An Overview of Systematic Reviews and Meta-Analyses of Clinical Studies of Acupuncture for Cancer Pain.
Systematic reviews (SRs) and meta-analyses (MAs) for the use of acupuncture for cancer pain have been increasing, but the evidence has not been systematically and comprehensively assessed. We aimed to perform an overview of the evidence quality of SRs/MAs of acupuncture for improving cancer pain. 8 databases were systematically searched to identify SRs/MAs of acupuncture for improving cancer pain. The A Measurement Tool to Assess Systematic Reviews 2 (AMSTAR-2), Risk of Bias in Systematic Reviews (ROBIS), Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA), and Grades of Recommendations, Assessment, Development, and Evaluation (GRADE), respectively, were applied by 2 independent reviewers to evaluate the methodological quality, risk of bias, reporting quality, and evidence quality. A total of 14 SRs/MAs were included in the present study. By AMSTAR-2, two reviews were rated as having high methodological quality, while 12 were given a critically low rating. All SRs/MAs in Phase 1, Domain 1, and Domain 4, according to ROBIS, were at low risk. Furthermore, 4 reviews in Domain 2, twelve reviews in Domain 3, and ten SRs/MAs in Phase 3, were rated as having low risk of bias. With reporting quality, some reporting flaws were identified in the topic of protocol and registration, additional analyses, and search strategy. According to GRADE, the level of evidence quality was "critically low" to "moderate," and risk of bias was the most common downgraded factor. Acupuncture may be beneficial in improving cancer pain. However, due to the identified limitations and inconsistent findings, we recommend further rigorous, and more standardized SRs/MAs to provide strong evidence for definitive conclusions.


Effect of chemical structure on the subglass relaxation dynamics of biobased polyesters as revealed by dielectric spectroscopy: 2,5-furandicarboxylic acid vs. trans-1,4-cyclohexanedicarboxylic acid.
The chemical structure-dynamics relationship for poly(trimethylene 2,5-furanoate) and poly(trimethylene 1,4-cyclohexanedicarboxylate) was investigated via dielectric spectroscopy and compared with that of poly(trimethylene terephthalate) in order to evaluate the impact on the subglass dynamics of the chemical nature of the ring. Further comparison was accomplished with the neopentyl glycol containing counterparts: poly(neopentyl 2,5-furanoate) and poly(neopentyl 1,4-cyclohexanedicarboxylate). Our study reveals a multimodal nature of the subglass β process. For the more flexible polymers (containing cyclohexane rings) three modes for the β process were detected. The faster mode was assigned to the relaxation of the oxygen linked to the aliphatic carbon, the slower one to the link between the aliphatic ring and the ester group, and the third mode to the aliphatic ring. For stiffer polymers (containing aromatic rings), the local modes appear more coupled. This effect is more evident in the polymers with the furan ring where essentially a single β mode can be resolved.


Thrombosis at mountain altitudes.
Victims of high-altitude pulmonary edema often have clots obstructing the pulmonary vessels. This, together with an apparent high incidence of thrombophlebitis and cerebral emboli at altitude suggests that mountain travel may predispose to hypercoagulability. A critical analysis of the available data suggests that, although thrombosis may be a late event complicating various forms of mountain sickness, the laboratory techniques of characterizing hypercoagulability are not sufficient to define and characterize the mechanism.


The sick role and the role of the physician reconsidered.
The main substance of this paper was presented orally at a meeting of the Sick Role, organized and chaired by Andrew Twaddle. It was a commentary on four papers and the oral discussion of them. In response to these the paper first discusses the relation of the sick role to deviant behavior and the motivation to become and remain ill. The position was taken that the author never had meant to confine the category of illness to deviant behavior, though its negative valuation should not be forgotten. Nor had he confined it to cases of acute illness, omitting consideration of chronic and other types. The most important issue, however, concerned the structure of the relation between physician and patient. Though insisting that interaction between them is two-way, not one-way, the author insisted that the relation is basically asymmetrical because of the physician's expertise in health matters, gained through training and experience, and his special fiduciary responsibility for the care of the sick. In this respect the relationship is different from others such as the competitive market or the democratic association, but is comparable to the relation of teacher and student in higher education.


Persistent hyperplastic primary vitreous in transgenic mice expressing IE180 of the pseudorabies virus.
Pseudorabies virus (PRV), a representative member of the alpha-herpesvirus family, causes nervous symptoms and ocular lesions, such as keratoconjunctivitis and retinal degeneration in piglets. The immediate-early protein IE180 of the PRV is known to be essential, not only in viral gene expression, but also in the cellular gene expression in host cells. The purpose of this study was to examine the effect of IE180 on the development of the mouse eye, by using transgenic technology. Transgenic mice expressing IE180 were generated and their eyes analyzed by histology, immunocytochemistry, and the bromodeoxyuridine cell proliferation assay. A fibrovascular retrolental tissue analogous to persistent hyperplastic primary vitreous (PHPV) in humans was observed in a transgenic mouse line expressing IE180. The gross anatomy of the eye showed white pupils. Analysis of hematoxylin and eosin-stained sections revealed that the retrolental tissue adhered to the neuroretina, the inner nuclear and ganglion cell layers were disorganized, and rosettelike arrangements of dysplastic photoreceptor cells were present. Bromodeoxyuridine-positive cells were detected in the retrolental tissues of postnatal day (P)1, P7, and P14 mice. The retrolental mass in the P7 transgenic mouse was composed of melanocytes and endothelial cells, which were detected by a cocktail of antibodies against endoglin, CD31, and VEGF receptor-2. The observation that the eye disease in transgenic mice is similar to that in PHPV in humans raises the possibility that expression of the immediate-early gene of alpha-herpesviruses may contribute to PHPV.


Limitations of the toxic equivalency factor approach for risk assessment of TCDD and related compounds.
Halogenated aromatic hydrocarbons (HAHs), such as polychlorinated biphenyls (PCBs), dibenzo-p-dioxins (PCDDs), and dibenzofurans (PCDFs), are industrial compounds or by-products that have been widely identified as environmental contaminants. Hazard and risk assessment of complex HAH mixtures have utilized a toxic equivalency factor (TEF) approach, where the toxic equivalents (TEQs) of any mixture are equal to the sum of the concentration of individual (i) congeners times their potencies (TEFi) relative to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, TEF = 1.0). TEQ = sigma [PCDDi] x TEFi + sigma [PCDFi] x TEFi + sigma [PCBi] x TEFi. The TEQ (or TCDD equivalents) can be readily calculated from analytical data and provides an estimate of the toxicity of any mixture containing HAHs. Several in vivo and in vitro studies with some PCDD/PCDF and PCB mixtures have demonstrated correlations between experimentally determined and calculated TEQs. However, results of several studies have also shown that for specific responses, the TEQ for some HAH mixtures are non-additive. For example, PCB mixtures and individual PCB congeners such as 2,2',4,4',5,5'-hexachlorobiphenyl inhibit toxic and biochemical responses induced by TCDD and related compounds. Another problem associated with hazard and risk assessment of background exposure to HAHs is the relative contribution of trace levels of HAHs (exodioxins) compared to relatively high exposure to naturally occurring aryl hydrocarbon receptor (AhR) agonists, which act through the same mechanistic pathway.


[Principles of selective inactivation of the viral genome. III. Kinetics of the inactivation of bacteriophage MS2 infectivity by beta-propiolactone].
It is shown that the action of beta-propiolactone on the bacteriophage MS2 under the wide range of conditions (pH, temperature, initial concentration of the reagent) the survival curves could be accurately described, taking into account the reagent consumption during inactivation. The requirements for accurate description of the infectivity inactivation of viruses by the action of any chemical agent were formulated. That allowed rational development of a principal stage in preparation of the killed antiviral vaccines--inactivation of the virus infectivity to the necessary extent by the action of chemical agents.


[Cooperative documentation of childhood malignancies (author's transl)].
Since January 1980 a nationwide documentation of childhood malignancies is performed in the FRG. The cooperative documentation system is supported by the Stiftung Volkswagen-werk and centralized at the Institut für Medizinische Statistik und Dokumentation (IMSD) of the university of Mainz. During the first year of the project the incidence of 1002 malignancies has been reported from a total of 62 hospitals with a still increasing number of cooperating centers. The documentation scheme is based on recommendations of the ADT (working group of tumor centers in the FRG) which are in accordance with international recommendations by the W.H.O., U.I.C.C. etc. A newly diagnosed malignancy is reported by a short standardized form to the IMSD which in turn sends out tumor-specific questionnaires of modular structure for obtaining relevant baseline variables. Patient follow-up is achieved by obtaining the status of all patients at least twice a year which is sent in a condensed format to the IMSD. Besides obtaining basic epidemiological data the system will provide detailed analyses on the course of the different malignancies, allow comparisons between different disease groups as well as different hospitals and will serve as a recruiting basis for controlled clinical trials.


Applied relaxation training for generalised anxiety and panic attacks: the efficacy of a learnt coping strategy on subjective reports.
The results of applied relaxation training in patients with generalised anxiety and panic attacks are reported. ART was taught during one session, by means of participant demonstration, written instructions, taped instructions, or a combination of all three, with instructions to practice at home. All four methods proved superior to a waiting list control, but there were no differences between the treatment groups. There was some evidence for the non-specific effect of expectancy, but this did not completely explain the treatment effect.


The role of heart rate and ivabradine in acute heart failure.
Resting heart rate (HR) is considered a powerful predictor of mortality both in healthy subjects and in cardiovascular (CV) patients, including those affected by heart failure (HF). Its reduction below 70 bpm is the treatment target in chronic HF with reduced ejection fraction (HFrEF) when sinus rhythm is present. In acute HF (AHF) HR is usually elevated but its role as risk marker is still unknown. Notably, in unstable patients, beta-blockers can be reduced or stopped, thus enhancing this phenomenon. Moreover, some data in literature suggest that HR reduction during hospitalization or HR at discharge or in the vulnerable phase after it are more predictive of early-term events and may be therapeutic targets. On the other hand, ivabradine is a pure HR-lowering drug with no effects on inotropism. Its role in the AHF setting has been recently investigated and is the object of this review.


Interaction of bile salts with gastrointestinal mucins.
The properties of three mucins were examined to identify the structural features responsible for their functional difterences. Bovine submaxillary mucin (BSM), porcine gastric mucin (PGM), and rat intestinal mucin (RIM) were each characterized, and high carbohydrate contents were found for RIM and PGM. The amino acid compositions were typical of mucin glycoproteins, with over half comprising small, neutral amino acids. Thereafter, each mucin was equilibrated with three different series of concentrations of the bile salts sodium taurocholate, sodium taurodeoxycholate, and sodium taurochenodeoxycholate. Following multiple centrifugations, the supernatant and mucin pellet concentrations of the bile salts were measured. The bile salt pellet concentration was plotted as a function of supernatant concentration, and from the slopes, the excluded volumes were calculated as 25, 29-44, and 28 55 mL/g for BSM, RIM, and PGM, respectively. The intercepts were 8-10, 2-3, and 1-3 mM for BSM, RIM, and PGM, respectively, which represents an estimate of the bound concentration of bile salt. Differences among the bile salts were observed in the excluded volume and amount bound, but no trends were evident. The bile salts may interact as aggregates with the hydrophobic areas and carbohydrate side chains of the mucins, providing favorable sites for association. The binding at low concentrations with exclusion at high concentrations is significant for modulating the absorption of lipid aggregates from the intestine. Finally, the differences among the mucins reflect the unique structure function relationship of these gastrointestinal mucins.


Development of nanosomes using high-pressure homogenization for gene therapy.
The aim of this project was to develop a novel lipid-based formulation suitable for gene therapy. Novel nanosize liposome (nanosome) formulations containing pDNA (plasmid DNA) were developed using high-pressure homogenization (HPH). The effect of lipid concentration was studied at two levels: 3 mm and 20 mm. The preformed nanosomes were incubated for 18-20 h with pDNA or pDNA/protamine sulfate (PS) complex. The physical properties of the pDNA nanosomes were compared by particle size distribution and zeta-potential measurements. Their biological properties were also compared by pDNA efficiency of encapsulation/complexation, integrity, nuclease digestion, transfection efficiency and cell cytotoxicity. pDNA nanosomes prepared with 20 mM lipid (nanosomes:pDNA:PS at a ratio of 8.6:1:2) had particle sizes of 170-422 nm (90% confidence). The zeta-potential of the formulation was 49.2 +/- 1.5 mV, and the pDNA encapsulation/complexation efficiency was approximately 98%. pDNA nanosomes prepared with 3 mM lipid (nanosomes:pDNA PS at a ratio of 2.09:1:2) had particle sizes of 140-263 nm (90% confidence). The zeta-potential of this formulation was 36.4 +/- 1.2 mV, and the pDNA encapsulation/complexation efficiency was approximately 100%. However, a comparison of the efficiency of transfection indicated that pDNA nanosomes prepared with low-concentration lipids (3 mM) showed significantly higher transfection efficiency compared with the pDNA nanosomes prepared with high-concentration lipids (20 mM), as well as those prepared with Fugene-6 (a commercially available transfection reagent). This particular formulation (pDNA nanosomes, 3 mM lipids) also showed significantly less cytotoxicity compared with the other pDNA nanosome formulations. To conclude, these results indicate that condensing pDNA with PS followed by subsequent complexation with low-concentration nanosomes generated from HPH can produce a pDNA nanosome formulation that will boost transfection efficiency, while minimizing cytotoxicity. This new technology appears to be an efficient tool for future commercial or large-scale manufacture of DNA delivery systems for gene therapy.


Biochemical evaluation of virtual screening methods reveals a cell-active inhibitor of the cancer-promoting phosphatases of regenerating liver.
Computationally supported development of small molecule inhibitors has successfully been applied to protein tyrosine phosphatases in the past, revealing a number of cell-active compounds. Similar approaches have also been used to screen for small molecule inhibitors for the cancer-related phosphatases of regenerating liver (PRL) family. Still, selective and cell-active compounds are of limited availability. Since especially PRL-3 remains an attractive drug target due to its clear role in cancer metastasis, such compounds are highly demanded. In this study, we investigated various virtual screening approaches for their applicability to identify novel small molecule entities for PRL-3 as target. Biochemical evaluation of purchasable compounds revealed ligand-based approaches as well suited for this target, compared to docking-based techniques that did not perform well in this context. The best hit of this study, a 2-cyano-2-ene-ester and hence a novel chemotype targeting the PRLs, was further optimized by a structure-activity-relationship (SAR) study, leading to a low micromolar PRL inhibitor with acceptable selectivity over other protein tyrosine phosphatases. The compound is active in cells, as shown by its ability to specifically revert PRL-3 induced cell migration, and exhibits similar effects on PRL-1 and PRL-2. It is furthermore suitable for fluorescence microscopy applications, and it is commercially available. These features make it the only purchasable, cell-active and acceptably selective PRL inhibitor to date that can be used in various cellular applications.


Studying the Proliferative Activity of Human Corneal Stromal Cell Populations.
The proliferative activity of populations of stromal cells (fibroblasts) obtained from human corneal lenticles under conditions of their differentiation into keratocytes was studied. It was shown that during differentiation, the number of dividing fibroblasts and the frequency of divisions, and motor activity of these cells (speed of movement along the cell trajectory and the length of the trajectory) sharply decreased. These findings indicate a decrease in the proliferative activity of fibroblasts under conditions of their differentiation and transformation into keratocytes. A period of 17 days is sufficient for differentiation of corneal fibroblasts into keratocytes.


Comparison of various radioactive payloads for a human monoclonal antibody to glycoprotein 41 for elimination of HIV-infected cells.
cART has significantly improved the life expectancy of people living with HIV (PLWH). However, it fails to eliminate the long-lived reservoir of latent HIV-infected cells. Radioimmunotherapy (RIT) relies on antigen-specific monoclonal antibodies (mAbs) for targeted delivery of lethal doses of ionizing radiation to cells. Previously, we have demonstrated that human mAb 2556 against HIV gp41 conjugated with 213Bismuth radioisotope (t1/2 = 46 min, alpha-emitter) selectively killed HIV-infected cells. 225Actinium (t1/2 = 9.92 d, alpha-emitter) and 177Lutetium (t1/2 = 6.7 d, beta-emitter) are two long-lived clinically proven radioisotopes for cancer treatment which might be more effective in killing infected cells systemically and in CNS. In this study we have conjugated 2556 mAb with 213Bi, 225Ac and 177Lu, and compared their ability to kill HIV-infected human peripheral blood mononuclear cells (PBMCs) and monocytes. PBMCs and monocytes from healthy donors were infected with HIVp49.5 and treated in vitro with increasing concentrations of 213Bi (4-20 μCi)-, 225Ac (20-100 nCi)- and 177Lu (4-50 μCi)-2556 mAb. After three days post-treatment of infected PBMCs and monocytes, 213Bi- and 177Lu-conjugated 2556 mAb reduced virus production measured by p24 level in a dose-dependent manner, whereas, 225Ac-2556 showed minimal effect. However, seven days post-treatment all three radioisotopes showed significantly more pronounced reduction of virus replication as compared to control labeled mAb with 225Ac-2556 showing the least non-specific killing. These results indicate that RIT holds promise as a novel treatment option for the eradication of HIV-infected cells that merits further study in combination with cART and reactivation drugs.


Depression, telomeres and mitochondrial DNA: between- and within-person associations from a 10-year longitudinal study.
Alterations in cellular aging, indexed by leukocyte telomere length (LTL) and mitochondrial DNA copy number (mtDNAcn), might partly account for the increased health risks in persons with depression. Although some studies indeed found cross-sectional associations of depression with LTL and mtDNAcn, the longitudinal associations remain unclear. This 10-year longitudinal study examined between- and within-person associations of depressive symptoms with LTL and mtDNAcn in a large community sample. Data are from years 15, 20 and 25 follow-up evaluations in 977 subjects from the Coronary Artery Risk Development in Young Adults study. Depressive symptoms (years 15, 20, 25) were assessed with the Center for Epidemiologic Studies Depression (CES-D) scale; LTL (years 15, 20, 25) and mtDNAcn (years 15, 25) were measured in whole blood by quantitative PCR. With mixed-model analyses, we explored between- and within-person associations between CES-D scores and cellular aging markers. Results showed that high levels of depressive symptomatology throughout the 10-year time span was associated with shorter average LTL over 10 years (B=-4.2; P=0.014) after covarying for age, sex, race and education. However, no within-person association was found between depressive symptoms and LTL at each year (B=-0.8; P=0.548). Further, we found no between-person (B=-0.2; P=0.744) or within-person (B=0.4; P=0.497) associations between depressive symptomatology and mtDNAcn. Our results provide evidence for a long-term, between-person relationship of depressive symptoms with LTL, rather than a dynamic and direct within-person relationship. In this study, we found no evidence for an association between depressive symptoms and mtDNAcn.


Increasing Environmental Complexity by Providing Different Types of Litter and Perches during Early Rearing Boosts Coping Abilities in Domestic Fowl Chicks.
Early experience of a complex environment can improve biologically relevant traits related to coping abilities. However, the mechanisms underlying these positive effects have not been well explored. We hypothesized that giving chicks possibilities to express choices within relevant resources could be an important part of the mechanism, as well as a novel way to increase environmental complexity. In a balanced design, laying hen hatchlings of the white hybrid Bovans Robust were reared in a "single-choice" environment (single litter and perch type) or a "multi-choice" environment (four different litter and perch types). Immunological and behavioral indicators of chicks' coping abilities were explored in this experimental study at three weeks of age. Chicks from "multi-choice" environments had shorter durations of tonic immobility, lower heterophil/lymphocyte ratios, higher natural antibody concentrations, and were more successful in gaining novel food rewards in a repeated opportunity test. These results imply that chicks having access to variation within resource types were less fearful, experienced less chronic stress, would be more able to cope with pathogenic challenges, and potentially had an improved learning ability. To conclude, the more complex environment, achieved by increasing chicks' possibilities to choose, seemed to make chicks better prepared for potential challenges, boosting their adaptive capacities and their ability to make the most of opportunities.


Hype versus hope: metformin and vitamin D as anticancer agents.
There has been increasing interest in the use of metformin and vitamin D to reduce cancer risk and improve outcomes. Metformin, an oral antidiabetic drug, improves insulin resistance and has been associated with reduced cancer incidence and cancer mortality. Low levels of vitamin D have also been associated with increased cancer risk, mainly in retrospective studies, and it has been suggested that vitamin D supplementation might play a role in cancer prevention. Preclinical data provide a biologic rationale for these associations; however, the human data arise predominantly from observational studies and caution is needed in their translation into clinical practice. This is because of the recognized limitations of observational studies, such as time-related survival biases, selection and referral biases, short follow-up, and the presence of confounding factors that can lead to spurious or inaccurate findings. Combined examination of associations with cancer risk and outcome (occurring when exposure in a population that does not yet have cancer is analyzed in relation to cancer death) may yield results that are difficult to interpret. Finally, associations across all cancers may differ from those in specific cancer types. These shortcomings can be overcome in properly designed and adequately powered prospective randomized trials; however, such trials are both expensive and time consuming. We review the literature examining the associations of metformin and vitamin D with cancer, discussing weakness and strengths and making recommendations for further research and clinical practice.


Decreased Neural Connectivity in the Default Mode Network Among Youth and Young Adults With Chronic Kidney Disease.
An increasing amount of literature has indicated that chronic kidney disease (CKD) is associated with cognitive deficits that increase with worsening disease severity. Although abnormalities in brain structure have been widely documented, few studies to date have examined the functioning of brain areas associated with the specific cognitive domains affected by CKD (namely, attention and executive functions). Furthermore, few studies have examined functional connectivity among CKD youth who are relatively early in the course of the disease. The present study used functional magnetic resonance imaging to examine the resting state connectivity in 67 youth with CKD (mean age, 17 y) and 58 age-matched healthy controls. Using seed-based multiple regression, decreased connectivity was observed within the anterior cingulate portion of the default mode network. In addition, decreased connectivity within the dorsolateral prefrontal cortex, paracingulate gyrus, and frontal pole were correlated significantly with disease severity. These data indicate that connectivity deficits in circuits implementing attentional processes may represent an early marker for cognitive decline in CKD.


Access to health care resources for family caregivers of elderly persons with dementia.
Concerns about the "elder care crisis" and changes in the provision of health care are fostering expectations that families should be responsible for taking care of their elderly members. The assumptions that families (1) are not providing enough care, (2) know how to provide care, and (3) have access to resources for the provision of care are embedded in the social expectation of family care for elderly persons with dementia. However, research shows that these assumptions are not based on fact.


The Impact of State Dementia Training Requirements for Nursing Homes on Antipsychotic Medication Use.
Nursing home (NH) staff often report not having adequate dementia-specific knowledge to effectively care for these residents. Between 2011 and 2019, 9 states in the United States implemented dementia training requirements for NH staff. This study evaluated whether the state-mandated dementia training for NH staff was associated with improving resident outcomes. Compared trends in antipsychotic medication before and after implementation of state training requirements to trends in states without requirements. NHs. Data from Care Compare for NHs and LTCFocus were linked to state policy data. We excluded 14 states that had implemented training requirements before the start of the study period in 2011. We estimated difference-in-differences models that compared trends in antipsychotic medication use before and after implementation of training requirements in states that have newly implemented requirements to trends in states without requirements. We also investigated whether the impact of training was larger in states with more stringent training requirements (eg, specifying a minimum number of training hours) and in NHs with a special care unit for dementia and examined similar analyses for restraint use and falls. We found that training requirements were associated with a 0.59-percentage point reduction (95% CI -0.91 to -0.27) in antipsychotics use. Effects were larger in NHs with a special care unit for dementia and in states that had stricter training requirements. We also found that training requirements were associated with a 0.17-percentage point reduction (95% CI -0.26 to -0.07) in restraint use measure and had no impact on falls. State requirements for NH staff dementia training were associated with a small, but significant, reduction in the use of antipsychotic medication and physical restraints.


[Burkholderia cepacia under different ecological conditions: the amount and variability of the bacterial population].
In a series of prolonged experiments with the use of the bacteriological method and PCR analysis the amount and state of B. cepacia population, associated and not associated with infusoria Tetrahymena pyriformis, were dynamically evaluated under different conditions: in water, brain heart broth, soil extract and at different temperature (4 degrees C and 25 degrees C). In soil extract at 25 degrees C B. cepacia existed in the vegetative state for the period of up to 3 months, while at 4 degrees C, in the absence of protozoa, the transition of these microorganisms into the uncultivable forms occurred in 9 days, and they could be detected only with the use of PCR. Protozoa maintained the existence of the vegetative bacteria for as long as 2 months, and in 3-4 months uncultivable forms of B. cepacia cells were registered. In water at low temperature B. cepacia disappeared in 2 months, evidently, eaten up by infusoria. The population variability of B. cepacia under different conditions of their existence was established: S-R dissociation, a decrease in biochemical activity, growth deceleration. A high level of cytopathogenicity in B. cepacia pigment-forming clones was noted. In the process of transition into the uncultivable state pigment formation in B. cepacia population decreased up. The ecological plasticity and multi-pathogenicity of B. cepacia as phytopathogens and the causative agents of human diseases are discussed.


Swine ANP32A Supports Avian Influenza Virus Polymerase.
Avian influenza viruses occasionally infect and adapt to mammals, including humans. Swine are often described as "mixing vessels," being susceptible to both avian- and human-origin viruses, which allows the emergence of novel reassortants, such as the precursor to the 2009 H1N1 pandemic. ANP32 proteins are host factors that act as influenza virus polymerase cofactors. In this study, we describe how swine ANP32A, uniquely among the mammalian ANP32 proteins tested, supports the activity of avian-origin influenza virus polymerases and avian influenza virus replication. We further show that after the swine-origin influenza virus emerged in humans and caused the 2009 pandemic, it evolved polymerase gene mutations that enabled it to more efficiently use human ANP32 proteins. We map the enhanced proviral activity of swine ANP32A to a pair of amino acids, 106 and 156, in the leucine-rich repeat and central domains and show these mutations enhance binding to influenza virus trimeric polymerase. These findings help elucidate the molecular basis for the mixing vessel trait of swine and further our understanding of the evolution and ecology of viruses in this host.IMPORTANCE Avian influenza viruses can jump from wild birds and poultry into mammalian species such as humans or swine, but they only continue to transmit if they accumulate mammalian adapting mutations. Pigs appear uniquely susceptible to both avian and human strains of influenza and are often described as virus "mixing vessels." In this study, we describe how a host factor responsible for regulating virus replication, ANP32A, is different between swine and humans. Swine ANP32A allows a greater range of influenza viruses, specifically those from birds, to replicate. It does this by binding the virus polymerase more tightly than the human version of the protein. This work helps to explain the unique properties of swine as mixing vessels.


Antibody responses to prostate-associated antigens in patients with prostatitis and prostate cancer.
An important focus of tumor immunotherapy has been the identification of appropriate antigenic targets. Serum-based screening approaches have led to the discovery of hundreds of tumor-associated antigens recognized by IgG. Our efforts to identify immunologically recognized proteins in prostate cancer have yielded a multitude of antigens; however, prioritizing these antigens as targets for evaluation in immunotherapies has been challenging. In this report, we set out to determine whether the evaluation of multiple antigenic targets would allow the identification of a subset of antigens that are common immunologic targets in patients with prostate cancer. Using a phage immunoblot approach, we evaluated IgG responses in patients with prostate cancer (n = 126), patients with chronic prostatitis (n = 45), and men without prostate disease (n = 53). We found that patients with prostate cancer or prostatitis have IgG specific for multiple common antigens. A subset of 23 proteins was identified to which IgG were detected in 38% of patients with prostate cancer and 33% patients with prostatitis versus 6% of controls (P < 0.001 and P = 0.003, respectively). Responses to multiple members were not higher in patients with advanced disease, suggesting antibody immune responses occur early in the natural history of cancer progression. These findings suggest an association between inflammatory conditions of the prostate and prostate cancer, and suggest that IgG responses to a panel of commonly recognized prostate antigens could be potentially used in the identification of patients at risk for prostate cancer or as a tool to identify immune responses elicited to prostate tissue.


Expression of recombinant myelin-associated glycoprotein in primary Schwann cells promotes the initial investment of axons by myelinating Schwann cells.
Myelin-associated glycoprotein (MAG) is an integral membrane protein expressed by myelinating glial cells that occurs in two developmentally regulated forms with different carboxyterminal cytoplasmic domains (L-MAG and S-MAG). To investigate the role of MAG in myelination a recombinant retrovirus was used to introduce a MAG cDNA (L-MAG form) into primary Schwann cells in vitro. Stably infected populations of cells were obtained that constitutively expressed MAG at the cell surface without the normal requirement for neuronal contact to induce expression. Constitutive expression of L-MAG did not affect myelination. In long term co-culture with purified sensory neurons, the higher level of MAG expression on infected Schwann cells was reduced to control levels on cells that formed myelin. On the other hand, unlike normal Schwann cells, infected Schwann cells associated with nonmyelinated axons or undergoing Wallerian degeneration expressed high levels of MAG. This suggests that a posttranscriptional mechanism modulates MAG expression during myelination. Immunostaining myelinating cultures with an antibody specific to L-MAG showed that L-MAG was normally transiently expressed at the earliest stages of myelination. In short term co-culture with sensory neurons, infected Schwann cells expressing only L-MAG segregated and ensheathed larger axons after 4 d in culture provided that an exogenous basal lamina was supplied. Similar activity was rarely displayed by control Schwann cells correlating with the low level of MAG induction after 4 d. These data strongly suggest that L-MAG promotes the initial investment by Schwann cells of axons destined to be myelinated.


Instrumental considerations for the effective operation of short, highly efficient fused-core columns. Investigation of performance at high flow rates and elevated temperatures.
Fused core or superficially porous columns offer the advantages of higher efficiency compared with totally porous columns of the same particle size, but similar operating pressures. However, their performance may be adversely affected by extra-column effects that become more significant as the column efficiency increases, and as the diameter of the column is reduced. In this study, we show that 10cmx0.46cm fused-core columns can be used on modified conventional instruments ("microbore systems") without serious loss in performance, and this approach is at present likely to yield superior results compared with use of 0.21cm columns (of identical efficiency) on current UHPLC instruments that have minimised extra-column volume. Furthermore, the true efficiency of commercial narrow-bore fused-core columns appears to be reduced compared with those of conventional bore, which may be due to packing difficulties for the former type. The fused-core columns in general gave excellent performance, showing no evidence of an upturn in the Knox plots at high flow velocities and elevated temperatures. Careful control of experimental conditions is necessary to ensure accurate data for these plots.


Open Prebiotic Environments Drive Emergent Phenomena and Complex Behavior.
We have been studying simple prebiotic catalytic replicating networks as prototypes for modeling replication, complexification and Systems Chemistry. While living systems are always open and function far from equilibrium, these prebiotic networks may be open or closed, dynamic or static, divergent or convergent to a steady state. In this paper we review the properties of these simple replicating networks, and show, via four working models, how even though closed systems exhibit a wide range of emergent phenomena, many of the more interesting phenomena leading to complexification and emergence indeed require open systems.


Mitochondrial matrix proteostasis is linked to hereditary paraganglioma: LON-mediated turnover of the human flavinylation factor SDH5 is regulated by its interaction with SDHA.
Mutations in succinate dehydrogenase (SDH) subunits and assembly factors cause a range of clinical conditions. One such condition, hereditary paraganglioma 2 (PGL2), is caused by a G78R mutation in the assembly factor SDH5. Although SDH5(G78R) is deficient in its ability to promote SDHA flavinylation, it has remained unclear whether impairment to its import, structure, or stability contributes to its loss of function. Using import-chase analysis in human mitochondria isolated from HeLa cells, we found that the import and maturation of human SDH5(G78R) was normal, while its stability was reduced significantly, with ~25% of the protein remaining after 180 min compared to ~85% for the wild-type protein. Notably, the metabolic stability of SDH5(G78R) was restored to wild-type levels by depleting mitochondrial LON (LONM). Degradation of SDH5(G78R) by LONM was confirmed in vitro; however, in contrast to the in organello analysis, wild-type SDH5 was also rapidly degraded by LONM. SDH5 instability was confirmed in SDHA-depleted mitochondria. Blue native PAGE showed that imported SDH5(G78R) formed a transient complex with SDHA; however, this complex was stabilized in LONM depleted mitochondria. These data demonstrate that SDH5 is protected from LONM-mediated degradation in mitochondria by its stable interaction with SDHA, a state that is dysregulated in PGL2.


Comparison of Postoperative Outcomes in Elderly Patients With a Do-Not-Resuscitate Order Undergoing Elective and Nonelective Hip Surgery.
Emergency hip surgery generally has worse outcomes than elective hip surgery, even when adjusted for patient and surgical factors. Do-not-resuscitate (DNR) status patients are typically at higher perioperative risk and undergo a narrow range of surgical procedures. We aimed to compare the outcomes after hip surgery of differing degrees of urgency in this cohort. Using National Surgical Quality Improvement Program (NSQIP) data, we conducted univariate and multivariate analyses comparing outcomes of DNR status patients after emergency and nonemergency hip surgery (2007-2013). We conducted a subanalysis of mortality in elective versus nonelective cases (elective variable introduced from 2011). Of 668 hip surgery cases in DNR status patients, 210 (31.4%) were emergency and 458 (68.8%) were nonemergency. There were no significant associations between emergency and nonemergency surgery regarding patient demographics, comorbidities, functional capacity, anesthesia type, or operative duration. There was no significant difference in the 30-day postoperative mortality between emergency (21.4%) and nonemergency (16.4%) or between elective (19.6%) and nonelective (18.3%) hip fracture surgeries performed in patients with preexisting DNR status. Morbidity patterns in emergency vs nonemergency cases demonstrated no significant differences, with the commonest 3 complications being transfusion (21.0% and 21.4%, respectively), urinary tract infection (9.5% and 7.9%, respectively), and pneumonia (both at 5.2%). The 30-day home discharge rates were low at 4.7% and 5.6%, respectively. Multivariate analysis demonstrated no significant associations between emergency and nonemergency surgery for mortality, discharge destination, length of stay or complications, except perioperative myocardial infarction (3.7% vs 1.3%, P < .04). For patients with DNR status, both emergent and non-emergent hip surgery carries high mortality, greatly exceeding rates predicted for that patient by American College of Surgeons NSQIP risk calculators. Morbidity rates and patterns for patients with DNR status are also similar in emergency and nonemergency groups. These data may be useful in discussing risk and obtaining adequately informed consent in DNR patients undergoing hip surgery.


Prevalence and factors associated with the intention to be vaccinated against COVID-19 in Peru.
To estimate the prevalence and factors associated with the intention to be vaccinated (ITV) against COVID-19 in Peru. Analytical cross-sectional study using the survey conducted by the University of Maryland, USA, on Facebook. The dependent variable is the ITV. Crude and adjusted prevalence ratios (PR) were calculated, with their 95% confidence intervals (95% CI) using generalized linear models of the Poisson family, in order to evaluate the association of sociodemographic variables, compliance with community mitigation strategies, symptoms of COVID-19, mental health and acceptance of vaccination before the recommendation (AVR) by various actors and health authorities, with the ITV. Data from 17,162 adults were analyzed. The overall prevalence of the ITV was 74.9%. A lower prevalence of the ITV was associated with the female sex (PR=0.95; 95% CI: 0.94-0.97), living in a town (PR=0.95; 95% CI: 0.91-0.99) or village or other rural area (PR=0.90; 95% CI: 0.86-0.93) and the AVR of politicians (PR=0.89; 95% CI: 0.87-0.92). Conversely, having COVID-19 symptoms (PR=1.06; 95% CI: 1.03-1.09), economic insecurity (PR=1.04; 95% CI: 1.01-1.06), fears of becoming seriously ill or that a family member becomes seriously ill from COVID-19 (PR=1.49; 95% CI: 1.36-1.64) and the AVR of family and friends (PR=1.10; 95% CI: 1.08-1.12), healthcare workers (PR=1.29; 95% CI: 1.26-1.32), World Health Organization (PR=1.34; 95% CI: 1.29-1.40) and government officials (PR=1.18; 95% CI: 1.15-1.22) was associated with a higher prevalence of the ITV. Three-quarters of the respondents had the ITV. There are potentially modifiable factors that could improve vaccine acceptance.


The activity of deoxyribonucleic acid polymerase in some species of algae.
1. The activities of DNA polymerase preparations from the algae Euglena gracilis, Chlamydomonas reinhardtii, Chlorella pyrenoidosa, Anabaena variabilis and Anacystis nidulans were measured. The blue-green algae Anabaena and Anacystis contain a 5-20-fold higher activity of the enzyme than do the green algae. DNA polymerases from the blue-green algae show a pH optimum of 9 and prefer a relatively low Mg(2+) concentration (1-3mm). DNA polymerases from the green algae, however, display a pH optimum between 7.5 and 8.5 and an optimum Mg(2+) concentration of 8mm. With all algae, a higher polymerase activity was obtained with denatured salmon sperm DNA as template than with native DNA. All four deoxyribonucleoside 5'-triphosphates must be present for full activity of the polymerases. 2. With one exception, the deoxyribonuclease activities in the preparations, measured under conditions of the DNA polymerase assay, are low compared with corresponding preparations from Escherichia coli. Chlamydomonas extracts contain a high deoxyribonuclease activity. 3. After purification on columns of DEAE-cellulose, the polymerase activity was linear over a wide range of protein concentrations, except for Chlamydomonas preparations, where the observed deviation from linearity was probably attributable to the high nuclease activity. 4. DNA polymerases from all these algae bind strongly to DNA-cellulose; 6-40-fold purifications of the enzyme were obtained by chromatography on columns of DNA-cellulose. 5. The partially purified polymerases of Euglena and Anacystis are heat-labile but become much more heat-stable when tested in the presence of DNA.


Continuous One-Step Synthesis of Porous M-XF6 -Based Metal-Organic and Hydrogen-Bonded Frameworks.
Metal-organic frameworks (MOFs) built up from connecting M-XF6 pillars through N-donor ligands are among the most attractive adsorbents and separating agents for CO2 and hydrocarbons today. The continuous, one-step spray-drying synthesis of several members of this isoreticular MOF family varying the anionic pillar (XF6 =[SiF6 ]2- and [TiF6 ]2- ), the N-donor organic ligand (pyrazine and 4,4'-bipyridine) and the metal ion (M=Co, Cu and Zn) is demonstrated here. This synthetic method allows them to be obtained in the form of spherical superstructures assembled from nanosized crystals. As confirmed by CO2 and N2 sorption studies, most of the M-XF6 -based MOFs synthesised through spray-drying can be considered "ready-to-use" sorbents as they do not need additional purification and time consuming solvent exchange steps to show comparable porosity and sorption properties with the bulk/single-crystal analogues. Stability tests of nanosized M-SiF6 -based MOFs confirm their low stability in most solvents, including water and DMF, highlighting the importance of protecting them once synthesised. Finally, for the first time it was shown that the spray-drying method can also be used to assemble hydrogen-bonded open networks, as evidenced by the synthesis of MPM-1-TIFSIX.


Spinal nerve root repair and reimplantation of avulsed ventral roots into the spinal cord after brachial plexus injury.
The authors review the first series of 10 cases in which injured intraspinal brachial plexus were surgically repaired. They describe the technique of spinal cord implantation or repair of ruptured nerve roots, as well as patient outcome. Spinal root repair/implantation was performed from 10 days to 9 months postinjury. There were nine male patients and one female patient. Postoperatively in most cases, regeneration of motor neurons from the spinal cord to denervated muscles could be demonstrated. The first signs of regeneration were noted approximately 9 to 12 months postoperatively. Useful function with muscle power of at least Medical Research Council Grade 3 occurred in three of 10 cases. Magnetic brain stimulation studies revealed a normal amplitude and latency from the cortex to reinnervated muscles on surgically treated and control sides. A certain degree of cocontraction between antagonistic muscles (for example, biceps-triceps) compromised function. With time there was a reduction of cocontractions, probably due to spinal cord plasticity. In these cases there was also, surprisingly, a return of sensory function, although the mechanism by which this occurred is uncertain. Sensory stimulation (thermal and mechanical) within the avulsed dermatomes was perceived abnormally and/or experienced at remote sites. There was some return of patients' sense of joint position. A short time lag between the accident and the surgery was recognized as a significant factor for a successful outcome. Reimplantation of avulsed nerve roots may be combined with other procedures such as nerve transfers in severe cases of brachial plexus injury.


Factors Affecting Mental Patients' Behaviors and Attitudes Regarding Smoking
Background: Patients with mental health problems are in high risk to develop addiction, since smoking incidence is three times higher than that of the general population. The aim of the study was to investigate the factors affecting mental health patients' smoking habits. Methods: The sample of study were 356 patients out of 403 initially approached, with 142 hospitalized in hospital facilities and 214 in community settings. The «Smoking in psychiatric hospitals" and General Health Questionnaire (GHQ-28) questionnaires were used. A principal component analysis was performed using the correlation coefficients of the various variables and an orthogonal varimax rotation, in order to interpret the seven factors emerging. Among the variables the most important factors appeared to be the type of healthcare facility, legal status, depression and age. Results: The type of healthcare facility was correlated to demographic characteristics, clinical features, psychopathology and functionality, but also to the attitudes and behaviors related to smoking. More specifically, the in-hospital patients were heavier smokers, about 90% of the patients said they would consider quitting smoking. The various variables had only a small effect on the intention to quit smoking. The comparison of the coefficients of determination of each variable, showed that age had the strongest effect (R2=0.152), while the GHQ D subscale (severe depression) had the least significant effect (R2=0.023). From all (7) factors, it appears that hospitalization was positively correlated with factor 5 and negatively with the factors 2, 3 and 6, legal status (commitment order) negatively with factors 1 and 4, while depression (or consuming antidepressants) positively factor 4 and negatively to factors 1 and 3. Finally, age was the only variable that is associated with the agent 7. Conclusions: Patients are permissive to staff's smoking in the healthcare facility and may resist attempts to restrict it. It is important that these conclusions are taken into account in any systematic attempt to limit smoking within mental health settings.


The surprising economics of a "people business".
When people are your most important asset, some standard performance measures and management practices become misleading or irrelevant. This is a danger for any business whose people costs are greater than its capital costs-that is, businesses in most industries. But it is particularly true for what the authors call "people businesses": operations with high employee costs, low capital investment, and limited spending on activities, such as R&D, that are aimed at generating future revenue. If you run a people business-or a company that includes one or more of them how do you measure its true performance? Avoid the trap of relying on capital-oriented metrics, such as return on assets and return on equity. They won't help much, as they'll tend to mask weak performance or indicate volatility where it doesn't exist. Replace them with financially rigorous people-oriented metrics-for example, a reformulation of a conventional calculation of economic profit, such as EVA, so that you gauge people, rather than capital, productivity. Once you have assessed the business's true performance, you need to enhance it operationally (be aware that relatively small changes in productivity can have a major impact on shareholder returns); reward it appropriately (push performance-related variable compensation schemes down into the organization); and price it advantageously (because economies of scale and experience tend to be less significant in people businesses, price products or services in ways that capture a share of the additional value created for customers).


Recent trend in the treatment of dysfunctional uterine bleeding.
Dysfunctional uterine bleeding (DUB) is defined as excessive uterine bleeding with no demonstrable organic cause either genital or extra-genital. Management of DUB should be individualised. The general measures, conservative approach, radical therapy and surgery as treatment modalities, as practised have been detailed here.


Elastic microphase separation produces robust bicontinuous materials.
Bicontinuous microstructures are essential to the function of diverse natural and synthetic systems. Their synthesis has been based on two approaches: arrested phase separation or self-assembly of block copolymers. The former is attractive for its chemical simplicity and the latter, for its thermodynamic robustness. Here we introduce elastic microphase separation (EMPS) as an alternative approach to make bicontinuous microstructures. Conceptually, EMPS balances the molecular-scale forces that drive demixing with large-scale elasticity to encode a thermodynamic length scale. This process features a continuous phase transition, reversible without hysteresis. Practically, EMPS is triggered by simply supersaturating an elastomeric matrix with a liquid, resulting in uniform bicontinuous materials with a well-defined microscopic length scale tuned by the matrix stiffness. The versatility of EMPS is further demonstrated by fabricating bicontinuous materials with superior mechanical properties and controlled anisotropy and microstructural gradients. Overall, EMPS presents a robust alternative for the bulk fabrication of homogeneous bicontinuous materials.


Toxicity evaluation of chromium picolinate nanoparticles in vivo and in vitro in rat.
The toxicity of nanoCrpic is still not understood and needs further investigation. Thus, this study investigated the effect of chromium picolinate nanoparticles (nanoCrpic) on the toxicity in vivo and in vitro in rat. In the in vivo study, 36 rats (Wistar, 8-week-old) were randomly divided into the control group (fed basal diet), the low-dose (300 ppb, μg/kg), and high-dose (1,000 ppb) nanoCrpic groups. The trial was conducted for 2 months; at the final stage of the trial, the rats were sacrificed, liver and kidney were examined, and samples of tissues were taken for histological examination. Hepatocytes isolated from 10-week-old Wistar male rats were used for in vitro study to examine the degree of DNA damage following exposure to 0 and 0.294 mM of H(2)O(2) for 30 min. Incubation medium was supplemented with 0 (control), 100, and 300 ppb nanoCrpic. In vivo study indicated that no lesions of liver or kidney were detected in 300 and 1,000 ppb nanoCrpic fed rats. The in vitro study evaluated DNA damage according to the percentage and distance of the fragments migration and revealed that there was insignificant difference between the nanoCrpic and control groups (p > 0.05). This study indicated that nanoCrpic at 300-1,000 ppb in vivo and at 100-300 ppb in vitro showed no signs of toxicity to rats.


The Changing Landscape of Genetic Testing for Inherited Breast Cancer Predisposition.
The advent of multiple-gene germline panel testing has led to significant advances in hereditary breast and ovarian cancer risk assessment. These include guideline-specific cancer risk management recommendations for patients and their families, such as screening with breast magnetic resonance imaging and risk-reducing surgeries, which have the potential to reduce substantially the morbidity and mortality associated with a hereditary cancer predisposition. However, controversy remains about the clinical validity and actionability of genetic testing in a broader patient population. We discuss events leading to the wider availability of commercialized multiple-gene germline panel testing, the recent data that support using this powerful tool to improve cancer risk assessment and reduction strategies, and remaining challenges to clinical optimization of this new genetic technology.


Monoclonal opsonic mouse antibodies specific for streptococcal IgG Fc-receptor.
Spleen cells from mice immunised with group-A type-M15 streptococci and boosted with purified IgG Fc-receptor (FcR) from this type were fused with Sp 2/0 mouse myeloma cells. The resulting hybridomas were screened by ELISA for antibody production. Two IgM-secreting cell lines were selected. The monoclonal antibodies and ascites fluids inhibited the binding of 125I-labelled human IgG and IgG Fc-fragments to group-A type-M15 streptococci. The monoclonal antibodies also displaced purified FcR towards the anode in electrophoresis. They opsonised group-A type M-15 streptococci for phagocytosis by human granulocytes in the presence of fresh human serum. It was concluded that FcR is important for group-A streptococcal virulence.


The US Public's Perception of the Threat of COVID-19 During the Rapid Spread of the COVID-19 Outbreak: Cross-Sectional Survey Study.
The rapid spread of the COVID-19 pandemic in the United States has made people uncertain about their perceptions of the threat of COVID-19 and COVID-19 response measures. To mount an effective response to this epidemic, it is necessary to understand the public's perceptions, behaviors, and attitudes. We aimed to test the hypothesis that people's perceptions of the threat of COVID-19 influence their attitudes and behaviors. This study used an open dataset of web-based questionnaires about COVID-19. The questionnaires were provided by Nexoid United Kingdom. We selected the results of a questionnaire on COVID-19-related behaviors, attitudes, and perceptions among the US public. The questionnaire was conducted from March 29 to April 20, 2020. A total of 24,547 people who lived in the United States took part in the survey. In this study, the average self-assessed probability of contracting COVID-19 was 33.2%, and 49.9% (12,244/24,547) of the respondents thought that their chances of contracting COVID-19 were less than 30%. The self-assessed probability of contracting COVID-19 among women was 1.35 times that of males. A 5% increase in perceived infection risk was significantly associated with being 1.02 times (OR 1.02, 95% CI 1.02-1.02; P<.001) more likely to report having close contact with >10 people, and being 1.01 times (OR 1.01, 95% CI 1.01-1.01; P<.001) more likely to report that cohabitants disagreed with taking steps to reduce the risk of contracting COVID-19. However, there was no significant association between participants who lived with more than 5 cohabitants or less than 5 cohabitants (P=.85). Generally, participants who lived in states with 1001-10,000 COVID-19 cases, were aged 20-40 years, were obese, smoked, drank alcohol, never used drugs, and had no underlying medical conditions were more likely to be in close contact with >10 people. Most participants (21,017/24,547, 85.6%) agreed with washing their hands and maintaining social distancing, but only 20.2% (4958/24,547) of participants often wore masks. Additionally, male participants and participants aged <20 years typically disagreed with washing their hands, maintaining social distancing, and wearing masks. This survey is the first attempt to describe the determinants of the US public's perception of the threat of COVID-19 on a large scale. The self-assessed probability of contracting COVID-19 differed significantly based on the respondents' genders, states of residence, ages, body mass indices, smoking habits, alcohol consumption habits, drug use habits, underlying medical conditions, environments, and behaviors. These findings can be used as references by public health policy makers and health care workers who want to identify populations that need to be educated on COVID-19 prevention and health.


Evidence for an immunological and functional relationship between superoxide dismutase and a high molecular weight osteoclast plasma membrane glycoprotein.
Large multinucleated osteoclasts are the major cells responsible for bone breakdown and have been reported to produce high levels of superoxides which may contribute to the process of bone resorption (Key et al.: J Bone and Mineral Res 4 [suppl. 1]:S206, 1989). Osteoclasts also possess high levels of superoxide dismutase, a protective enzyme capable of converting toxic superoxides to less dtoxic H2O2 (Fridovich: J Biol Chem 264:7761-7764, 1989). The amino acid sequence of manganese and/or iron superoxide dismutase has a conserved region which exhibits substantial homology with a fragment obtained from a high molecular weight osteoclast surface marker glycoprotein which is reactive with monoclonal antibody 121F. In this report, evidence is presented substantiating immunological, biochemical, and functional similarities between the osteoclast membrane antigen recognized by the 121F monoclonal antibody and superoxide dismutase. Western blot and immunoprecipitation studies show that a monospecific polyclonal antibody generated against immunoaffinity purified antigen is cross-reactive with superoxide dismutase. Both the antigen and a high molecular weight superoxide dismutase activity have been detected in osteoclast plasma membrane preparations. The levels of superoxide dismutase activity and the membrane antigen have been found to correlate in antigen depletion studies and in western blots probing osteoclasts and closely related marrow-derived giant cells. Moreover, regions of osteoclast superoxide dismutase activity identified by electrophoretic zymogram analysis have been shown by gel electrophoresis and western blots to contain the high molecular weight antigen, or complexes of the antigen with the 121F monoclonal antibody when these were premixed prior to nondenaturing electrophoresis. It is proposed that the osteoclast plasma membrane possesses a high molecular weight superoxide dismutase activity. Furthermore, it appears that this activity is associated with the osteoclast antigen recognized by the 121F monoclonal antibody.


Rapamycin and mTOR: a serendipitous discovery and implications for breast cancer.
Rapamycin was discovered more than thirty years ago from a soil sample from the island of Rapa Nui. It was isolated from Streptomyces hygroscopicus and initial characterization focused on its antifungal activities. Subsequent characterization showed that it has immunosuppressive properties and has been used successfully to reduce organ rejection with kidney transplantation. Rapamycin has proven to be a versatile compound with several seemingly unrelated properties, including antifungal, immunosuppressive, and anticancer. The National Cancer Institute (NCI) Developmental Therapeutics Program demonstrated that rapamycin inhibited cell growth in tumor cell lines. These observations stimulated research to explore the underlying mechanism of anti-tumor activities. Cell growth inhibition involves binding to the mammalian Target of Rapamycin (mTOR). The mTOR signaling pathway is critical to cell growth, proliferation, and survival and rapamycin inhibits these hallmark processes of cancer. Binding of growth factors activates mTOR signaling, which in turn leads to downstream phosphorylation of protein kinases, e.g., p70S6 kinase and lipid kinases in the phosphorylation of phosphoinositides. Understanding of mTOR signaling provided the biological basis for targeted chemotherapeutics development, including several rapamycin analogues for treating breast and other cancers.


Regional Anesthesia for Dentistry and Orofacial Surgery in Rhesus Macaques (Macaca mulatta).
Regional anesthesia is a commonly used adjunct to orofacial dental and surgical procedures in companion animals and humans. However, appropriate techniques for anesthetizing branches of the mandibular and maxillary nerves have not been described for rhesus monkeys. Skulls of 3 adult rhesus monkeys were examined to identify relevant foramina, establish appropriate landmarks for injection, and estimate injection angles and depth. Cadaver heads of 7 adult rhesus monkeys (4 male, 3 female) were then injected with thiazine dye to demonstrate correct placement of solution to immerse specific branches of the mandibular and maxillary nerves. Different volumes of dye were injected on each side of each head to visualize area of diffusion, and to estimate the minimum volume needed to saturate the area of interest. After injection, the heads were dissected to expose the relevant nerves and skull foramina. We describe techniques for blocking the maxillary nerve as well as its branches: the greater palatine nerve, nasopalatine nerve, and infraorbital nerve. We also describe techniques for blocking branches of the mandibular nerve: inferior alveolar nerve, mental (or incisive) nerve, lingual nerve, and long buccal nerve. Local anesthesia for the mandibular and maxillary nerves can be accomplished in rhesus macaques and is a practical and efficient way to maximize animal welfare during potentially painful orofacial procedures.


Acute hibernation and reperfusion of the ischemic heart.
Recovery from prolonged low-flow ischemia was studied in isolated, isovolumically beating neonatal piglet hearts (n = 11) and compared with controls (n = 5). Hearts were perfused with red blood cell-enhanced Krebs-Henseleit buffer with physiological oxygen-carrying capacity. Left ventricular mechanical function was assessed with a fluid-filled balloon. Measurements of peak systolic pressure, pressure-rate product (PRP), and +dP/dtmax were obtained at various filling pressures. Myocardial oxygen delivery and metabolism (MVO2) and lactate uptake were measured at 30-minute intervals. Control data were obtained with coronary flow (CF) set at 2 ml.min-1.g-1. CF was then reduced to 0.2 ml.min-1.g-1 for 2 hours. Thereafter, reperfusion was instituted at control levels. Hearts not subjected to ischemia were studied at identical time intervals. In these, function remained at greater than 80% after more than 3.5 hours of study. Reduction of CF to 10% was accompanied by an abrupt diminution in function (pressure-rate product) and MVO2 to 20% of control and by lactate release. These measures remained constant for the full 2 hours of ischemia. Incremental return of CF caused a lockstep increase in mechanical function and metabolism. At 30 minutes of reperfusion, PRP was 78% of time-matched controls (p = 0.05), and dP/dtmax did not differ. Increasing calcium to 5 mmol/l returned PRP (and dP/dtmax) to preischemia levels. Myocardial ATP and creatine phosphate concentrations were identical in both groups, although glycogen was lower in the ischemic hearts. Acute hibernation is associated with protection of the in vitro heart from prolonged normothermic ischemia. Systolic function was only modestly lower, and velocity (dP/dtmax) did not differ from control hearts. The minimal "stunning" was fully reversible with calcium.


Long-term outcomes of foreskin reconstruction in distal hypospadias; a cohort study spanning twenty years.
Surgical correction of hypospadias aims to achieve normal functionality and appearance. This entails foreskin reconstruction (FR) in countries where the uncircumcised penis constitutes the norm. Long-term data are however scarce. To investigate the long-term outcome of FR in cohort of patients operated for distal hypospadias combined with approximately 20 years after surgery. The hospital management system was searched for patients operated for distal hypospadias in conjunction with FR between 1997 and 2004. Prospective participants were invited to participate in an online questionnaire. Signed consent allowed for extended medical chart review, with regards to hypospadias grade, surgical procedure and complications. Response rate of 44.6 %. For 113 participants, median age at primary surgery was 5.2 (1.0-15.5) years. Two-thirds had a distal meatus while the remaining, meatus was mid to distal shaft. Urethroplasties performed were mainly glanular approximation procedures and meatal based flap procedures in 85 %. Foreskin fistula developed in 15 % of cases. There was no significant relationship between urethroplasty procedure or meatal position and risk of foreskin complications. Three layer closure of foreskin resulted in significantly less complications than two layer closure. Twenty years on 95 % of the men still had an intact foreskin, of whom 16.8 % had received treatment for phimosis. Foreskin was retractable in 92.5 % and 74.7 % in the flaccid and erect states respectively. Ninety intact men had had their sexual debut and in those 23.3 % reported foreskin related issues with intercourse. Evolution of foreskin retractability can be seen in the figure. Current results show that three layer FR in conjunction with hypospadias surgery is feasible and that short-term complication rates were comparable with what has previously been published in the literature. Long-term results indicate that FR is durable with regards to anatomical reconstruction however foreskin function especially in relation to sexual function was compromised in about 25 %. Foreskin retractability after surgery predicted retractability in adulthood for the flaccid but not erect penis. Limitations of this study include the retrospective nature of data collection, and that the questionnaire used was not validated. We however achieved a decent response rate and were able to capture important long-term data. FR has an acceptable complication rate. Long-term results two decades on are remarkably durable with regards to the anatomical preservation of the prepuce, however functionality was compromised with regards to retractability and sexual function in approximately 25 %.


The spindle assembly checkpoint is satisfied in the absence of interkinetochore tension during mitosis with unreplicated genomes.
The accuracy of chromosome segregation is enhanced by the spindle assembly checkpoint (SAC). The SAC is thought to monitor two distinct events: attachment of kinetochores to microtubules and the stretch of the centromere between the sister kinetochores that arises only when the chromosome becomes properly bioriented. We examined human cells undergoing mitosis with unreplicated genomes (MUG). Kinetochores in these cells are not paired, which implies that the centromere cannot be stretched; however, cells progress through mitosis. A SAC is present during MUG as cells arrest in response to nocodazole, taxol, or monastrol treatments. Mad2 is recruited to unattached MUG kinetochores and released upon their attachment. In contrast, BubR1 remains on attached kinetochores and exhibits a level of phosphorylation consistent with the inability of MUG spindles to establish normal levels of centromere tension. Thus, kinetochore attachment to microtubules is sufficient to satisfy the SAC even in the absence of interkinetochore tension.


Active and specific recruitment of a soluble cargo protein for endoplasmic reticulum exit in the absence of functional COPII component Sec24p.
Exit of proteins from the yeast endoplasmic reticulum (ER) is thought to occur in vesicles coated by four proteins, Sec13p, Sec31p, Sec23p and Sec24p, which assemble at ER exit sites to form the COPII coat. Sec13p may serve a structural function, whereas Sec24p has been suggested to operate in selection of cargo proteins into COPII vesicles. We showed recently that the soluble glycoprotein Hsp150 exited the ER in the absence of Sec13p function. Here we show that its ER exit did not require functional Sec24p. Hsp150 was secreted to the medium in a sec24-1 mutant at restrictive temperature 37 degrees C, while cell wall invertase and vacuolar carboxypeptidase Y remained in the ER. The determinant guiding Hsp150 to this transport route was mapped to the C-terminal domain of 114 amino acids by deletion analysis, and by an HRP fusion protein-based EM technology adapted here for yeast. This domain actively mediated ER exit of Sec24p-dependent invertase in the absence of Sec24p function. However, the domain was entirely dispensable for ER exit when Sec24p was functional. The Sec24p homolog Sfb2p was shown not to compensate for nonfunctional Sec24p in ER exit of Hsp150. Our data show that a soluble cargo protein, Hsp150, is selected actively and specifically to budding sites lacking normal Sec24p by a signature residing in its C-terminal domain.


Biochemical and immunological responses of hairy cell leukemia patients to interferon beta.
Ten hairy-cell leukemia patients were treated with interferon beta (IFN-beta) at a dose rate of 2 x 10(6) IU/m2 x 5 days for 4 weeks (induction therapy) and, thereafter, at the same dose three times a week for 11 months (maintenance therapy). The effect of this treatment on serum neopterin, beta 2-microglobulin, (2'-5')oligoadenylate [(2'-5')An] levels, intracellular (2'-5')An values and human Mx protein synthesis was analysed. There were significant rises in serum neopterin and (2'-5')An levels during both induction and maintenance, whereas beta 2-microglobulin levels rose only during induction. Rises in intracellular (2'-5')An were documented mainly during induction, but they were not significantly higher than pretherapy values. IFN beta provoked an increase in human Mx protein synthesis over the entire induction-maintenance period, but was only significantly higher than baseline during induction. All markers proved useful for monitoring the effects of IFN beta dose schedules, but were not predictive of clinical outcome. Natural killer activity and IFN gamma production, which were initially defective, followed a different trend from that of the other factors studied, in that increases were documented only late in the course of therapy when the disease was already in remission.


Effect of cannabinoid receptor activation on spreading depression.
The objective of this study was to evaluate the effect of cannabinoid on cortical spreading depression (CSD) in rat brain. Cannabis has been used for centuries for both symptomatic and prophylactic treatment of different types of headaches including migraine. CSD is believed to be a putative neuronal mechanism underlying migraine aura and subsequent pain. The effects of Delta9-tetrahydrocannabinol (THC), as well as, cannabinoid CB1 and CB2 receptor agonists on CSD in rat neocortical slices were investigated. Furthermore, the effect of cannabinoid CB1 agonist was tested on field excitatory postsynaptic potentials (fEPSP) and long-term potentiation (LTP). HC (1-20 microM) dose dependently suppressed CSD amplitude, duration, and propagation velocity. Cannabinoid CB1 agonist, WIN 55,212-2 mesylate (1-10 microM), also significantly suppressed all characteristic features of CSD. However, cannabinoid CB2 agonist, JWH-133 (1-20 microM), did not affect CSD. FEPSP and induction of LTP were suppressed by application of WIN55212-2. Suppression of CSD by activation of CB1 receptors points to the potential therapeutic effects of cannabinoids in migraine with aura. More research is needed before we know whether cannabinoids may be helpful in treating migraine pain.


Hepatitis B virus infection is not associated with fatty liver disease: Evidence from a cohort study and functional analysis.
Chronic hepatitis B virus (HBV) infection has been reported to be associated with the prevalence of non‑alcoholic fatty liver disease (NAFLD). However, the present study demonstrated that the incidence of fatty liver disease in HBV‑infected subjects (16/152, 10.5%) was not significantly different from in non‑HBV‑infected subjects (292/1,714, 17%), following adjustment for age (odds ratio=0.656; 95% confidence interval=0.379‑1.134; P=0.131). Hepatitis B protein X (HBx) is considered a key regulator in HBV infection and several studies have confirmed that HBx serves a pivotal role in the process of fatty liver disease. In the present study, it was demonstrated that HBx‑expressing cells exhibited increased mitochondrial membrane potential, ATP generation, and endogenous mitochondrial respiration. In addition, higher levels of mitochondrial reactive oxygen species (ROS) were detected in HBx‑expressing cells compared with in control cells. Increased ROS production may contribute to increased lipid droplet formation in HBx‑expressing cells, whereas the removal of ROS with N‑acetylcysteine may decrease the accumulation of lipid droplets in a time‑dependent manner. In conclusion, the present findings indicated that HBV, and perhaps more specifically HBx, was not a protective factor against NAFLD. HBx may function as a risk factor for fatty liver disease, based on the findings of the present functional study; however, further studies are required to clarify the effects of HBx on hepatic steatosis.


[The results of a controlled field trial of a dried erythrocytic immunoglobulin diagnostic agent for detecting the hepatitis A virus antigen].
The results of the controlled field trial of lyophilized erythrocytic immunoglobulin diagnosticum for the detection of hepatitis A virus antigen in the urine and feces of patients are presented. This diagnosticum was used for the study of urine and fecal samples from 225 patients (of these, 176 had hepatitis A) and 54 healthy persons in the passive hemagglutination (PHA) test. Their blood sera were studied in the PHA test (to detect HBsAg) and the radioimmunoassay (to detect anti-HAV IgM). The immunoglobulin diagnosticum under study was found to be nonspecific and faintly sensitive and, therefore, unsuitable for use in medical practice.


Cerebrospinal fluid concentration of gefitinib and erlotinib in patients with non-small cell lung cancer.
Several cases have been reported in which central nervous system (CNS) metastases of non-small cell lung cancer (NSCLC) resistant to gefitinib were improved by erlotinib. However, there has been no study in which cerebrospinal fluid (CSF) concentrations of gefitinib and erlotinib are directly compared. Thus, we aimed to compare them. We examined 15 Japanese patients with NSCLC and CNS metastases with epidermal growth factor receptor gene mutations who received CSF examinations during epidermal growth factor receptor-tyrosine kinase inhibitors treatment (250 mg daily gefitinib or 150 mg daily erlotinib). Plasma and CSF concentrations were determined using high-performance liquid chromatography with tandem mass spectrometry. The concentration and penetration rate of gefitinib (mean ± standard deviation) in the CSF were 3.7 ± 1.9 ng/mL (8.2 ± 4.3 nM) and 1.13 ± 0.36 %, respectively. The concentration and penetration rate of erlotinib in the CSF were 28.7 ± 16.8 ng/mL (66.9 ± 39.0 nM) and 2.77 ± 0.45 %, respectively. The CSF concentration and penetration rate of erlotinib were significantly higher than those of gefitinib (P = 0.0008 and <0.0001, respectively). The CNS response rates of patients with erlotinib treatment were preferentially (but not significantly) higher than those with gefitinib treatment. (1/3 vs. 4/7, respectively). Leptomeningeal metastases in one patient, which were refractory to gefitinib, dramatically responded to erlotinib. This study suggested that higher CSF concentration could be achieved with erlotinib and that erlotinib could be more effective for the treatment for CNS metastases, especially leptomeningeal metastases, than gefitinib.


Intergenerational care: an exploration of consumer preferences and willingness to pay for care.
To identify feasible models of intergenerational care programmes, that is, care of children and older people in a shared setting, to determine consumer preferences and willingness to pay. Feasible models were constructed in extensive consultations with a panel of experts using a Delphi technique (n = 23) and were considered based on their practical implementation within an Australian setting. This informed a survey tool that captured the preferences and willingness to pay for these models by potential consumers, when compared to the status quo. Information collected from the surveys (n = 816) was analysed using regression analysis to identify fundamental drivers of preferences and the prices consumers were willing to pay for intergenerational care programmes. The shared campus and visiting models were identified as feasible intergenerational care models. Key attributes of these models included respite day care; a common educational pedagogy across generations; screening; monitoring; and evaluation of participant outcomes. Although parents were more likely to take up intergenerational care compared to the status quo, adult carers reported a higher willingness to pay for these services. Educational attainment also influenced the likely uptake of intergenerational care. The results of this study show that there is demand for the shared campus and the visiting campus models among the Australian community. The findings support moves towards consumer-centric models of care, in line with national and international best practice. This consumer-centric approach is encapsulated in the intergenerational care model and enables greater choice of care to match different consumer demands.


The psychometric properties of a tinnitus handicap questionnaire.
The psychometric properties of a tinnitus handicap questionnaire are reported. There were two phases in this study. In Phase I, 87 questions were administered to 100 tinnitus patients. From their responses, 59 items that were either redundant, insensitive, or had low item-total correlations were eliminated. In Phase II, the resulting 27-item questionnaire was administered to 319 patients. Fifty-three of these patients also completed psychological and psychophysical measures that were used to validate the questionnaire. A factor analysis of patients' responses revealed a three-factor structure. These three factors appeared to reflect the physical, emotional, and social consequences of tinnitus (Factor 1), hearing ability of the patient (Factor 2), and the patients' view of tinnitus (Factor 3). Although the 27-item questionnaire had high internal consistency reliability and validity as reflected by correlations with life satisfaction and depression scales, it is recommended that only the items on the Factor 1 and the Factor 2 subscales be scored because of the low internal consistency reliability of the Factor 3 subscale. This questionnaire can be used to compare a patient's tinnitus handicap with the norm, identify specific areas of handicaps, and to monitor a patient's progress with particular treatment programs.


The accuracy of urine dipsticks as a screening test for proteinuria in hypertensive disorders of pregnancy.
Proteinuria is used as a criterion in the classification system for hypertensive disorders of pregnancy including preeclampsia. The aim of the study was to evaluate the accuracy of dipstick urinalysis in a single voided urine sample and in an aliquot of a 24-hour urine collection in the assessment of proteinuria in hypertensive pregnant women, using the 24-hour urine protein excretion as the gold standard. One hundred ninety-eight women who presented with hypertension in pregnancy were recruited at the antenatal clinic at King Edward VIII Hospital in Durban, South Africa, a tertiary referral center. Exclusion criteria included women with eclampsia, urinary tract infection, and chronic renal disease. Routine dipstick urinalysis (Bayer) was performed by midwives for proteinuria, and a 24-hour urine specimen was collected for quantitative protein assessment. A laboratory technician performed urine dipstick test for protein on a mixed aliquot of the 24-hour urine specimen. This result, together with that of the screening dipstick urinalysis, was compared to the 24-hour urine protein excretion. The results of the 198 patients were analyzed, of the total, 72 had preeclampsia. Using a value of = 0.3 g protein excretion per 24 hours (1 + to 4 + on urine dipsticks) as positive, sensitivity, specificity, and predictive values for dipstick urinalysis were calculated. The positive predictive value for dipstick urinalysis ranged from 64.9% (single voided urine sample) to 94.2% (24-hour urine aliquot). The negative predictive value ranged from 75.2% (single voided urine sample) to 84.2% (24-hour urine aliquot). Dipstick urinalysis is not very accurate: therefore, all women presenting with hypertension during pregnancy should have a 24-hour urine protein measurement.


Recent developments of direct rhenium-catalyzed [1,3]-transpositions of allylic alcohols and their silyl ethers.
The direct metal-catalyzed [1,3]-transposition of allylic alcohols and allylic silyl ethers is a synthetically useful isomerization process that occurs via [3,3]-sigmatropic rearrangement induced by high oxidation state oxometal complexes. The isomerization requires only a catalytic amount of promoter, and high chirality transfer can be achieved. Thus, it bears a significant potential to become a powerful tool in multistep synthesis. Although [1,3]-transposition of allylic alcohols has been known since the late 1960s, the development of synthetically useful protocols that allow for a high level of regio- and stereoselectivity control and their synthetic applications have emerged only recently. This tutorial review summarizes recently developed regioselective [1,3]-transpositions of allylic alcohols and silyl ethers and their applications to natural product synthesis.


Locomotor Behaviour and Clock Neurons Organisation in the Agricultural Pest Drosophila suzukii.
Drosophila suzukii (Matsumara) also called Spotted Wing Drosophila (SWD), is an invasive pest species originally from Asia that has now spread widely across Europe and North America. The majority of drosophilids including the best known Drosophila melanogaster only breed on decaying fruits. On the contrary, the presence of a strong serrated ovipositor and behavioural and metabolic adaptations allow D. suzukii to lay eggs inside healthy, ripening fruits that are still on the plant. Here we present an analysis of the rhythmic locomotor activity behaviour of D. suzukii under several laboratory settings. Moreover, we identify the canonical clock neurons in this species by reporting the expression pattern of the major clock proteins in the brain. Interestingly, a fundamentally similar organisation of the clock neurons network between D. melanogaster and D. suzukii does not correspond to similar characteristics in rhythmic locomotor activity behaviour.


Hypohydration and heat acclimation: plasma renin and aldosterone during exercise.
This study was designed to assess the effects of hydration, acclimation, environment, and exercise on plasma levels of renin and aldosterone. Sixteen subjects exercised (1.34 m X s-1), both pre- and postacclimation, when euhydrated or hypohydrated (-5% of body wt) in a comfortable (20 degrees C, rh = 40%), hot-wet (35 degrees C, rh = 79%), or hot-dry (49 degrees C, rh = 20%) environment. Although light exercise in a thermoneutral environment had no effects on plasma levels of renin activity (PRA) or aldosterone (ALD), exercise in both hot environments resulted in significantly increased levels of both. Increments in both PRA and ALD were greater when hypohydrated, and PRA effects were significantly moderated by heat acclimation in both the euhydration and hypohydration experiments. Although PRA and ALD responses were generally correlated, acclimation did not consistently attenuate ALD increments. We concluded that hydration state, acclimation level, and environmental conditions all affected the responses of PRA and ALD to light exercise.


Immunization with a Plasmid DNA Vaccine Encoding the N-Terminus of Insulin-like Growth Factor Binding Protein-2 in Advanced Ovarian Cancer Leads to High-level Type I Immune Responses.
Cancer vaccines targeting nonmutated proteins elicit limited type I T-cell responses and can generate regulatory and type II T cells. Class II epitopes that selectively elicit type I or type II cytokines can be identified in nonmutated cancer-associated proteins. In mice, a T-helper I (Th1) selective insulin-like growth factor binding protein-2 (IGFBP-2) N-terminus vaccine generated high levels of IFNγ secreting T cells, no regulatory T cells, and significant antitumor activity. We conducted a phase I trial of T-helper 1 selective IGFBP-2 vaccination in patients with advanced ovarian cancer. Twenty-five patients were enrolled. The IGFBP-2 N-terminus plasmid-based vaccine was administered monthly for 3 months. Toxicity was graded by NCI criteria and antigen-specific T cells measured by IFNγ/IL10 ELISPOT. T-cell diversity and phenotype were assessed. The vaccine was well tolerated, with 99% of adverse events graded 1 or 2, and generated high levels of IGFBP-2 IFNγ secreting T cells in 50% of patients. Both Tbet+ CD4 (P = 0.04) and CD8 (P = 0.007) T cells were significantly increased in immunized patients. There was no increase in GATA3+ CD4 or CD8, IGFBP-2 IL10 secreting T cells, or regulatory T cells. A significant increase in T-cell clonality occurred in immunized patients (P = 0.03, pre- vs. post-vaccine) and studies showed the majority of patients developed epitope spreading within IGFBP-2 and/or to other antigens. Vaccine nonresponders were more likely to have preexistent IGFBP-2 specific immunity and demonstrated defects in CD4 T cells, upregulation of PD-1, and downregulation of genes associated with T-cell activation, after immunization. IGFBP-2 N-terminus Th1 selective vaccination safely induces type I T cells without evidence of regulatory responses.


Effectiveness of formal physical therapy following total shoulder arthroplasty: A systematic review.
Physical therapy is considered routine practice following total shoulder arthroplasty. To date, current regimens are based on clinical opinion, with evidence-based recommendations. The aim of this systematic review was to evaluate the effectiveness of total shoulder arthroplasty physical therapy programmes with a view to inform current clinical practice, as well as to develop a platform upon which future research might be conducted. An electronic search of MEDLINE, EMBASE, CINAHL and Cochrane Library to March 2018 was complemented by hand and citation-searching. Studies were selected in relation to pre-defined criteria. A narrative synthesis was undertaken. A total of 506 papers were identified in the electronic database search, with only one study showing moderate evidence of early physical therapy promoting a more rapid return of short-term improvement in function and pain. No studies evaluated the effectiveness of physical therapy programmes in reverse total shoulder arthroplasty procedures. Restoring range of motion and strength following total shoulder arthroplasty is considered important for patients to obtain a good outcome post-surgery and, when applied early, may offer more rapid recovery. Given the rising incidence of total shoulder arthroplasties, especially reverse total shoulder arthroplasty, there is an urgent need for high-quality, adequately powered randomised controlled trials to determine the effectiveness of rehabilitation programmes following these surgeries.


Functional aspects of the vestibular dark cells in the guinea pig: morphological investigation using ruthenium red staining technique.
The functional significance of the vestibular dark cells in the guinea pig was investigated using ruthenium red staining technique. The apical cell surface of the dark cell was covered by the fuzzy layer of the glycocalyx, which could be responsible for water and ion transport across the apical plasma membrane. It has been suggested that the otoconia have been at first demineralized by an unknown mechanism when they are attached to the dark cell surface, and the mucopolysaccharide and mucoproteins in the otoconial matrix are then absorbed by active pinocytosis in the dark cells. These functions may be closely related to the possible regulation of the calcium ion in the vestibular endolymph.


A comparison of analytic hierarchy process and conjoint analysis methods in assessing treatment alternatives for stroke rehabilitation.
With growing emphasis on patient involvement in health technology assessment, there is a need for scientific methods that formally elicit patient preferences. Analytic hierarchy process (AHP) and conjoint analysis (CA) are two established scientific methods - albeit with very different objectives. The objective of this study was to compare the performance of AHP and CA in eliciting patient preferences for treatment alternatives for stroke rehabilitation. Five competing treatments for drop-foot impairment in stroke were identified. One survey, including the AHP and CA questions, was sent to 142 patients, resulting in 89 patients for final analysis (response rate 63%). Standard software was used to calculate attribute weights from both AHP and CA. Performance weights for the treatments were obtained from an expert panel using AHP. Subsequently, the mean predicted preference for each of the five treatments was calculated using the AHP and CA weights. Differences were tested using non-parametric tests. Furthermore, all treatments were rank ordered for each individual patient, using the AHP and CA weights. Important attributes in both AHP and CA were the clinical outcome (0.3 in AHP and 0.33 in CA) and risk of complications (about 0.2 in both AHP and CA). Main differences between the methods were found for the attributes 'impact of treatment' (0.06 for AHP and 0.28 for two combined attributes in CA) and 'cosmetics and comfort' (0.28 for two combined attributes in AHP and 0.05 for CA). On a group level, the most preferred treatments were soft tissue surgery (STS) and orthopedic shoes (OS). However, STS was most preferred using AHP weights versus OS using CA weights (p < 0.001). This difference was even more obvious when interpreting the individual treatment ranks. Nearly all patients preferred STS according to the AHP predictions, while >50% of the patients chose OS instead of STS, as most preferred treatment using CA weights. While we found differences between AHP and CA, these differences were most likely caused by the labeling of the attributes and the elicitation of performance judgments. CA scenarios are built using the level descriptions, and hence provide realistic treatment scenarios. In AHP, patients only compared less concrete attributes such as 'impact of treatment.' This led to less realistic choices, and thus overestimation of the preference for the surgical scenarios. Several recommendations are given on how to use AHP and CA in assessing patient preferences.


Recurrent transitions to Little Ice Age-like climatic regimes over the Holocene.
Holocene climate variability is punctuated by episodic climatic events such as the Little Ice Age (LIA) predating the industrial-era warming. Their dating and forcing mechanisms have however remained controversial. Even more crucially, it is uncertain whether earlier events represent climatic regimes similar to the LIA. Here we produce and analyse a new 7500-year long palaeoclimate record tailored to detect LIA-like climatic regimes from northern European tree-ring data. In addition to the actual LIA, we identify LIA-like ca. 100-800 year periods with cold temperatures combined with clear sky conditions from 540 CE, 1670 BCE, 3240 BCE and 5450 BCE onwards, these LIA-like regimes covering 20% of the study period. Consistent with climate modelling, the LIA-like regimes originate from a coupled atmosphere-ocean-sea ice North Atlantic-Arctic system and were amplified by volcanic activity (multiple eruptions closely spaced in time), tree-ring evidence pointing to similarly enhanced LIA-like regimes starting after the eruptions recorded in 1627 BCE, 536/540 CE and 1809/1815 CE. Conversely, the ongoing decline in Arctic sea-ice extent is mirrored in our data which shows reversal of the LIA-like conditions since the late nineteenth century, our record also correlating highly with the instrumentally recorded Northern Hemisphere and global temperatures over the same period. Our results bridge the gaps between low- and high-resolution, precisely dated proxies and demonstrate the efficacy of slow and fast components of the climate system to generate LIA-like climate regimes. The online version contains supplementary material available at 10.1007/s00382-021-05669-0.