natural attenuation of hydrocarbon-impacted hypersaline environments.


Clinical evaluation of global change in Alzheimer's disease: identifying consensus.
It is important that clinicians who rate global change as part of Alzheimer's disease (AD) clinical drug trials agree on a relevant set of behaviors and information to be considered in formulating their rating. Yet, consensus among raters has been difficult to establish, and inter-rater reliability of clinical global impression of change (CGIC) ratings has been low. In preparation for the development of a new CGIC scale to be used in AD clinical trials, the Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change (ADCS-CGIC), we surveyed clinicians at sites comprising the National Institute on Aging-sponsored ADCS participating centers to identify whether or not consensus regarding CGICs exists. Overall, respondents reported that a CGIC should include an assessment of the patient's function and mental status, a care giver interview, and a standardized set of questions, and it should take approximately 20 minutes per interview. Depending on a patient's level of impairment, raters consider different areas of behavior in formulating a CGIC rating. These findings demonstrate the considerable consensus regarding the CGIC rating process, and were integrated into the design of the ADCS-CGIC, currently in use.


Assessment of the genotoxic potential of indirect chemical mutagens in HepaRG cells by the comet and the cytokinesis-block micronucleus assays.
Many chemical carcinogens require metabolic activation to form genotoxic compounds in human. Standard in vitro genotoxicity assays performed with activation systems, such as rat liver S9, are recognised to lead to a high number of false positives. The aim of this study was to evaluate the suitability of differentiated human hepatoma HepaRG cells as an in vitro model system for the detection of DNA damage induced by promutagens using the comet and the cytokinesis-block micronucleus assays. Several promutagens were tested, including aflatoxin B1 (AFB1), benzo[a]pyrene (B[a]P), acrylamide, N-nitrosodimethylamine (NDMA), cyclophosphamide (CPA), 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) and 2-amino-3-methylimidazo[4,5-f]quinoline (IQ). Cytotoxicity of these compounds was assessed by measuring lactate dehydrogenase leakage. A 24 h exposure was generally needed to obtain an obvious positive response in differentiated HepaRG cells in the comet and in the cytokinesis-block micronucleus assays. Comet formation was observed with all compounds except IQ. B[a]P, CPA and AFB1 showed a dose-dependent increase in micronucleated cells, whereas no increase was observed with PhIP, IQ and acrylamide. These preliminary data on genotoxicity in differentiated HepaRG cells are promising but more chemicals must be tested to determine the ability of HepaRG cells to assess genotoxicity of chemicals in humans.


Psychophysiological responses of schizophrenic patients to high and low expressed emotion relatives.
Measurements of spontaneous fluctuations in skin conductance in 20 acutely ill schizophrenic patients were made in a video-tape studio. Recordings were made initially with the patient talking to an interviewer, then during a video-taped interview conducted with the patient's key relative. The Expressed Emotion (EE) of the patient's key relative had been measured previously. Significant differences in the type of spontaneous fluctuation activity between patients who had low EE and high EE relatives were demonstrated when the relative was present, but not when the relative was absent. The findings were not related to phenothiazine medication.


Peripheral location and infiltrative margin predict invasive features of papillary thyroid microcarcinoma.
Tumor location in papillary thyroid microcarcinoma (PTMC) might determine tumor outgrowth from the thyroid gland. However, the clinical implications of tumor location and minimal extrathyroid extension (mETE) have not been well elucidated. We aimed to investigate the relationship between tumor location and mETE to predict the aggressiveness of PTMC. A total of 858 patients with PTMC were grouped according to tumor location on ultrasonography: central (cPTMC) and peripheral PTMC (pPTMC). PTMC without mETE (PTMC-mETE(-)) was divided further according to margin shape: encapsulated (E-) or infiltrative (I-). To understand the molecular biologic characteristics of PTMC presenting with an I-margin and mETE, transcriptome data from TCGA-THCA were analyzed using Gene Set Enrichment Analysis (GSEA). pPTMC (n = 807, 94.1%) accounted for the majority of cases; mETE was identified only in pPTMC (403/807; 49.9%). pPTMC-mETE(+) showed aggressive clinical characteristics that increased the odds ratio (OR) for lymph node metastasis (LNM). Interestingly, subgroup analysis of PTMC-mETE(-) revealed that the I-margin also increased the OR for LNM, independent of other clinical factors. GSEA of TCGA-THCA data suggested coordinated upregulation of genes related to epithelial-mesenchymal transition (EMT) in PTC with mETE. Immunohistochemical staining for laminin subunit gamma 2 (LAMC2), CD59, E-cadherin and vimentin showed that these markers of EMT were associated with progressive changes in E-margin PTMC-mETE(-), I-margin PTMC-mETE(-) and pPTMC-mETE(+). mETE related to peripheral location of PTMC is an important predictor of tumor invasiveness, as is the I-margin, which presents with EMT features similar to mETE. I-margin PTMC-mETE(-) and pPTMC-mETE(+) might reflect the pattern of invasive PTMC.


Engineering homogeneous doping in single nanoparticle to enhance upconversion efficiency.
Upconversion nanoparticles (UCNPs) have shown considerable promises in many fields; however, their low upconversion efficiency is still the most serious limitation of their applications. Herein, we report for first time that the homogeneous doping approach based on the successive layer-by-layer method can greatly improve the efficiency of the UCNPs. The quantum yield as high as 0.89 ± 0.05% is realized for the homogeneous doping NaGdF4:Yb,Er/NaYF4 UCNPs, which is nearly 2 times higher than that of the heterogeneous doping NaGdF4:Yb,Er/NaYF4 UCNPs (0.47 ± 0.05%). The influences of spatial distributions and local relative concentrations of the dopants on the optical properties of UCNPs were investigated in the single particle level. It was found that heterogeneous doping indeed existed during the spontaneous growth process of the nanoparticles. The heterogeneous doping property can further induce many negative effects on the optical properties of UCNPs, especially the luminescent efficiency. The spatial distributions and local relative concentrations of the dopants can be well controlled by the successive layer-by-layer homogeneous doping method on the monolayer level and homogeneously distributed in the single particle level. Furthermore, by using homogeneous doping NaGdF4:Yb,Tm as initial core, the multicolor emission intensity of NaGdF4:Yb,Tm/NaGdF4:A (A = Tb(3+), Eu(3+)) core/shell nanoparticles can also exhibit 20%-30% improvement. We believe that such a homogeneous doping model can open the door to improve the upconversion optical properties by engineering the local distribution of the sensitizer, activator, host, etc., in a microcosmic and provide a track for engineering the high quality UCNPs with advanced nanostructure and optical properties.


Knowledge and Attitudes of Physicians about Lipids.
A sample of 323 physicians from Edmonton, Alberta, was surveyed to evaluate their attitudes and knowledge level concerning heart disease and lipids. Of the sample, 117 physicians returned the questionnaire. When asked to choose significant risk factors of cardiovascular disease, 69% of the physicians indicated hypertension; 85% indicated smoking; and 87% indicated elevated serum cholesterol. Concerning the minimal low-density lipoprotein level that warrants treatment, 82% of the general practitioners and 50% of the specialists indicated that 4.2 mmol/L was the minimal level. This is in contrast to the level of 3.4 mmol/L for low-density lipoprotein recommended by the Canadian Consensus Conference on Cholesterol as the level at which treatment should be initiated.


Histopathologic Evaluation of Polymer Supports for Pintucci-type Keratoprostheses: An Animal Study.
To report histopathological findings for different types of polymers proposed as support for a Pintucci-type keratoprosthesis. Six polymers, including three types of polyesters ( # 1-3), one type of polytetrafluoroethylene (PTFE, # 4), polyethylene ( # 5), and expanded polytetrafluoroethylene (ePTFE, # 6) were evaluated. Four samples of each material were placed under the orbicularis oculi muscles of 12 rabbits. After five weeks, the samples were removed and evaluated histopathologically. Fibrovascular tissue ingrowths were investigated in terms of tissue penetration depth into the materials (graded as none, mild, moderate, and intense) and fibrovascular ingrowth area at the ultimate level of tissue penetrance. ImageJ software was used to calculate fibrovascular tissue area between the material fibers, and the mean area values were compared between the materials. Polyester materials # 1 and # 3 demonstrated intense fibrovascular tissue penetration with a large fibrovascular ingrowth area; no overt tissue ingrowth was observed into material #6. The mean area of penetrated fibrovascular tissues was significantly different between materials ( P < 0.001). Materials # 2, # 4, and # 5 showed moderate fibrovascular tissue ingrowth and the area of presented fibrovascular tissue at the paracentral parts of material # 4 was significantly smaller than that of materials # 1 ( P = 0.02) and # 3 ( P = 0.01). Two polyester materials that had relatively large pore sizes demonstrated a deep and large area of fibrovascular ingrowth. Given that material #3 is thicker and more consistent than material # 1, the former can be used as the appropriate material for supporting the Pintucci-type keratoprosthesis.


Cervical cancer screening practice and knowledge among Hispanic migrant and seasonal farmworkers of Michigan.
High incidence of cervical cancer among Hispanics and low utilization of cervical screening among farmworkers led us to examine Pap test use and knowledge among Hispanic farmworkers in Michigan. Patients and potential patients of Northwest Michigan Health Services, Inc were surveyed in 2 communities (A and B) about their screening knowledge, attitudes, and practice. In all, 324 farmworkers participated, including 184 seasonal and 125 migrant farmworkers. Among the entire study population, 87.7% women reported receiving a Pap test recently, with no difference between migrant and seasonal farmworkers (88.0% and 87.4%, respectively, P = .088). More women from community B reported a recent Pap (93%) compared with those from community A (83%, P = .01). Only 35% of the participants had knowledge of any cervical cancer risk factors. Migrant farmworkers may not experience more difficulty in accessing Pap tests than seasonal farmworkers in Michigan. Knowledge about cervical cancer risk factors is low and needs to be addressed in future educational interventions.


Targeting of the VHL-hypoxia-inducible factor-hypoxia-induced gene pathway for renal cell carcinoma therapy.
Treatment of advanced renal cancer has made little progress in the past 30 yr. Most clinical efforts have incorporated cytokine-based therapy. The presumption has been that the cytokines may trigger a host immune response against the renal cancer. Only IFN-alpha and high-dose IL-2 seemed to have positive effects on patient outcomes. IFN has prolonged the lives of patients by a few months, and high-dose IL-2 is capable of inducing very prolonged remissions (>5 yr) for a small number of patients. Nephrectomy in the presence of metastatic disease has been established as an effective procedure for select patients, providing palliation and prolonging survival. Finally, enthusiasm has focused on the use of nonmyeloablative allogeneic stem cell transplantation and donor leukocyte infusion for the induction of graft versus tumor effects. Early results are both provocative and promising. A number of agents that target the critical gene products downstream from pVHL and hypoxia-inducible factor-1, such as vascular endothelial growth factor, PDGF, EGF receptor, and TGF-alpha, have recently become available. The new agents are capable of inhibiting specific cellular targets, and the biologic characteristics of clear cell carcinoma of the kidney support their application. If the correct targets are carefully selected for inhibition in tumors in which the targets are present (clear cell histologic features and loss of VHL expression), then results should resemble those others have observed with targeted therapy, such as the use of STI-571 (Gleevec; Novartis Pharmaceuticals, East Hanover, NJ) for treatment of chronic myelogenous leukemia and gastrointestinal stromal tumors or anti-HER2/neu (Herceptin; Genentech, South San Francisco, CA) for treatment of breast cancer.


Quick diagnostic approach for HIV/STDs among migrants: results from a monocentric Italian cohort.
Migration has a direct influence on sexual health. Differences both in sexual networks and the risk of sexually transmitted diseases (STDs) between racial or ethnic minorities and the native population have been described in the literature. We collected data on medical history, physical examination, and human immunodeficiency virus (HIV)/STDs tests. Screenings were proposed basing on Centers for Disease Control (CDC) 2018 guidelines on STDs. Patients underwent peer-to-peer counselling before screening. We included data of 391 patients (both outpatients and migrants living in facility centers). The median age was 30 (range 24-38) years, and the majority were male (198/391; 50.6%). Among them, 389 (99.4%) were counselled, and 371 (94.8%) accepted the screening. We found 155 (41.7%) HBsAg/Anti-HBc positive tests, 4 (1%) HIV positive screenings, 1 (0.2%) hepatitis C virus (HCV) infection, 47 (12%) genital/perianal warts, 29 (2.3%) cases of syphilis, and 13 (3.3%) molluscum contagiosum. Migrants have high-risk sexual behavior. Despite this, they may have a low perception of risk and healthcare needs. An approach based on quick tests was demonstrated to be useful in increasing the screening acceptance. However, the retainment in care was low, as in previous studies. Access to HIV/STDs screening and treatment should be implemented. The development of specific retainment in care pathways is still needed to reduce the lack of follow-up.


Location and orientation of homologous sequences in the genomes of five herpesviruses.
Molecular hybridization experiments were carried out to investigate homologous regions in the genomes of herpes simplex virus types 1 and 2 (HSV-1 and HSV-2), equid herpesvirus 1 (EHV-1), pseudorabies virus (PRV) and varicella-zoster virus (VZV). Virion DNA probes from EHV-1, PRV and VZV hybridized to similar regions of the HSV genome, and the use of cloned DNA probes allowed heterologous genomes to be oriented with respect to homologous regions. The HSV-1 and HSV-2 genomes are colinear, the EHV-1 and VZV genomes are colinear with the IL or ISL genome arrangement of HSV, and the PRV genome is essentially colinear with the IL genome arrangement of HSV except that the region 0.1 to 0.4 fractional genome units appears to be inverted. A detailed analysis of sequences in the HSV-2 and PRV genomes to which the HSV-1 major capsid protein gene hybridized was carried out in order to demonstrate the application of molecular hybridization to the location of genes in heterologous genomes. The lesion in a DNA-positive temperature-sensitive mutant of PRV was mapped within the putative PRV major capsid protein gene. We conclude that the herpesviruses we have studied possess several highly conserved genes, and propose that they are similar in genetic organization despite presumably separate evolutionary histories.


Relation of cognitive reserve and task performance to expression of regional covariance networks in an event-related fMRI study of nonverbal memory.
Cognitive reserve (CR) has been established as a mechanism that can explain individual differences in the clinical manifestation of neural changes associated with aging or neurodegenerative diseases. CR may represent individual differences in how tasks are processed (i.e., differences in the component processes), or in the underlying neural circuitry (of the component processes). CR may be a function of innate differences or differential life experiences. To investigate to what extent CR can account for individual differences in brain activation and task performance, we used fMRI to image healthy young individuals while performing a nonverbal memory task. We used IQ estimates as a proxy for CR. During both study and test phase of the task, we identified regional covariance patterns whose change in subject expression across two task conditions correlated with performance and CR. Common brain regions in both activation patterns were suggestive of a brain network previously found to underlie overt and covert shifts of spatial attention. After partialing out the influence of task performance variables, this network still showed an association with the CR, i.e., there were reserve-related physiological differences that presumably would persist were there no subject differences in task performance. This suggests that this network may represent a neural correlate of CR.


Pathophysiologic significance of host reactions in human cancer tissue: desmoplasia and tumor immunity.
Invasive growth of malignant cells, particularly carcinoma cells, induces host reaction within and around tumor tissue. Representatives of them are desmoplasia, angiogenesis and immune reactions. Desmoplasia, a process of fibrosis, is induced by activation of fibroblasts with increased production of matrix proteins and matrix degrading enzymes. Angiogenesis is prerequisite for the growth of solid tumor. Inhibition of this is now a target of cancer therapy. The present author has proposed a concept that tumor vessels are composed of nutrient vessels and immune/inflammatory vessels. The latter is similar to venules in inflammatory lesions expressing the cell adhesion molecules to facilitate the transmigration of inflammatory cells to the tissue. In colon cancer, venules distributed along the invasive margin correspond to these vessels, which express E-, and P-selectins, and ICAM-1. These venules are considered to be an entry site of immune/inflammatory cells to cancer tissue. To further analyze immune mechanism, the present authors have confirmed that macrophages distributed along the invasive margin of colon cancer express costimulatory molecules B7.1/B7.2, which are required for the proliferation of T-cells. T-cells were co-localized with these cells. Clinicopathologic analysis confirmed that CD8+ T-cells distributed within cancer cell nest (intraepithelial) have the most significant impact on the patients' survival in colorectal cancer. These data suggest that various host reactions take place in the stroma of cancer tissue, which modulate the biologic behavior of cancer.


Placenta accreta: changing clinical aspects and outcome.
In an effort to determine if a changing clinical picture for placenta accreta exists in the late 1970s, 22 cases from January 1, 1975, to May 30, 1979, at Los Angeles County/University of Southern California (LAC/USC) Medical Center were reviewed. An incidence of clinically diagnosed placenta accreta of 1 per 2562 deliveries for all cases and 1 per 4027 for pathologically confirmed cases (ie, hysterectomy specimens) was found. Mean age of the patients was 29.5 years, and mean gravidity, parity, and abortion were 3.4, 2, and 0.27, respectively. Placenta previa was found in 14 patients (63.6%), 6 of whom had previously undergone cesarean section. No obvious etiology was found in 1 patient. Sixteen patients underwent cesarean section. Hysterectomy was performed on 14 patients, and conservative measures were employed in 8 patients. One maternal death (4.5%) occurred, but there was no perinatal mortality. The clinical picture of placenta accreta today is one of higher reported incidence, lower parity, greater incidence of associated placenta previa, individualized management, and decreasing maternal and perinatal mortality.


Gallstones, cholecystectomy, and colorectal cancer.
To examine the controversial association of gallstones, cholecystectomy and colorectal cancer. Methodologic explanations for the association include ascertainment bias, unequal diagnostic testing, and necropsy selection bias. Necropsy screening, which eliminates unequal diagnostic testing and ascertainment bias and reduces necropsy selection bias, was used to study this controversy. Adult necropsies at the University of Kansas Medical Center from 1950 to 1984 were reviewed. Patients with colorectal cancer, gallstones, or who had cholecystectomy during life were excluded. The remaining patients were those in whom neither colorectal cancer nor gallstones were suspected during life (reducing selection bias). The occurrence of gallstones and colorectal cancer among these individuals was then determined (reducing ascertainment bias and unequal diagnostic testing). Of 7485 persons receiving necropsy, 239 had colorectal cancer diagnosed during life and an additional 604 had gallstones or cholecystectomy, leaving 6642 patients available for study. Overall, no association between colorectal cancer and gallstones was found. In women, gallstones were associated with colorectal cancer; 6/447 (1.3%) with gallstones had colorectal cancer compared with 11/2259 (0.4%) without gallstones who had colorectal cancer, p = 0.048, odds ratio 2.78 (95% CI 0.84-8.25). A stronger association was found between right-sided colorectal cancer and gallstones (odds ratio 6.79, 95% CI 1.14-46.46). These data suggest an association between gallstones and colorectal cancer among women. Gallstones may indicate patients at higher risk for colorectal cancer. Studies associating cholecystectomy with colorectal cancer may be explained--not by ascertainment bias--but, rather, by susceptibility bias. The reason for the cholecystectomy (gallstones) may be the correct association and not the cholecystectomy itself.


Neighborhood informal social control and child maltreatment: A comparison of protective and punitive approaches.
This paper introduces a new measure of informal social control of child maltreatment (henceforth ISC_CM) by neighbors. Research literature typically uses collective efficacy (Sampson, Raudenbush, & Earls, 1997) to examine neighborhood informal social control. We argue that double standards about the application of informal social control to family versus street crime requires a measure of informal social control specific to child maltreatment. We also argue that how neighbors intervene may matter as much as whether they intervene. Neighbors may engage in ISC_CM aimed at protecting the child and calming the parent, or more punitive ISC_CM aimed at deterring future abuse. We tested the relationship of both with very severe physical abuse and with abuse related child behavior problems. We used a random, 2-stage cluster design of Hanoi to collect the sample. Thirty Hanoi wards were randomly selected using probability proportional to size sampling. A simple random sample of families in each ward was then drawn using local government lists of ward residents. Based on power analysis, the target sample size was 300. Of 315 residents contacted, 293 participated, yielding a response rate of 93%. Random effects regression models (which estimate a random effect for each ward) were run in Stata11. We found that protective ISC_CM is associated with lower odds of very severe physical abuse and lower reported externalizing problems when abuse is present. Perceived collective efficacy and punitive ISC_CM is not associated with lower odds of very severe physical abuse. Implications for research, policy and practice are discussed. We conclude that further investigation of neighbor ISC_CM is needed to replicate the findings in other cultural contexts, ultimately followed by experimental manipulation of ISC_CM in a neighborhood context to examine the effects on child maltreatment. If further research corroborates the current findings, the development of neighborhood intervention programs to enhance protective ISC_CM may assist materially in reducing very severe child abuse and negative consequences stemming from such abuse.


Fur controls iron homeostasis and oxidative stress defense in the oligotrophic alpha-proteobacterium Caulobacter crescentus.
In most bacteria, the ferric uptake regulator (Fur) is a global regulator that controls iron homeostasis and other cellular processes, such as oxidative stress defense. In this work, we apply a combination of bioinformatics, in vitro and in vivo assays to identify the Caulobacter crescentus Fur regulon. A C. crescentus fur deletion mutant showed a slow growth phenotype, and was hypersensitive to H(2)O(2) and organic peroxide. Using a position weight matrix approach, several predicted Fur-binding sites were detected in the genome of C. crescentus, located in regulatory regions of genes not only involved in iron uptake and usage but also in other functions. Selected Fur-binding sites were validated using electrophoretic mobility shift assay and DNAse I footprinting analysis. Gene expression assays revealed that genes involved in iron uptake were repressed by iron-Fur and induced under conditions of iron limitation, whereas genes encoding iron-using proteins were activated by Fur under conditions of iron sufficiency. Furthermore, several genes that are regulated via small RNAs in other bacteria were found to be directly regulated by Fur in C. crescentus. In conclusion, Fur functions as an activator and as a repressor, integrating iron metabolism and oxidative stress response in C. crescentus.


Experimental anticancer therapy with vascular-disruptive peptide and liposome-entrapped chemotherapeutic agent.
Vasculature is essential for the sustained growth of solid tumors and metastases. Tumor cells surviving vascular-disruptive therapeutic intervention (especially those present at the tumor rim) can contribute to tumor regrowth. The aim was to strengthen, by carrier-mediated delivery of a chemotherapeutic, the curative effects of a bifunctional anti-vascular oligopeptide capable of inducing vascular shutdown and tumor shrinkage. For the in vitro experiments and animal therapy, ACDCRGDCFC-GG-(D)(KLAKLAK)(2) peptide (900 microM in D-PBSA, i.e. Dulbecco's PBS without Ca(2+) and Mg(2+)) and size-calibrated, passively or actively targeted liposomes based on distearoylphosphatidylcholine, cholesterol, and N-carbamoyl-methoxypolyethyleneglycol coupled to distearoylphosphatidylethanolamine (PEG-DSPE) and containing gradient-entrapped doxorubicin were used. The KB (human nasopharyngeal carcinoma) cell line overexpressing folate receptors was used in the fluorescence studies of liposomal uptake. The B16-F10 melanoma cell line was used for confirming, by flow cytometry and confocal microscopy, doxorubicin intracellular transfer as well as to induce experimental tumors in C57BL/6 mice. Animal therapy was achieved with injections of vascular-disrupting peptide, doxorubicin-loaded liposomes, or alternating combined therapy. The results (tumor growth inhibition and survival) were compared using the Mann-Whitney U test and the log-rank test. Necrosis in H&E-stained tumor sections was assessed microscopically by pathologists. Treatment of C57BL/6 mice bearing B16-F10 experimental tumors with a combination of vascular-disruptive peptide and doxorubicin-carrying pegylated liposomes (either passively targeted liposomes (PTL) or folate receptor targeted) gave better therapeutic effects when tumor development was re-challenged with a second cycle of combined therapy. Marked inhibition of tumor growth and a statistically significant extension of the lifespan of the treated mice were observed when the re-challenge involved the use of folate receptor-targeted liposomes (FTL). Anticancer therapy involving vascular-disruptive peptide and doxorubicin delivered via pegylated folate receptor-targeted liposomes is more effective than either monotherapy, especially when tumor growth is re-challenged with the therapeutic combination.


Late development of pancreas necrosis during acute pancreatitis: an underestimated phenomenon associated with high morbidity and mortality.
The purpose of this study is to assess the prognostic significance of late parenchymal pancreas necrosis as observed on serial contrast-enhanced computed tomographic (CT) scan. Eighty-four patients with acute necrotizing pancreatitis were included. All initial CT scans were examined on complete contrast enhancement of the pancreas parenchyma (viable pancreas) or incomplete enhancement indicating parenchymal necrosis of the pancreas (PN). Secondly, all serial CT scans were evaluated to investigate whether late PN occurred in the group with a viable pancreas on initial CT scan. Characteristics of this group were evaluated. Thirteen patients showed signs of PN on initial CT scan. Late necrosis occurred in 5 patients. The average hospital stay in this subgroup was 46.7 days; complication rate, 100%; and mortality, 40%. A significant difference in hospital stay (average of 45.1 days vs 24.3 days; P = 0.003), complication rate (72% vs 33%; P = 0.006), and mortality (28% vs 6%; P = 0.019) was found when the group with eventual PN was compared with the group with no signs of PN (on initial and serial CT). This study shows a significant increase in hospital stay, complication rate, and mortality when eventual PN is shown on CT scan. Patients with late PN especially have a poor prognosis.


Effects of poly (ADP-ribose) polymerase-1 (PARP-1) inhibition on sulfur mustard-induced cutaneous injuries in vitro and in vivo.
Early studies with first-generation poly (ADP-ribose) polymerase (PARP) inhibitors have already indicated some therapeutic potential for sulfur mustard (SM) injuries. The available novel and more potential PARP inhibitors, which are undergoing clinical trials as drugs for cancer treatment, bring it back to the centre of interest. However, the role of PARP-1 in SM-induced injury is not fully understood. In this study, we selected a high potent specific PARP inhibitor ABT-888 as an example to investigate the effect of PARP inhibitor in SM injury. The results showed that in both the mouse ear vesicant model (MEVM) and HaCaT cell model, PARP inhibitor ABT-888 can reduce cell damage induced by severe SM injury. ABT-888 significantly reduced SM induced edema and epidermal necrosis in MEVM. In the HaCaT cell model, ABT-888 can reduce SM-induced NAD(+)/ATP depletion and apoptosis/necrosis. Then, we studied the mechanism of PARP-1 in SM injury by knockdown of PARP-1 in HaCaT cells. Knockdown of PARP-1 protected cell viability and downregulated the apoptosis checkpoints, including p-JNK, p-p53, Caspase 9, Caspase 8, c-PARP and Caspase 3 following SM-induced injury. Furthermore, the activation of AKT can inhibit autophagy via the regulation of mTOR. Our results showed that SM exposure could significantly inhibit the activation of Akt/mTOR pathway. Knockdown of PARP-1 reversed the SM-induced suppression of the Akt/mTOR pathway. In summary, the results of our study indicated that the protective effects of downregulation of PARP-1 in SM injury may be due to the regulation of apoptosis, necrosis, energy crisis and autophagy. However, it should be noticed that PARP inhibitor ABT-888 further enhanced the phosphorylation of H2AX (S139) after SM exposure, which indicated that we should be very careful in the application of PARP inhibitors in SM injury treatment because of the enhancement of DNA damage.


Sequence and expression analysis of deer mouse interferon-gamma, interleukin-10, tumor necrosis factor, and lymphotoxin-alpha.
Deer mice (Peromyscus maniculatus) are the principal host species of Sin Nombre (SN) virus, the primary etiologic agent of hantavirus cardiopulmonary syndrome in North America. The disease is a cytokine-mediated immunopathology characterized by pulmonary mononuclear infiltrates without discernible viral pathology. Infected deer mice remain life-long carriers and virus is found in many organs, including the lungs, but without pathology. It is unclear how deer mice respond to SN virus because no tools exist to examine the immune response in infected animals. As an initial step in examining host responses to SN virus, we have cloned partial cDNAs of deer mouse interferon-gamma (IFN-gamma), interleukin-10 (IL-10), tumor necrosis factor (TNF) and lymphotoxin-alpha (LTalpha). IL-10, TNF and LTalpha sequences are highly conserved compared to orthologs of other mammalian species, while IFN-gamma is substantially less conserved. Phylogenetic analyses indicate that the amino acid sequences of IFN-gamma and TNF may be useful in resolving relationships at the subfamily level within the rodent family Muridae. While all four sets of analyses were able to reconstruct clade Rodentia, they were not able to resolve the relationships among the mammalian orders represented in this study. Reverse transcriptase polymerase chain reaction (RT-PCR) analysis of concanavalin A-stimulated splenocytes determined that maximal IFN-gamma and TNF expression occurred rapidly while IL-10 and LTalpha expression was maximal at 24 h.


Ethics frameworks in Canadian health policies: foundation, scaffolding, or window dressing?
Health policy documents increasingly feature ethics frameworks that outline key guiding principles. It is unclear whether such frameworks function as scaffolding for creating policy, foundations for responding to policy, or mere aesthetic frames to make policies appear ethical. This study investigates the nature and quality of ethics frameworks in Canadian health documents. We reviewed the ethics frameworks of 24 strategic health policy documents published from 1998 to 2005 by Canadian government agencies. We found that frameworks typically appear as a list of principles or values. These elements vary widely across the terminal, procedural, and substantive values of conventional ethics, and many are better characterized as goals than as ethics. No two ethics frameworks matched, despite common topic areas and presumably broadly shared values within the Canadian health system. Elements shared by at least half of the documents include: access, accountability, autonomy, client-centredness, collaboration, efficiency, equity, and evidence. However, common elements are interpreted quite differently. The genesis of the framework and its elements is seldom described. Only one third of the documents relate specific ethical elements to specific policies. In conclusion, we draw on the clinical guidelines literature to propose some features of a robust, coherent and meaningful ethics framework.


Training future clinicians in telehealth competencies: outcomes of a telehealth curriculum and teleOSCEs at an academic medical center.
This study describes the program and learning outcomes of a telehealth skills curriculum based on the Association of American Medical Colleges (AAMC) telehealth competencies for clerkship-level medical students. A total of 133 third- and fourth-year medical students in a required family medicine clerkship at Stanford University School of Medicine participated in a telehealth curriculum, including a telehealth workshop, site-specific telehealth clinical encounters, and telemedicine objective structured clinical examinations (teleOSCEs) between July 2020 and August 2021. Their workshop communication and physical examination competencies were assessed in two teleOSCEs utilizing a novel telehealth assessment tool. Students' attitudes, skills, and self-efficacy were assessed through voluntary pre-clerkship, post-workshop, and post-OSCE surveys. Most learners reported low confidence in their telehealth physical examinations [n = 79, mean = 1.6 (scale 0-5, 5 = very confident, SD = 1.0)], which improved post-workshop [n = 69, 3.3 (0.9), p < 0.001]; almost all (97%, 70/72) felt the workshop prepared them to see patients in the clinic. In formative OSCEs, learners demonstrated appropriate "webside manner" (communication scores 94-99%, four items) but did not confirm confidentiality (21%) or review limitations of the visit (35%). In a low back pain OSCE, most learners assessed pain location (90%) and range of motion (87%); nearly half (48%) omitted strength testing. Our telehealth curriculum demonstrated that telehealth competencies can be taught and assessed in medical student education. Improvement in self-efficacy scores suggests that an 80-min workshop can prepare students to see patients in the clinical setting. Assessment of OSCE data informs opportunities for growth for further development in the curriculum, including addressing visit limitations and confidentiality in telehealth visits.


Perceived health is partially associated with the symptomatological profile in patients with benign and severe conditions: the case of congenital heart disease.
Individuals with serious medical conditions can perceive their health status as good. This might be explained by the symptomatology inherent to the condition. Research in this respect is scarce. Congenital heart disease (CHD) is a spectrum of mild, moderate, and complex heart defects, representing more benign and severe chronic conditions. We investigated (1) symptomatology (i.e., symptom frequency and symptom distress) of CHD patients; (2) the extent to which symptomatology was independently related to perceived health; and (3) the relative importance of individual symptoms for perceived health. A secondary data analysis on two separate patient samples (629 Belgian and 1,109 Dutch patients) was conducted. Patients' symptomatology was measured with the TAAQOL-CHD. Perceived health was measured by the EQ-5Dvas in Belgian patients, and by a single item (EVGFP rating) of the SF-36 in Dutch patients. Linear regression analyses were performed to investigate the relationship between symptoms and perceived health, while controlling for sex, age, disease complexity, and functional status. The most frequently occurring symptoms were dizziness, palpitations, and nycturia. Symptom distress was associated with perceived health, independent of confounders. Symptom distress with respect to shortness of breath while walking; palpitations; and dizziness were independently related to perceived health. Perceived health in CHD patients is partially associated with their symptomatology. This finding underscores the possibility that differences in perceived health across patient groups with more benign and severe conditions may be caused by the different impact conditions have--in terms of symptoms--on the day-to-day life.


Extraction of organism groups from phylogenetic profiles using independent component analysis.
In recent years, the analysis of orthologous genes based on phylogenetic profiles has received popularity in bioinfomatics. We propose a new method to extract organism groups and their hierarchy from phylogenetic profiles using the independent component analysis (ICA). The method involves first finding independent axes in the projected space from the multivariate data matrix representing phylogenetic profiles for a number of orthologous genes. Then the extracted axes are correlated with major organism groups, according to the extent of affiliation of axes scores for all the genes to specific organisms. The ICA was applied to the phylogenetic profiles created for 2,875 orthologs in 77 organisms by using the KEGG/GENES database. The 9 extracted components out of 18 predefined components well represented the organism groups as categorized in KEGG. Furthermore, we performed the cluster analysis and obtained the hierarchy of organism groups.


CORRESPONDENCE OF LEAKAGE ON FLUORESCEIN ANGIOGRAPHY AND OPTICAL COHERENCE TOMOGRAPHY PARAMETERS IN DIAGNOSIS AND MONITORING OF MYOPIC CHOROIDAL NEOVASCULARIZATION TREATED WITH BEVACIZUMAB.
To describe the morphologic alterations on spectral domain optical coherence tomography in active myopic choroidal neovascularization (CNV) receiving intravitreal bevacizumab and to evaluate its diagnostic accuracy, taking fluorescein angiography as a reference examination. Thirty patients (30 eyes) were prospectively enrolled. Each eye was imaged with fluorescein angiography and spectral domain optical coherence tomography at the baseline and at 1-, 2-, and 3-month examinations. Spectral domain optical coherence tomography parameters consisting of intraretinal/subretinal fluid and absence of external limiting membrane (ELM) visibility were considered signs of CNV activity and collated with the presence/absence of leakage on fluorescein angiography. Main outcome measures were frequencies of the retinal alterations associated with myopic CNV at the diagnosis and during monitoring of anti-vascular endothelial growth factor therapy. At the diagnosis, spectral domain optical coherence tomography identified subretinal fluid in 14 eyes (46%), intraretinal fluid associated with subretinal fluid in 12 eyes (40%), and absence of ELM visibility in 30 of the 30 eyes (100%). During the follow-up, fluorescein leakage was noted in 32 visits (18, 8, and 6 eyes at the 1-, 2- and 3-month examinations, respectively). Taking into consideration spectral domain optical coherence tomography features of active myopic CNVs on fluorescein angiography, subretinal fluid was identified in 24 examinations (75%), intraretinal cysts with subretinal fluid were noted in 5 visits (15.6%), and the absence of ELM visibility was visible in 32 examinations (100%). The alterations of the ELM corresponded to the location of the fluorescein leakage. This study provides evidence that the absence of ELM visibility is a more reliable parameter for evaluating CNV activity than intraretinal/subretinal fluid collection and may constitute a useful option in diagnosing and monitoring the myopic CNV during anti-vascular endothelial growth factor therapy.


Effect of Cyproheptadine on Ventilatory Support-free Days in Critically Ill Patients with COVID-19: An Open-label, Randomized Clinical Trial.
Serotonin is a mediator of pulmonary hypoxic vasoconstriction. Experimental studies have shown that serotonin-mediated pulmonary vasoconstriction can be inhibited by cyproheptadine. The aim of this study is to assess whether treatment with cyproheptadine compared to usual care increases ventilatory support-free days during the first 28 days in patients with coronavirus disease 2019 (COVID-19) requiring ventilatory support. This randomized, single-center, open-label clinical trial included patients who were admitted to the intensive care unit (ICU) requiring ventilatory support due to COVID-19. Patients allocated to the intervention group received cyproheptadine for 10 days. The primary outcome was ventilator-free days during the first 28 days. Nineteen patients were randomized to receive cyproheptadine and 21 to the control group. The number of ventilatory support-free days during the first 28 days was not different between the two groups (15.0; 95% CI, 0.0-24.0 days in the control group vs 7.0; 95% CI, 0.0-19.0 days in the intervention group; p = 0.284). In patients with COVID-19 and in need of ventilatory support, the use of cyproheptadine plus usual care, compared with usual care alone, did not increase the number of ventilatory support-free days in 28 days. Boniatti MM, Nedel WL, Rihl MF, Schwarz P, Parolo E, Moretti MMS, et al. Effect of Cyproheptadine on Ventilatory Support-free Days in Critically Ill Patients with COVID-19: An Open-label, Randomized Clinical Trial. Indian J Crit Care Med 2023;27(7):517-521.


Cesarean delivery may affect the early biodiversity of intestinal bacteria.
The gastrointestinal tract of neonates becomes colonized immediately after birth with environmental microorganisms, mainly from the mother; strong evidence suggests that the early composition of the microbiota of neonates plays an important role for the postnatal development of the immune system. The present study was designed to evaluate by means of a molecular biology approach the relation between the intestinal ecosystem of the newborn and the mode of delivery. The intestinal bacterial composition on d 3 of life was investigated in 23 infants born by vaginal delivery and in 23 infants delivered by cesarean section. PCR-denaturing gradient gel electrophoresis and PCR-temperature gradient gel electrophoresis have been utilized, together with the specific amplifications for 10 Bifidobacterium species, 3 Ruminococcus species, and Bacteroides. The intestinal microbiota of neonates delivered by cesarean delivery appears to be less diverse, in terms of bacteria species, than the microbiota of vaginally delivered infants. The intestinal microbiota after cesarean delivery is characterized by an absence of Bifidobacteria species. Vaginally delivered neonates, even if they showed individual microbial profiles, were characterized by predominant groups such as B. longum and B. catenulatum. Our data demonstrate that the mode of delivery has a deep impact on the composition of the intestinal microbiota at the very beginning of human life. This study opens the path to further investigations to confirm the link between microbiota composition and immune system development and to identify tools for the modulation of the intestinal microbiota of cesarean-delivered neonates. Additionally, we underline the importance of adequate microbiological tools used to support clinically relevant trials, if intestinal microbiota is considered as a study outcome.


[Genetic transfer of pAP38, pAP39, and pAP41 plasmids into E. coli, Erwinia, and Hafnia strains].
Genetic transfer factors pAP38, pAP39 and pAP41 can be transferred to E. coli, both typed and untypecd, as well as to Erwinia and Hafnia strains, with different frequency (10(-2) to 10(-8)). The transconjugates thus obtained possess donor activity and can transfer the factors they have received to recipient E. coli strains. After transfer these factors are stably maintained in a new host for at least 10 days. Under the action of ethidium bromide or elevated temperature the elimination of the transfer factors from host bacteria is observed. The studied transfer factors pAP38, pAP39 and pAP41 (F-like factors) are plasmids fi+.


Natural history of hepatitis C virus infection: from chronic hepatitis to cirrhosis, to hepatocellular carcinoma.
Hepatitis C is a heterogeneous disease and is responsible for considerable mortality and morbidity. The hepatitis C virus (HCV) infects nearly 170 million people world-wide. More than 80% of infected individuals develop chronic infection; the remaining 10-20% develop spontaneous clearance with natural immunity. Acute hepatitis is icteric in only 20% of patients and is rarely severe. The majority of patients who develop chronic HCV infection are asymptomatic; but 60-80% develop chronic hepatitis as indicated by elevated alanine aminotransferase (ALT), around 30% maintain persistently normal ALT levels despite having detectable HCV-RNA in serum. One-third of chronically infected patients develop progressive liver injury, fibrosis and cirrhosis over a period of 20-30 years. The relationship between virus load, HCV genotype, quasi-species variability and progression of liver disease is controversial. Acquired infection after age 40, male sex, excessive alcohol-consumption, hepatitis B virus (HBV) or HIV co-infection, steatosis, and immunosuppressed state have been identified as co-factors associated with progression of fibrosis and development of cirrhosis. In patients with cirrhosis, the incidence of hepatocellular carcinoma is 2-5% per year. At present, HCV-related end-stage cirrhosis is the first cause of liver transplantation.


Comparison of degree of dependence of canine renal arteries and veins on high and low affinity calcium for responses to norepinephrine and potassium.
The relationships between tension responses to norepinephrine (NE) and high potassium (KCl) and high affinity 45Ca binding and mobilization were compared in canine renal arteries and veins. Contractile responses to 80 mM KCl were inhibited 83 (veins) and 88% (arteries) after respective 5-min and 60-min incubation periods in solutions with no added Ca++; responses to 10(-4) M NE were inhibited 87% (veins) and only 44% (arteries) after 60 min in the same solution. In solutions favoring low affinity binding of Ca++ (5.0 mM), uptake of 45Ca was similar in canine renal arteries and veins. However, in solutions favoring high affinity Ca++ binding (0.03 mM Ca++), 45Ca uptake was greater in arteries than in veins. Comparison of 45Ca efflux rates indicates a more rapid efflux and a greater Ca++-45Ca exchangeability in veins. After incubation with 45Ca and subsequent washout in an isosmotic (80.8 mM) La+++-substituted solution at 0.5 degrees C, 45Ca retention (residual Ca++ uptake) was proportionately greater in arteries than in veins at both high and low affinity sites. NE (10(-6) M) significantly increased La+++-resistant 45Ca uptake at both high and low affinity sites in veins but not in arteries. Thus, the NE-induced responses in veins depend upon extracellular Ca++ to a greater degree than in arteries. Even though veins have a lower number of high affinity Ca++ binding sites and this decreases the ability of the veins to retain sufficient Ca++ at these sites to maintain the response to NE, the responsiveness to NE appears to be maintained by an alternate mechanism, uptake of Ca++ at lower NE concentrations.