S100 proteins: structure, functions and pathology.
S100 proteins regulate intracellular processes such as cell growth and motility, cell cycle regulation, transcription and differentiation. Twenty members have been identified so far, and altogether, S100 proteins represent the largest subgroup in the EF-hand Ca2+ -binding protein family. A unique feature of these proteins is that individual members are localized in specific cellular compartments from which some are able to relocate upon Ca2+ activation, transducing the Ca2+ signal in a temporal and spacial manner by interacting with different targets specific for each S100 protein. Some members are even secreted from cells exerting extracellular, cytokine-like activities partially via the surface receptor RAGE (receptor for advanced glycation endproducts) with paracrine effects e.g. on neurons, promoting their survival during development or after injury. Another important aspect is that 14 bona fide S100 genes are found in a gene cluster on human chromosome 1q21 where a number of chromosomal abnormalities occur. This results in a deregulated expression of some S100 genes associated with neoplasias. Recently, S100 proteins have received increasing attention due to their close association with several human diseases including cardiomyopathy, neurodegenerative disorders and cancer. They have also been proven to be valuable in the diagnostic of these diseases, as predictive markers of improving clinical management, outcome and survival of patients and are considered having a potential as drug targets to improve therapies.


The Delphi definition for selective fetal growth restriction may not improve detection of pathologic growth discordance in monochorionic twins.
A consensus definition of selective fetal growth restriction in monochorionic diamniotic twins was recently proposed following a Delphi procedure involving an international panel of experts. The new definition augments the traditional definition with additional sonographic criteria. We sought to determine whether the augmentations of the "Delphi definition" identified additional morbidity and mortality compared with a traditional definition. Furthermore, we sought to determine the benefit of each definition in identifying pathologic growth restriction relative to uncomplicated monochorionic diamniotic twins. This was a retrospective analysis of unselected monochorionic diamniotic twins that underwent fortnightly ultrasound surveillance at a single center between 2011 and 2020. Patients with concomitant twin-to-twin transfusion syndrome, twin anemia polycythemia sequence, or twin reversed arterial perfusion sequence at the time of diagnosis of selective fetal growth restriction were excluded. The diagnosis of selective fetal growth restriction using the Delphi definition required either an estimated fetal weight of <3rd percentile or presence of 2 of 4 observations in the smaller twin: (1) estimated fetal weight of <10th percentile, (2) estimated fetal weight discordance of >25% compared with the larger twin, (3) abdominal circumference of <10th percentile, (4) umbilical artery pulsatility index of >95th percentile. Diagnosis using the traditional definition required an estimated fetal weight of <10th percentile and an estimated fetal weight discordance of >25%. To determine the efficacy of the augmentations in the Delphi definition, 3 groups were compared: group I, uncomplicated monochorionic diamniotic twins; group II, twins with selective fetal growth restriction using the traditional definition (and therefore the Delphi definition); and group III, twins with selective fetal growth restriction solely using the Delphi definition. Demographic characteristics, subsequent development of twin-to-twin transfusion syndrome or twin anemia polycythemia sequence, pregnancy outcomes, and neonatal outcomes were compared. There were 325 patients with monochorionic diamniotic twins that met inclusion criteria. Of these, 213 (66%; group I) were uncomplicated, 37 (11%; group II) met the traditional definition for selective fetal growth restriction, and 112 (35%) met the Delphi definition for selective fetal growth restriction with 75 (67%) meeting solely the Delphi definition (group III). Demographic characteristics were similar between groups. Patients in group II delivered earlier than uncomplicated twins (32.1 vs 35.7 weeks of gestation; P<.01) and patients in group III (32.1 vs 35.6 weeks of gestation; P<.01). Furthermore, they were more likely to have critical umbilical artery Doppler abnormalities (38% vs 4%; P<.01) and be delivered for deteriorating fetal status (30% vs 5%; P<.01) than those in group III. Overall, survival was lower in group II than groups I and III (89% vs 96% and 100%, respectively; P=.04). Moreover, composite neonatal morbidity and mortality were greater in group II (30%) than either group I (6%; P<.01) or group III (9%; P<.01). The rates of composite neonatal morbidity and mortality were similar between groups I and III (P=.28). The addition of abdominal circumference and umbilical artery pulsatility index thresholds and isolated estimated fetal weight of <3%, as proposed by the Delphi definition, increased the diagnosis of selective fetal growth restriction; however, there was no added benefit in the identification of growth discordant pregnancies at risk of adverse outcomes. Prospective analysis of monochorionic diamniotic twins is required to contextualize these findings.


Treatment of Patellofemoral Instability and Chondral Lesions.
Lateral patellar instability is one of the most common knee disorders among adolescents. Numerous anthropometric features, including trochlear dysplasia, patella alta, high tibial tubercle-to-trochlear groove distance, and coronal and rotational plane malalignment, are considered primary risk factors for patellar dislocation, and the understanding of their complex interplay is continuously evolving. Because of the multifactorial nature of patellar instability, there is a lack of consensus regarding many aspects of surgical intervention. Medial patellofemoral ligament reconstruction is considered to be the essential procedure in preventing recurrent instability. However, there is growing interest in addressing underlying anatomic risk factors that contribute to patellar instability. It is important to discuss the diagnosis and management of patellar instability, surgical considerations in medial patellofemoral ligament reconstruction, mitigation/correction of anatomic risk factors, and treatment of associated chondral lesions.


Responses to interaural time delay in human cortex.
Humans use differences in the timing of sounds at the two ears to determine the location of a sound source. Various models have been posited for the neural representation of these interaural time differences (ITDs). These models make opposing predictions about the lateralization of ITD processing in the human brain. The weighted-image model predicts that sounds leading in time at one ear activate maximally the opposite brain hemisphere for all values of ITD. In contrast, the pi-limit model assumes that ITDs beyond half the period of the stimulus center frequency are not explicitly encoded in the brain and that such "long" ITDs activate maximally the side of the brain to which the sound is heard. A previous neuroimaging study revealed activity in the human inferior colliculus consistent with the pi-limit. Here we show that cortical responses to sounds with ITDs within the pi-limit are in line with the predictions of both models. However, contrary to the immediate predictions of both models, neural activation is bilateral for "long" ITDs, despite these being perceived as clearly lateralized. Furthermore, processing of long ITDs leads to higher activation in cortex than processing of short ITDs. These data show that coding of ITD in cortex is fundamentally different from coding of ITD in the brain stem. We discuss these results in the context of the two models.


Psychiatric morbidity as a risk factor for hospital readmission for acute myocardial infarction: an 8-year follow-up study in Spain.
Most previous studies assess the effect of depression and other psychiatric variables as risk factors for acute myocardial infarction; however, studies that assess the effect of psychiatric disorders as a whole are scarce, compared with other non-psychiatric factors. The aim of this study is to assess the importance of psychiatric morbidity, compared with other risk factors, in hospital readmission for acute myocardial infarction. This is a 8-year follow-up study in which the Hospital Discharge Administrative Database was used. From the total sample (11,062 patients), 590 patients (4.88%) were diagnosed with some mental disorder. Psychiatric disorders were more common in women than in men with myocardial infarction (4.76 % and 6.20%, respectively, p-value = 0.002). For those who have had recurrence of stroke, mental disease influences in the consecutive readmission for AMI with the same severity as did tobacco, diabetes, or obesity. The main finding of this study is the enormous impact of psychiatric disorders on readmissions for AMI, comparable to diabetes, obesity, cerebral vascular disease, and hypertension. Interestingly, the efforts made to treat and prevent psychiatric disorders in AMI patients are clearly lower than those health authorities make with respect to classic risk factors.


Complementary and alternative medicine (CAM) among Australian hospital-based nurses: knowledge, attitude, personal and professional use, reasons for use, CAM referrals, and socio-demographic predictors of CAM users.
This study was intended to examine CAM among Australian hospital-based nurses, identifying their knowledge, attitude, personal and professional use, reasons for use, CAM referrals, and socio-demographic predictors of CAM users. Nurses holding a qualification in nursing and working in surgical wards were included using a convenience sampling technique. A self-complete questionnaire was developed to achieve the aims of the study. Descriptive and non-parametric statistics were calculated to describe and analyse data. Overall, 95.7% and 49.7% of nurses reported personal and professional use of CAM, respectively. The most popular CAM/CAM domain personally and professionally used by nurses was massage therapy and mind-body therapies. The primary reason for personal use of CAM was "[it] fits into my way of life/philosophy". Furthermore, massage therapists were the most commonly recommended CAM practitioners to patients. Only 15.8% of nurses would always ask patients about use of herbal medicines as part of nursing history taking. Over one-fifth (22.4%) of nurses rated their attitude as having a very positive, and 60.3% rated themselves as having very little or no knowledge of CAM. A positive correlation was also found between knowledge and attitude about CAM. Positive attitude and higher knowledge about CAM were positively correlated to CAM referrals. Several socio-demographic factors predicted personal and professional use of CAM. This study revealed that nurses generally believe not to have sufficient knowledge of CAM but are open to use CAM with patients. Nurses' positive attitude toward and personal use of CAM could be an indication that they are poised for further integration of evidence-based CAM into nursing practice to treat whole person.


The effects of the COVID-19 pandemic on neuropsychiatric symptoms in dementia and carer mental health: an international multicentre study.
As a global health emergency, the rapid spread of the novel coronavirus disease (COVID-19) led to the implementation of widespread restrictions (e.g., quarantine, physical/social distancing measures). However, while these restrictions reduce the viral spread of COVID-19, they may exacerbate behavioural and cognitive symptoms in dementia patients and increase pressure on caregiving. Here, we aimed to assess the impact of COVID-19 and related restrictions on both carers and people living with dementia across the world. We conducted an international survey (Australia, Germany, Spain, and the Netherlands) to assess the impact of COVID-19 on carers and people living with dementia. People with dementia experienced worsened neuropsychiatric symptoms since the outbreak of COVID-19, most commonly, depression, apathy, delusions, anxiety, irritability, and agitation. Regression analyses revealed that limited understanding of the COVID-19 situation and not living with the carer was associated with worsened neuropsychiatric symptoms. Carers also reported a decline in their own mental health, increased stress and reduced social networks as a result of COVID-19 and related restrictions. Regression analyses revealed uncertainty about the future and loneliness were associated with worsened carer mental health. Findings from this study will inform strategies for the development of support services and compassionate protocols that meet the evolving needs of those living with dementia and their carers.


Identification and characterization of a Golgi retention signal in feline coronavirus accessory protein 7b.
Feline coronaviruses encode five accessory proteins with largely elusive functions. Here, one of these proteins, called 7b (206 residues), was investigated using a reverse genetic approach established for feline infectious peritonitis virus (FIPV) strain 79-1146. Recombinant FIPVs (rFPIVs) expressing mutant and/or FLAG-tagged forms of 7b were generated and used to investigate the expression, processing, glycosylation, localization and trafficking of the 7b protein in rFIPV-infected cells, focusing on a previously predicted ER retention signal, KTEL, at the C-terminus of 7b. The study revealed that 7b is N-terminally processed by a cellular signalase. The cleavage site, 17-Ala|Thr-18, was unambiguously identified by N-terminal sequence analysis of a 7b processing product purified from rFIPV-infected cells. Based on this information, rFIPVs expressing FLAG-tagged 7b proteins were generated and the effects of substitutions in the C-terminal 202KTEL206 sequence were investigated. The data show that (i) 7b localizes to and is retained in the medial- and/or trans-Golgi compartment, (ii) the C-terminal KTEL sequence acts as a Golgi [rather than an endoplasmic reticulum (ER)] retention signal, (iii) minor changes in the KTEL motif (such as KTE, KTEV, or the addition of a C-terminal tag) abolish Golgi retention, resulting in relocalization and secretion of 7b, and (iv) a KTEL-to-KDEL replacement causes retention of 7b in the ER of rFIPV-infected feline cells. Taken together, this study provides interesting new insights into an efficient Golgi retention signal that controls the cellular localization and trafficking of the FIPV 7b protein in virus-infected feline cells.


Not whale-fall specialists, Osedax worms also consume fishbones.
Marine annelid worms of the genus Osedax exploit sunken vertebrate bones for food. To date, the named species occur on whale or other mammalian bones, and it is argued that Osedax is a whale-fall specialist. To assess whether extant Osedax species could obtain nutrition from non-mammalian resources, we deployed teleost bones and calcified shark cartilage at approximately 1000 m depth for five months. Although the evidence from shark cartilage was inconclusive, the teleost bones hosted three species of Osedax, each of which also lives off whalebones. This suggests that rather than being a whale-fall specialist, Osedax has exploited and continues to exploit a variety of food sources. The ability of Osedax to colonize and to grow on fishbone lends credibility to a hypothesis that it might have split from its siboglinid relatives to assume the bone-eating lifestyle during the Cretaceous, well before the origin of marine mammals.


Phenotypic transition maps of 3D breast acini obtained by imaging-guided agent-based modeling.
We introduce an agent-based model of epithelial cell morphogenesis to explore the complex interplay between apoptosis, proliferation, and polarization. By varying the activity levels of these mechanisms we derived phenotypic transition maps of normal and aberrant morphogenesis. These maps identify homeostatic ranges and morphologic stability conditions. The agent-based model was parameterized and validated using novel high-content image analysis of mammary acini morphogenesis in vitro with focus on time-dependent cell densities, proliferation and death rates, as well as acini morphologies. Model simulations reveal apoptosis being necessary and sufficient for initiating lumen formation, but cell polarization being the pivotal mechanism for maintaining physiological epithelium morphology and acini sphericity. Furthermore, simulations highlight that acinus growth arrest in normal acini can be achieved by controlling the fraction of proliferating cells. Interestingly, our simulations reveal a synergism between polarization and apoptosis in enhancing growth arrest. After validating the model with experimental data from a normal human breast line (MCF10A), the system was challenged to predict the growth of MCF10A where AKT-1 was overexpressed, leading to reduced apoptosis. As previously reported, this led to non growth-arrested acini, with very large sizes and partially filled lumen. However, surprisingly, image analysis revealed a much lower nuclear density than observed for normal acini. The growth kinetics indicates that these acini grew faster than the cells comprising it. The in silico model could not replicate this behavior, contradicting the classic paradigm that ductal carcinoma in situ is only the result of high proliferation and low apoptosis. Our simulations suggest that overexpression of AKT-1 must also perturb cell-cell and cell-ECM communication, reminding us that extracellular context can dictate cellular behavior.


[Cloning and expression of the 3C-proteinase gene from the poliomyelitis virus in E. coli cells].
Expression of the 3C protease gene of poliovirus type 1 (Mahoney) in E. coli cells using various vectors was studied. The 3C gene was shown to be expressed effectively upon its cloning in HindII/HindII (bases 5240 to 6770) and in HindII/HindIII (bases 5240 to 6056) fragments of poliovirus cDNA in pTTQ8 vector containing tac-promoter and lacI-repressor gene. Products of processing at the N-terminal 3C protease Gln-Gly site and polypeptides formed upon translation from an alternative methionine, which was coded by bases 5516-5518 of poliovirus cDNA, were found among virus-specific proteins. Processing at the C-terminal 3C protease Gln-Gly site was not observed.


First-time DWI offenders are at risk of recidivating regardless of sanctions imposed.
OBJECTIVE: Research demonstrates that punitive approaches to DWI employed by the judiciary have failed to significantly reduce recidivism. However, little is known about the deterrent effects of administrative and diversion sanctions. We examine whether such sanctions deter first-time DWI offenders. METHODS: We grouped combinations of administrative, judicial, and diversion sanctions routinely employed in the state of Maryland for processing drivers arrested for DWI into one of eight mutually exclusive disposition sequences. We applied this classification to Maryland drivers who had been licensed in the state and had precisely one DWI on their record prior to January 1, 1999. We then used a proportional hazards model to estimate the probability of remaining free of a new DWI during a 6-year period (January 1, 1999 - December 31, 2004) as a function of the disposition of the index violation, and of selected factors that could affect that probability. RESULTS: Drivers with a prior DWI were at relatively high risk of recidivating regardless of how they were sanctioned. Those who received administrative and alternative sanctions had a risk of recidivating similar to that of drivers who were convicted. CONCLUSION: All dispositions sequences, not just convictions, indicate that first-time DWI offenders are at high risk of recidivating.


Variation in allelic expression associated with a recombination hotspot in Zea mays.
Gene expression is a complex process, requiring precise spatial and temporal regulation of transcription factor activity; however, modifications of individual cis- and trans-acting modules can be molded by natural selection to create a sizeable number of novel phenotypes. Results from decades of research indicate that developmental and phenotypic divergence among eukaryotic organisms is driven primarily by variation in levels of gene expression that are dictated by mutations, either in structural or regulatory regions, of genes. The relative contributions and interplay of cis- and trans-acting regulatory factors to this evolutionary process, however, remain poorly understood. Analysis of eight genes in the Bz1-Sh1 interval of Zea mays (maize) indicates significant allele-specific expression biases in at least one tissue for all genes, ranging from 1.3-fold to 36-fold. All detected effects were cis-regulatory in nature, although genetic background may also influence the level of expression bias and tissue specificity for some allelic combinations. Most allelic pairs exhibited the same direction and approximate intensity of bias across all four tissues; however, a subset of allelic pairs show alternating dominance across different tissue types or variation in the degree of bias in different tissues. In addition, the genes showing the most striking levels of allelic bias co-localize with a previously described recombination hotspot in this region, suggesting a naturally occurring genetic mechanism for creating regulatory variability for a subset of plant genes that may ultimately lead to evolutionary diversification.


Femoral component revision with use of impaction bone-grafting and a cemented polished stem: a concise follow-up, at fifteen to twenty years, of a previous report.
We previously reported our results for thirty-three consecutive femoral component revisions with impaction bone-grafting, performed with the X-change femoral revision system and a cemented polished Exeter stem, at a minimum of eight years of follow-up. The present updated study shows the results after fifteen to twenty years. One stem was revised again for mechanical reasons during a rerevision of an acetabular cup. The probability of survival at seventeen years was 96% (95% confidence interval [CI], 72% to 99%) with a femoral rerevision for any reason as the end point and 100% (95% one-sided CI, 69% to 100%) with rerevision for aseptic loosening as the end point. The average subsidence was 3 mm and stable relative to our previous report. Although three early femoral fractures occurred after this surgery, in this update no additional fractures were seen. In conclusion, the probability of survival of femoral component revisions with impaction bone-grafting and a cemented polished stem was excellent at a mean of seventeen years.


Low concordance with HIV testing guidelines in a retrospective review of intensive care practice.
Records were reviewed (n=1052) for patients admitted to a large general intensive care unit (GICU) and examined for HIV testing criteria published in UK national testing guidelines (UKNG). All actual tests sent from GICU were also examined for comparison. Strict application of the UKNG revealed 30% of patients met criteria for HIV testing on admission to GICU. With pragmatic application, 18% of admissions met criteria for testing. Less than 5% of admissions were actually tested when no testing guideline was adopted. The UKNG can be adopted in a representative GICU to increase HIV testing rate by 4-6-fold.


Phantom validation of multichannel magnetocardiography source localization.
Multichannel magnetocardiography (MMCG) is used clinically for noninvasive localization of the site of origin of cardiac arrhythmias. However, its accuracy in unshielded environments is still unknown. The aim of this study was to test the accuracy of three-dimensional localization of intracardiac sources by means of MMCG in an unshielded catheterization laboratory using a saline-filled phantom, together with a nonmagnetic catheter designed for multiple monophasic action potential recordings in a clinical setting. A nine-channel direct current superconducting quantum interference device (DC-SQUID) system (sensitivity fT/Hz0.5) was used for MMCG from 36 points in a measuring area of 20 x 20 cm. The artificial sources to be localized were dipoles embedded in the distal end of the catheter, placed 12 cm below the sensor's plane. Equivalent current dipoles, effective magnetic dipoles, and distributed currents models were used for the inverse solution. The localization error was estimated as the three-dimensional difference between the physical position of the tip of the catheter and the three-dimensional localization of the dipoles derived by means of the inverse solution calculated from MMCG data. The reproducibility was tested by repeating the MMCG after repositioning the phantom and the measurement system. The average location error of the catheter dipole was 9 +/- 4 mm and was due primarily to imprecise depth estimation. Localization was reproducible within 0.73 mm. The distributed currents model provided an accurate image of current distribution centered over the catheter tip. The authors conclude that MMCG estimation is accurate enough to guarantee proper localization of cardiac dipolar sources even in an unshielded clinical electrophysiological laboratory.


[Conformational stability of glutamate dehydrogenase and its complexes with specific ligands].
The isotermic denaturation of glutamatdehydrogenase (GDH) and its complexes with co-enzymes, substrates and allosteric regulators under the action of urea was studied. It was shown that the reaction of the enzyme with an allosteric inhibitor GTP is accompanied by a decrease in conformational stability of the catalytically active hexsamer GDH. Formation of a complex with the allosteric activator ADP increases the conformational stability of the enzyme. Studies on the isotermic unfolding of GDH in the presence of various phosphoric ethers of adenosine gave evidence that the stabilizing effect of ADP is based on the reaction of the enzyme with the adenine base of the regulator.


Conservative treatment using a sponge cast for transfer fractures in nursing home patients.
Transfer fractures in the lower limbs of bedridden and chair-bound nursing home patients can result from trauma induced by the usual lifting, moving, turning, or transferring maneuvers. Treatment entails immobilization for pain control and position change; however, splints/hard casts increase the risk of pressure sores. Therefore, we evaluated the use of a sponge cast. Between March 2011 and October 2017, 17 patients with a lower limb transfer fracture due to transferring maneuvers in a nursing home were recruited. We evaluated the improvement in pseudo-motion and divided the patients as having bony union, fibrous union, or remaining pseudo-motion. We also investigated the occurrence of pressure sores due to immobilization up until the final follow-up. Femur fractures occurred in 15 patients and lower leg fractures in two. Six of the 15 femur fractures were periprosthetic (four hip arthroplasty and two knee arthroplasty). Pseudo-motion was improved in 15 of 17 cases, within an average of 17.3 weeks for the improvement (14-23 weeks; bony union: 11 cases and fibrous union: four cases). Pseudo-motion remained in two cases: one periprosthetic fracture around the knee arthroplasty and the other, a femur neck fracture. No pressure sores occurred. A sponge cast appears to be one of the effective treatment options available for bedridden or chair-bound patients with a lower limb fracture due to its low risk of complications and satisfactory clinical results.


Effects of long-chain PUFA supplementation in infant formula on cognitive function in later childhood.
Evidence is accumulating that a dietary supply of long-chain polyunsaturated fatty acids (LC-PUFAs) enhances the development of attention and efficient information processing in infants. However, it is uncertain whether LC-PUFAs in infancy influence cognitive development in later childhood. The objective was to determine the effects of dietary LC-PUFAs in infancy on measures of cognitive function at age 6 y. Infants were randomly assigned to receive formula containing either docosahexaenoic acid and arachidonic acid or no LCPUFAs for a period of 4 mo. A reference breastfed group was also included. In a follow-up conducted at age 6 y, children received assessments of intelligence quotient (IQ), attention control (Day-Night Test), and speed of processing on the Matching Familiar Figures Test (MFFT). At follow-up there were 71 children in the LC-PUFA group, 76 in the control group, and 88 in the breastfed group. The formula groups did not differ on measures of Full-Scale IQ (LCPUFA mean = 98.0; control mean = 100.9) or attention control (LCPUFA mean = 12.7; control mean = 12.8). MFFT error scores were the same for both formula groups, but when making correct responses, the LC-PUFA group was significantly faster (mean = 6.2 s) than the control group [mean = 7.8 s; F(1, 131) = 6.09, P = 0.015]. IQ scores of children who were fed a formula containing either LC-PUFAs or no LC-PUFAs did not differ at age 6 y. However, children who received LC-PUFAs were faster at processing information compared with children who received unsupplemented formula. Variation in the dietary supply of LC-PUFAs in the first months of life may have long-term consequences for the development of some cognitive functions in later childhood.


Western blotting versus ELISA detection of stress proteins induced in the blue mussel Mytilus edulis exposed to cadmium and tributyltin.
Stress proteins of the Hsp70 family induced in the blue mussel Mytilus edulis exposed in the laboratory to increased concentrations of cadmium (Cd) or tributhyltin (TBT) were analysed using Western blotting and/or ELISA tests. Statistical evaluation of results indicated that increased concentrations of Hsp70 were detected by means of the ELISA tests as compared with control organisms in extracts from the gills of mussels exposed to both Cd or TBT (p = 0.022). Results of analysis by means of Western blotting showed no differences in the levels of Hsp70 in the extracts (p = 0.151). It was concluded that the ELISA test allowed a more sensitive detection of Hsp70 than did Western blotting.


Thyroglobulin autoantibodies as surrogate biomarkers in the management of patients with differentiated thyroid carcinoma.
Differentiated thyroid cancer is a rare malignancy, but leaves numerous survivors for life-long follow-up. The cornerstone in current guidelines for follow-up is by measuring the thyroid specific tumour marker, thyroglobulin in serum. Most patients can be followed by this method, but some thyroid cancer patients have antithyroglobulin antibodies in serum, both at diagnosis and after treatment, where follow-up is commenced. These antibodies interfere technically in the immunological methods for measuring thyroglobulin, and the antithyroglobulin antibody positive patients are thus eliminated from following current guidelines. In recent years studies have indicated that following the concentration of antithyroglobulin antibodies in serum may be a surrogate marker for recurrence of the thyroid carcinoma. This has recently resulted in publication of an expert position paper, providing a flow scheme for these particular patients. The current review summarises the literature which is the basis for the paper.


Programmed death 1 Ligand 1 expression in breast cancer and its association with patients' clinical parameters.
To evaluate the expression of programmed death 1 ligand 1 (PD-L1) in the cancer tissues and tumor-adjacent normal tissues of patients with invasive ductal carcinoma of the breast and to analyze the relationship between the expression of PD-L1 and the clinicopathological features of patients. This study included 112 cases of patients with invasive ductal carcinoma of breast who received surgical treatment from March 2012 to February 2016 in Xuzhou Cancer Hospital. The clinical materials of included patients were retrospectively analyzed. The immunohistochemical assay and real-time polymerase chain reaction (PCR) assay were applied to examine the expression of mRNA and protein of PD-L1 in breast cancer specimens of 112 cases and paired tumor-adjacent tissue specimens of 57 cases. The relationship between PD-L1 protein expression and clinicopathological features of patients was analyzed. PD-L1 protein was mainly expressed in the cytoplasm. The positive rate of PD-L1 expression in invasive ductal carcinoma was 19.6% (22/112), and the positive rate of PD-L1 expression of tumor-adjacent normal tissues was 3.5% (2/57), indicating that the positive rate of PD-L1 expression of cancerous tissues was significantly higher than that of in tumor-adjacent normal tissues (P < 0.05); the positive expression of PD-L1 was not related with the patients' age, menopause history, family history of breast cancer, tumor size, and location of the tumor (P > 0.05) while it was related with lymph node metastasis, the clinic staging, and histopathological grading (P < 0.05). Real-time PCR was applied to detect the mRNA expression of PD-L1 in breast-invasive ductal carcinoma with the mean ΔCt value of 7.79 ± 2.25. However, the mRNA expression of PD-L1 in normal tumor-adjacent tissues was of low expression with the mean ΔCt value of 12.37 ± 3.33. The difference was statistically significant (P< 0.05). The expression of PD-L1 in breast-invasive ductal carcinoma was significantly increased, and it was related to histological grading, clinical staging, and lymph node metastasis of breast cancer. PD-L1 may be a significant marker for the prognosis of breast cancer patients.


Positive organizational behavior: Longitudinal effects on subjective well-being.
Increasing individual subjective well-being has various positive outcomes, knowledge about its antecedents and the mediators of this relationship can therefore help to increase subjective well-being and the accompanying positive effects. The more future oriented facets of psychological capital, i.e. optimism, hope and self-efficacy have been shown in several studies to be positively related to subjective well-being and negatively to ill-being. Furthermore, recent studies suggest coping strategies as mediators for these relationships. In our study, we examined the longitudinal relation of optimism, hope and self-efficacy with subjective well-being and ill-being in a German panel dataset and tested the mediating effect of flexible goal adjustment in a path model. Our results show a statistically significant positive effect of self-efficacy and optimism on subjective well-being as well as a statistically significant negative effect of optimism on depression over three years. All three predictors show a statistically significant relation with flexible goal adjustment, but flexible goal adjustment did not mediate the effect on subjective well-being or depression.


Combined effects of hypertension and hypercholesterolemia on radial artery function.
Compliance and distensibility of middle-sized conduit arteries are increased in hypertension and reduced in hypercholesterolemia. Despite their frequent association in the same individual, the combined effect of these two conditions on arterial mechanical properties is unknown. We studied four groups of age- and sex-matched subjects: 10 normotensive normocholesterolemic subjects, 10 mild hypertensive normocholesterolemic subjects, 10 mild hypercholesterolemic normotensive subjects, and 10 mild hypertensive and mild hypercholesterolemic subjects. We measured radial artery diameter by an echotracking device and beat-to-beat blood pressure from an ipsilateral finger. Compliance-pressure and distensibility-pressure curves were derived by Langewouters' formula. Between-group comparisons were made by calculating for both compliance and distensibility the integral of the area under the portion of the curve common to the four groups ("isobaric" compliance and distensibility). Blood pressure was similarly elevated in the two hypertensive groups, and serum cholesterol was similarly elevated in the two hypercholesterolemic groups. Compared with values in normotensive normocholesterolemic subjects, isobaric compliance and distensibility were greater in hypertensive normocholesteroclemic (+38% and 47%, respectively) and smaller in normotensive hypercholesterolemic (-6% and -23%) subjects. However, when both hypertension and hypercholesterolemia were present, isobaric compliance and isobaric distensibility were significantly reduced (-26% and -18%, P < .05). Therefore, hypercholesterolemia reverses the effect of hypertension on arterial compliance and causes arterial stiffening, as when present alone.


[Validity of the concept of human dignity in health care: a literary perspective].
In 2003 Ruth Macklin published a short paper questioning the usefulness of the concept ″human dignity. ″ Since then the debate has been kept alive, although in the world of Law, ethics and clinical practice, this concept continues to be used normally. In the spotlight of that criticism was the bioethics of Leon Kass, built on the concept of dignity and sustained in a narrative methodology. In homage to Leon Kass, in this work I approach the concept of dignity from a literary perspective and focusing on nursing health care, in which the usefulness of the concept of human dignity is especially visible.


Repeated stress in combination with pyridostigmine Part II: changes in cerebral gene expression.
Organophosphates (OP) represent a potential threat in terrorism or during military conflicts. Due to its faculty to protect cholinesterase (ChE) activity against irreversible inactivation by OP, pyridostigmine bromide (PB) was used as a prophylaxis treatment during the first Persian Gulf War. To explain dysfunctions reported by Gulf War Veterans (GWV), it was suggested a potentiation of the operational stress effects by PB given to soldiers. Our companion paper (see part 1 in the same journal issue) describes that PB treatment administered in repeated stress conditions results in long-term perturbations of learning and social behaviour. The present paper examines, in adult male Wistar rats, consequences of the association of repeated stress and PB treatment on gene expression in hypothalamus and hippocampus. PB treatment (1.5 mg/kg/day) was orally administered 30 min before each stress session to inhibit 40% of blood ChE as recommended by NATO. 10 days of stress alone induce a decrease in hypothalamic Il-1alpha expression. Treatment with PB alone increases mineralocorticoid receptor expression in hypothalamus which means that PB may thus modify stress perception by animals. Stressed-PB animals showed increase in hippocampal expression of BDNF, TrkB and CamKIIalpha, three genes implicated in memory development. As a supplement to previous studies showing behavioural and biochemical effects of the association of stress with PB, our data reveal that behavioural effects of this association may be linked with genomic changes in hippocampus. Mechanisms underlying these modifications and their link with memory disturbances reported by GWV remain to be further determined.


Inverse roles of emotional labour on health and job satisfaction among long-term care workers in Japan.
Emotional labour increases among long-term care workers because providing care and services to impaired elders causes conflicting interpersonal emotions. Thus, we investigated the associations between emotional labour, general health and job satisfaction among long-term care workers. We conducted a cross-sectional study among 132 established, private day care centres in Tokyo using a mail survey. The outcome variables included two health-related variables and four job satisfaction variables: physical and psychological health, satisfaction with wages, interpersonal relationships, work environment and job satisfaction. We performed multiple regression analyses to identify significant factors. Directors from 36 facilities agreed to participate. A total of 123 responses from long-term care workers were analysed. Greater emotional dissonance was associated with better physical and psychological health and worse work environment satisfaction (partial regression coefficient: -2.93, p = .0389; -3.32, p = .0299; -1.92, p = .0314, respectively). Fewer negative emotions were associated with more job satisfaction (partial regression coefficient: -1.87, p = .0163). We found that emotional labour was significantly inversely associated with health and job satisfaction. Our findings indicated that the emotional labour of long-term care workers has a negative and positive influence on health and workplace satisfaction, and suggests that care quality and stable employment among long-term care workers might affect their emotional labour. Therefore, we think a programme to support emotional labour among long-term care workers in an organized manner and a self-care programme to educate workers regarding emotional labour would be beneficial.


Phase I results of a phase I/II study of weekly nab-paclitaxel in paediatric patients with recurrent/refractory solid tumours: A collaboration with innovative therapies for children with cancer.
nab-Paclitaxel has demonstrated efficacy in adults with solid tumours and preclinical activity in paediatric solid tumour models. Results from phase I of a phase I/II study in paediatric patients with recurrent/refractory solid tumours treated with nab-paclitaxel are reported. Patients with recurrent/refractory extracranial solid tumours received nab-paclitaxel on days 1, 8 and 15 every 4 weeks at 120, 150, 180, 210, 240, or 270 mg/m2 (rolling-6 dose-escalation) to establish the maximum tolerated dose (MTD) and recommended phase II dose (RP2D). Sixty-four patients were treated. Dose-limiting toxicities were grade 3 dizziness at 120 mg/m2 and grade 4 neutropenia >7 days at 270 mg/m2. The most frequent grade 3/4 adverse events were haematologic, including neutropenia (36%), leukopenia (36%) and lymphopenia (25%). Although the MTD was not reached, 270 mg/m2 was declared non-tolerable due to grade 3/4 toxicities during cycles 1-2 (neutropenia, n = 5/7; skin toxicity, n = 2/7; peripheral neuropathy, n = 1/7). Of 58 efficacy-evaluable patients, complete response occurred in one patient (2%; Ewing sarcoma) and partial responses in four patients (7%; rhabdomyosarcoma, Ewing sarcoma, renal tumour with pulmonary metastases [high-grade, malignant] and sarcoma not otherwise specified); all responses occurred at ≥210 mg/m2. Thirteen patients (22%) had stable disease (5 lasting ≥16 weeks) per RECIST. nab-Paclitaxel 240 mg/m2 qw3/4 (nearly double the adult recommended monotherapy dose for this schedule in metastatic breast cancer) was selected as the RP2D based on the tolerability profile, pharmacokinetics and antitumour activity. Phase II is currently enrolling patients with recurrent/refractory neuroblastoma, rhabdomyosarcoma and Ewing sarcoma. CLINICALTRIALS.GOV: NCT01962103. 2013-000144-26.


Sialylated keratan sulfate proteoglycans are Siglec-8 ligands in human airways.
Human siglecs are a family of 14 sialic acid-binding proteins, most of which are expressed on subsets of immune cells where they regulate immune responses. Siglec-8 is expressed selectively on human allergic inflammatory cells-primarily eosinophils and mast cells-where engagement causes eosinophil apoptosis and inhibits mast cell mediator release. Evidence supports a model in which human eosinophils and mast cells bind to Siglec-8 sialoglycan ligands on inflammatory target tissues to resolve allergic inflammation and limit tissue damage. To identify Siglec-8-binding sialoglycans from human airways, proteins extracted from postmortem human trachea were resolved by size-exclusion chromatography and composite agarose-acrylamide gel electrophoresis, blotted and probed by Siglec-8-Fc blot overlay. Three size classes of Siglec-8 ligands were identified: 250 kDa, 600 kDa and 1 MDa, each of which was purified by affinity chromatography using a recombinant pentameric form of Siglec-8. Proteomic mass spectrometry identified all size classes as the proteoglycan aggrecan, a finding validated by immunoblotting. Glycan array studies demonstrated Siglec-8 binding to synthetic glycans with a terminal Neu5Acα2-3(6-sulfo)-Gal determinant, a quantitatively minor terminus on keratan sulfate (KS) chains of aggrecan. Treating human tracheal extracts with sialidase or keratanase eliminated Siglec-8 binding, indicating sialylated KS chains as Siglec-8-binding determinants. Treating human tracheal histological sections with keratanase also completely eliminated the binding of Siglec-8-Fc. Finally, Siglec-8 ligand purified from human trachea extracts induced increased apoptosis of freshly isolated human eosinophils in vitro. We conclude that sialylated KS proteoglycans are endogenous human airway ligands that bind Siglec-8 and may regulate allergic inflammation.


Effect of N-acetyl-D-glucosamine on gene expression in Vibrio parahaemolyticus.
We analyzed the effect of N-acetyl-D-glucosamine (GlcNAc) on gene expression in the marine bacterium Vibrio parahaemolyticus. The total number of genes whose expression was induced and repressed genes in the presence of GlcNAc was 81 and 55, respectively. The induced genes encoded a variety of products, including proteins related to energy metabolism (e.g. GlcNAc and chitin utilization), transport, central metabolism and chemotaxis, hypothetical proteins, mannose-sensitive hemagglutinin pilus (MSHA), and a PilA protein, whereas the repressed genes encoded mainly hypothetical proteins. GlcNAc appears to influence directly or indirectly a variety of cellular processes, including energy metabolism, chitin utilization, competence, biofilm formation and pathogenicity. GlcNAc, one of the most abundant aminosugars in the oceans, is used by V. parahaemolyticus as an energy source and affects the cellular functioning of this marine bacterium.


Bioflocculation as a microbial response to substrate limitations.
Previous theories of nutrient supply to microbial floes assumed that transport within the flocs was by molecular diffusion, and they predict that overall nutrient uptake is reduced in floes compared to dispersed cells. Calculations, supported by recent advances in understanding fluid flow through suspended aggregates, however, have shown that substantial fluid flow may occur through highly permeable bacterial floes. Since bioflocculation of microorganisms in bioreactors is known to occur under conditions of low substrate availability, the rate of substrate uptake is assumed to be mass transfer limited. The hydrodynamic environment of a cell then determines cellular uptake rates. Through development of a relative uptake factor, the overall uptake by cells in flocs in sheared fluids and floes attached to bubbles are compared with the uptake by an identical quantity of dispersed cells. Bioflocculation is found to increase the rate of substrate transport to cells in permeable floes compared to dispersed cells, particularly for large-molecular-weight substrates and when bubbles are present.


Optic Canal Decompression With Unexpected Changes in Cerebrospinal Fluid of the Optic Canal.
Optic neuritis is a common inflammatory disease of the optic nerve. And the cerebral spinal fluid (CSF) in the subarachnoid space of optic nerve is thought to be homogeneous as in spine. We report a case of optic neuritis, some unexpected opaque fluid observed to flow out from the optic canal during the optic canal decompression surgery when the CSF in spine is normal. One day after the surgery, the visual acuity of the patient improved dramatically to 0.4 from 0.05. This report highlights the possible restrictive pathological changes of the CSF in the optic nerve of acute optic neuritis, which may be the reason of the dysfunction of the optic nerve.


[Synthesis of Fe/nitrogen-doped Carbon Nanotube/Nanoparticle Composite and Its Catalytic Performance in Oxygen Reduction].
The cathode catalyst plays an important role in the electricity generation of microbial fuel cells (MFCs). In order to achieve the large-scale application of MFCs, cathode catalyst with low cost and high oxygen reduction reaction (ORR) has great sense to substitute the precious catalyst of Pt/C. Here chemical vapor deposition (CVD) method was utilized accompanied with melamine as a nitrogen and carbon precursor, oxidized carbon powder (Black Pearls 2000 or Acetylene Black) as carbon precursor and iron acetate as an iron precursor so as to synthesize two kinds of Fe and nitrogen doped carbon nanotube/nanoparticle composites (FeNCB and FeNCC) as MFCs cathode catalysts. The cyclic voltammetry and rotating ring-disk electrode were applied to analyze the ORR activity discrepancies of FeNCB, FeNCC, and Pt/C (20%), which was confirmed by MFC operation. The results showed that the ORR performance of FeNCB was slightly better than Pt/C and dramatically better than FeNCC. Moreover, the catalysis of ORR by FeNCB was through a four-electron transfer pathway. Besides, the performance of MFC-FeNCB was higher than MFC-Pt/C and observably higher than MFC-FeNCC which was a contribute to promote the scale of MFC. MFC-FeNCB achieved the maximum power output density of 1212.8 mW x m(-2), an open circuit potential of 0.875 V, and a stabilized voltage of (0.500 +/- 0.025) V. Further analysis via X-ray diffraction, X ray photoelectron spectroscopy, and Raman exhibited that the diameter of carbon nanotube, the types of N and Fe as well as the concentration of nitrogen, iron and oxygen was the reason for the discrepancies of ORR characteristics for the prepared catalysts.


Treatment patterns and clinical outcomes of extensive stage small cell lung cancer (SCLC) in the real-world evidence ESME cohort before the era of immunotherapy.
Small cell lung cancer (SCLC) is a highly aggressive entity of lung cancer with tendency toward early recurrence after first-line treatment. As per recently updated European Society for Medical Oncology recommendations, first-line treatment with up to 4 cycles of platinum-etoposide combined with immune checkpoint inhibitor (ICIs)-targeting PD-L1, is now the standard of care. The purpose of the current analysis is to identify current patient profiles and treatment strategies in real life clinical practice, and report outcomes in Extensive Stage (ES)-SCLC. Non-interventional, retrospective, multicentre, comparative study was carried out to describe the outcome of ES-SCLC patients included in the Epidémiologie Stratégie Médico-Economique (ESME) data platform for advanced and metastatic lung cancer. Patients were selected from 34 health care facilities between January 2015 and December 2017, before the era of immunotherapy. 1315 patients were identified, including 64% male and 78% under 70 year-old; 24% had at least 3 metastatic sites, mainly liver metastases (43%), bone metastases (36%), brain metastases (32%). 49% received only one line of systemic treatment; 30% and 21% received 2 and 3 lines or more, respectively. Carboplatin was more frequently used than cisplatin (71% and 29%, respectively). Prophylactic cranial irradiation was infrequent (4% of patients), but 16% of patients received thoracic radiation therapy, mainly after the completion of first-line chemotherapy (72% of patients); such strategies were more frequently applied in cisplatin/etoposide than carboplatin/etoposide patients (p = 0.006 and p = 0.015, respectively). After a median follow-up time of 21.8 (95% CI: 20.9-23.3) months, median real-world Progression-Free Survival (rw-PFS) was 6.2 (95% CI: 5.7; 6.9) and 6.1 (95% CI: 5.8; 6.3) months for cisplatin/etoposide and carboplatin/etoposide doublet regimens, respectively; 24-month rwPFS and Overall Survival were 3.2% (95% CI: 2.3; 4;2) and 22.2% (95% CI: 19.4; 25.1) in the whole population, respectively. Our data provide with landmark reference findings on ES-SCLC before the immunotherapy era, and cover many aspects of the treatment strategy, while highlighting on the role of radiotherapy, subsequent lines of therapy, and the outcomes of patients. Generation of real-world data focusing on patients who received platinum-based chemotherapy combined with immune checkpoint inhibitors is under way.


An apple oligogalactan prevents against inflammation and carcinogenesis by targeting LPS/TLR4/NF-κB pathway in a mouse model of colitis-associated colon cancer.
Evidence strongly supported a link between inflammation and cancer. Patients with colitis have high risk for development of colon cancer. Nuclear factor-kappa B (NF-κB), partially induced by lipopolysaccharide (LPS) binding to Toll-like receptor (TLR) 4, is a vital molecule in supervising the transformation of colitis to colon cancer. It could be a good strategy to prevent colitis carcinogenesis for targeting LPS/TLR4/NF-κB pathway. In the present study, we obtained an oligogalactan composed of five galacturonic acids from apple pectin and evaluated its protective efficacy on intestinal toxicities and carcinogenesis in a mouse model of colitis-associated colon cancer induced by 1,2-dimethylhydrazine and dextran sodium sulfate (DSS). The apple oligogalactan (AOG) was highly effective against intestinal toxicities and carcinogenesis and decreased the elevated levels of TLR4 and tumor necrosis factor-α (TNF-α) induced by inflammation in vivo in this model system. In vitro studies, AOG alone only slightly increased the levels of protein expression and messenger RNA of TLR4, phosphorylation of IκBα and production of TNF-α in HT-29 cells. However, AOG significantly decreased the elevation of all the biomarkers induced by LPS when it was combined with LPS. The effect of AOG may be related to membrane internalization and redistribution of TLR4 from cell membrane to cytoplasm. AOG is active against inflammation and carcinogenesis through targeting LPS/TLR4/NF-κB pathway. Both AOG and LPS are agonists of TLR4 for sharing the same ligand but AOG has a much lower intrinsic activity than that of LPS. AOG may be useful for treatment of colitis and prevention of carcinogenesis in the clinics.


Effect of Heat Shock on the Thermotolerance and Protein Composition of Yersinia enterocolitica in Brain Heart Infusion Broth and Ground Pork.
The optimum conditions required to induce a heat-shock response in Yersinia enterocolitica in brain heart infusion (BHI) broth were determined. The production of heat-shock proteins and the increased thermotolerance of heat-shocked Yersinia cells in ground pork when exposed to higher temperatures was also examined. Heat shocking Y. enterocolitica cells at 45°C for 60 min consistently resulted in an increased number of survivors to a subsequent treatment of 55 or 60°C in BHI broth when compared with non-heat-shocked controls. D values at 55°C were calculated as 7.7 and 2.0 min and at 60°C as 1.6 and 1.2 min for heat-shocked and control cells, respectively. After examination of heat-shocked cells by sodium dodecyl sulfate-polyacrilamide gel electrophoresis (SDS-PAGE), two distinct heat-shock proteins with molecular masses of 70.5 and 58.0 kDa were observed that were not present in the control. Evaluation of heat-shocked and control cell survival in ground pork revealed D55 values of 15.6 and 6.5 min and D60 values of 6.7 and 1.7 min, respectively. The results indicate that prior heat shock can induce increased resistance in Y. enterocolitica in ground pork to higher heat treatments. Survival of Yersinia enterocolitica in cooked meat due to the phenomenon of the heat-shock response can become a cause of concern regarding microbiological food safety.


HPV knowledge, attitudes, and cultural beliefs among Hispanic men and women living on the Texas-Mexico border.
US Hispanic women have higher cervical cancer incidence rates than non-Hispanic White and African-American women and lower rates of cervical cancer screening. Knowledge, attitudes, and cultural beliefs may play a role in higher rates of infection of human papillomavirus (HPV) and decisions about subsequent diagnosis and treatment of cervical cancer. To explore the level of HPV knowledge, attitudes, and cultural beliefs among Hispanic men and women on the Texas-Mexico border. Informed by feminist ethnography, the authors used an interpretive approach to understand local respondents' concerns and interests. Focus group sessions were analyzed using thematic content analysis. RECRUITMENT AND SAMPLE: Promotoras (lay health workers) recruited participants using convenience sampling methods. Group sessions were held in public service centers in Brownsville. Participants' ages ranged from 19 to 76 years. METHODS ANALYSIS: Focus group discussions were audio-recorded and transcribed in Spanish. Researchers read and discussed all the transcripts and generated a coding list. Transcripts were coded using ATLAS.ti 5.0. Participants had little understanding about HPV and its role in the etiology of cervical cancer. Attitudes and concerns differed by gender. Women interpreted a diagnosis of HPV as a diagnosis of cancer and expressed fatalistic beliefs about its treatment. Men initially interpreted a diagnosis of HPV as an indication of their partners' infidelity, but after reflecting upon the ambiguity of HPV transmission, attributed their initial reaction to cultural ideals of machismo. Men ultimately were interested in helping their partners seek care in the event of a positive diagnosis. Results suggest that understanding Hispanics' cultural norms and values concerning disease, sexuality, and gender is essential to the design and implementation of interventions to prevent and treat HPV and cervical cancer.


Prevalence and control of cardiovascular risk factors in Poland. Assumptions and objectives of the NATPOL 2011 Survey.
Cardiovascular diseases (CVD) have been the main cause of death in Poland for the last five decades. In 2010, CVD caused 46.0% of all deaths in Poland. An analysis performed using the IMPACT model, have shown that the reduction in mortality due to ischaemic heart disease, which took place in Poland, was primarily a result of lifestyle changes and of changes affecting risk factors in the population of adults. From the perspective of health policy planning it is very important to know the prevalence of CVD risk factors and to be aware of trends in the population. The NATPOL 2011 Survey was a cross-sectional observational study aimed to assess the prevalence and control of CVD risk factors in Poland. The aim of this paper is to describe the objectives and methodology of the NATPOL 2011 project. The survey was designed as a representative observational study and was carried out on a representative sample of Polish residents aged 18-79 years. The planned size of the research sample was 2,400 subjects. Participants were randomly selected in bundles, in a stratified, proportional draw performed in three stages. The study was composed of a questionnaire interview, blood pressure and anthropometric measurements as well as a blood and urine sample collection. The examination consisted of two visits at subjects' homes and was performed by well-trained nurses. Letters of invitation were sent to 4,420 potential participants. Of those, 786 persons could not be contacted because the addresses were wrong, the respondents resided at an address other than their registered place of residence or, in some cases, the respondents died prior to the survey. Among 3,634 addresses of the persons sampled for the study there were 661 (M: 328, F: 333) "closed doors" (the nurse was unable to contact the respondent during three consecutive attempts) and 560 (M: 295, F: 265) direct refusals. Finally, 2,413 subjects participated in the study and 2,401 of them completed all the procedures in the survey. The data mentioned above give the response rate of 66.4%.The structure of the study sample, including age groups and gender is almost identical to the structure of the adult population of Poland in 2010, according to the Central Statistical Office data. The sample reflected the structure of the adult population quite well, therefore the weights' adjustments calculated for epidemiological analyses were in range from 0.36 to 4.11.


[Origin and importance of the Latin American Kawasaki Disease Network (REKAMLATINA)].
Kawasaki disease is the leading cause of acquired cardiac disease in children. Although the epidemiology of the disease has been well described in Japan, other Asian countries, Europe, Australia and North America, the epidemiology and disease burden in Latin American children is unknown. For this reason, the idea of establishing a research network on Kawasaki disease in children from Latin America was born, becoming this the largest Kawasaki disease international multinational research network and in which 20 countries of the region will be integrated.


The metabolism of 18:0 and 18:2(n-6) by the ovine placenta at 120 and 150 days of gestation.
The effects of approach of parturition in the sheep on the incorporation of 18:0 and 18:2(n-6) into the placenta lipids and on the activities of the delta 9- and delta 6-desaturase enzymes of placental tissue have been studied in vitro. The incorporation of 18:0 into the esterified lipids of placental tissue between the 120th and 150th days of gestation declined markedly; the high level of incorporation of 18:2(n-6) into the esterified lipids of the placenta (some 2-fold higher than 18:0) remained constant over the gestational period. While placental delta 9-desaturase activity was the same at 150 days as at 120 days of gestation, the activity of the delta 6-desaturase enzyme increased significantly. These results are discussed in relation to the fetal demand for fatty acids near term and the differences that exist between the mechanisms of maternal-fetal transfer of 18:0 and 18:2(n-6) in the sheep.


Influencing physician referrals.
Primary care physicians have several external sources of information available when referring a patient to a specialist. The most-used sources were a fellow physician, followed by the specialist, the patient or the patient's family, and to a lesser extent, hospital-controlled sources including referral directories, call services, and sales representatives. The authors tested a cost-benefit model where source usage was predicted to increase as the costs of using the source decreased and benefits increased.


Hemizygosity for Atm and Brca1 influence the balance between cell transformation and apoptosis.
In recent years data from both mouse models and human tumors suggest that loss of one allele of genes involved in DNA repair pathways may play a central role in genomic instability and carcinogenesis. Additionally several examples in mouse models confirmed that loss of one allele of two functionally related genes may have an additive effect on tumor development. To understand some of the mechanisms involved, we examined the role of monoallelic loss or Atm and Brca1 on cell transformation and apoptosis induced by radiation. Cell transformation and apoptosis were measured in mouse embryo fibroblasts (MEF) and thymocytes respectively. Combinations of wild type and hemizygous genotypes for ATM and BRCA1 were tested in various comparisons. Haploinsufficiency of either ATM or BRCA1 resulted in an increase in the incidence of radiation-induced transformation of MEF and a corresponding decrease in the proportion of thymocytes dying an apoptotic death, compared with cells from wild-type animals. Combined haploinsufficiency for both genes resulted in an even larger effect on apoptosis. Under stress, the efficiency and capacity for DNA repair mediated by the ATM/BRCA1 cell signalling network depends on the expression levels of both proteins.


High power and good beam quality of two-dimensional VCSEL array with integrated GaAs microlens array.
High power and good beam quality of two-dimensional bottom-emitting vertical-cavity surface-emitting laser array with GaAs microlens on the substrate is achieved. Uniform and matched convex microlens is directly fabricated by one-step diffusion-limited wet-etching techniques on the emitting windows. The maximum output power is above 1 W at continuous-wave operation at room temperature, and the far-field beam divergence is below 6.6° at a current of 4 A. These properties between microlens-integrated and conventional device at different operating current are demonstrated.


Laminin alpha1 chain improves laminin alpha2 chain deficient peripheral neuropathy.
Absence of laminin alpha2 chain leads to a severe form of congenital muscular dystrophy (MDC1A) associated with peripheral neuropathy. Hence, future therapies should be aimed at alleviating both muscle and neurological dysfunctions. Pre-clinical studies in animal models have mainly focused on ameliorating the muscle phenotype. Here we show that transgenic expression of laminin alpha1 chain in muscles and the peripheral nervous system of laminin alpha2 chain deficient mice reduced muscular dystrophy and largely corrected the peripheral nerve defects. The presence of laminin alpha1 chain in the peripheral nervous system resulted in near-normal myelination, restored Schwann cell basement membranes and improved rotarod performance. In summary, we postulate that laminin alpha1 chain is an excellent substitute for laminin alpha2 chain in multiple tissues and suggest that treatment with laminin alpha1 chain may be beneficial for MDC1A in humans.


Lowered threshold energy for femtosecond laser induced optical breakdown in a water based eye model by aberration correction with adaptive optics.
In femtosecond laser ophthalmic surgery tissue dissection is achieved by photodisruption based on laser induced optical breakdown. In order to minimize collateral damage to the eye laser surgery systems should be optimized towards the lowest possible energy threshold for photodisruption. However, optical aberrations of the eye and the laser system distort the irradiance distribution from an ideal profile which causes a rise in breakdown threshold energy even if great care is taken to minimize the aberrations of the system during design and alignment. In this study we used a water chamber with an achromatic focusing lens and a scattering sample as eye model and determined breakdown threshold in single pulse plasma transmission loss measurements. Due to aberrations, the precise lower limit for breakdown threshold irradiance in water is still unknown. Here we show that the threshold energy can be substantially reduced when using adaptive optics to improve the irradiance distribution by spatial beam shaping. We found that for initial aberrations with a root-mean-square wave front error of only one third of the wavelength the threshold energy can still be reduced by a factor of three if the aberrations are corrected to the diffraction limit by adaptive optics. The transmitted pulse energy is reduced by 17% at twice the threshold. Furthermore, the gas bubble motions after breakdown for pulse trains at 5 kilohertz repetition rate show a more transverse direction in the corrected case compared to the more spherical distribution without correction. Our results demonstrate how both applied and transmitted pulse energy could be reduced during ophthalmic surgery when correcting for aberrations. As a consequence, the risk of retinal damage by transmitted energy and the extent of collateral damage to the focal volume could be minimized accordingly when using adaptive optics in fs-laser surgery.


Precedent-setting professional liability claims involving optometry.
For optometrists, malpractice claims are relatively rare and seldom result in litigation. Therefore, there are very few reported court cases dealing with the optometric malpractice issue. In fact, within the last ten years there have been only five reported cases. Claims involving failure to diagnose have been the most devastating to optometrists, and have resulted in the five recently reported court cases. This paper discusses the facts of these five cases and considers their relevance to contemporary optometric practice.


Measuring and explaining changing patterns of inequality in institutional deliveries between urban and rural women in Ghana: a decomposition analysis.
Despite recent progress in improving access to maternal health services, the utilization of these services remains inequitable among women in developing countries, and rural women are particularly disadvantaged. This study sought to measure i) disparities in the rates of institutional births between rural and urban women in Ghana, ii) the extent to which existing disparities are due to differences in the distribution of the determinants of institutional delivery between rural and urban women, and iii) the extent to which existing disparities are due to discrimination in resource availability. Using Demographic and Health Survey data from 2003, 2008, and 2014, this study decomposed inequalities in institutional delivery rates among urban and rural Ghanaian woman using the Oaxaca, the Blinder, and related decompositions for non-linear models. The determinants of the observed inequalities were also analyzed. Institutional delivery rates in urban areas exceeded those of rural areas by 32.4 percentage points due to differences in distribution of the determinants of institutional delivery between the two areas. The main determinants driving the observed disparities were wealth, which contributed to about 16.1% of the gap, followed by education level, and number of antenatal visits. Relative to urban women, rural women have lower rates of institutional deliveries due primarily to lower levels of wealth, which results in financial barriers in accessing maternal health services. Economic empowerment of rural women is crucial in order to close the gap in institutional delivery between urban and rural women.


Iron Supplements Modulate Colon Microbiota Composition and Potentiate the Protective Effects of Probiotics in Dextran Sodium Sulfate-induced Colitis.
Iron is an important nutrient for both the host and colonizing bacteria. Oral iron supplementation may impact the composition of the microbiota and can be particularly damaging to patients suffering from inflammatory bowel disease (IBD). However, patients with IBD may require iron supplementation to treat their anemia. We fed mice with diets supplemented with ferrous sulfate at different doses (5, 50, and 500 mg of iron/kg chow) and with different iron formulations (ferrous sulfate, ferrous bisglycinate and ferric ethylenediaminetetraacetic acid [FEDTA]), and analyzed the effects on the composition of the gut microbiota by 16S ribosomal RNA gene sequencing. Using the dextran sodium sulfate (DSS)-induced colitis mouse model, we investigated the effects of iron supplementation in colitis severity, as well as the use of the probiotic Escherichia coli Nissle 1917 (EcN) in combination with iron supplementation. Iron supplementation at different doses induced shifts in the gut microbial communities and inferred metabolic pathways. However, depending on the iron formulation used in the diets, iron supplementation during dextran sodium sulfate-induced colitis was either beneficial (ferrous bisglycinate) or highly detrimental (FEDTA). Finally, the beneficial effect of the probiotic EcN in the dextran sodium sulfate-induced colitis model was potentiated by oral iron supplementation with ferrous sulfate. These results show that the iron formulations used to treat iron deficiency influence the gut microbiota and colitis in mice and suggest that distinct iron compounds may be of particular relevance to patients with IBD. In addition, the beneficial action of probiotics in IBD may be enhanced by oral iron supplementation.


[Treatment of medulloblastoma--the pediatric oncologist's viewpoint (author's transl)].
Within the interdisciplinary therapy team, the pediatrician is in charge of the clinical diagnosis, the application and control of chemotherapy as well as the follow-up of the patients. Th value of chemotherapy for the treatment of the medulloblastoma is still under discussion. However, a certain improvement of the survival rates of patients treated additionally by chemotherapy as against only postirradiated patients can be seen from the results of some recent international, co-operative, prospective, and randomized studies. New ways of treatment should be tried out in order to further improve the therapy results and to reduce the side effects caused by the treatment. Thus co-operative therapy study conducted since 1980 by the Society of Pediatric Oncology recommends the administration of an intensive chemotherapy during eight to ten weeks between operation and irradiation. The reasons of this therapeutic conception are explained and the experiences obtained hitherto are presented.


Enrichment of peat yields novel methanogens: approaches for obtaining uncultured organisms in the age of rapid sequencing.
Methanogens are among the oldest forms of life on Earth and are detectable in a wide range of environments, but our knowledge of their overall diversity and functioning is limited. Peatlands in particular host a broad range of methanogens that contribute large amounts of methane to the atmosphere, but are largely under-represented in pure cultures. Here, we anaerobically enriched peat with common growth substrates, supplements and antibiotics to identifying novel methanogen sequences and potential growth conditions. Over 3 years, we obtained 28 new mcrA sequences from taxa that have remained previously uncultured and undescribed beyond distantly related clones or sequences detected in environmental samples. Evidence suggests that the novel methanogens, representing five of the seven known orders, were capable of growing on H2 as well as acetate and at temperatures ranging from 6 to ca. 22°C. Methods involving the use of ampicillin proved useful, although obtaining high methane production in the absence of H2 was difficult. Our results also indicate that many methanogens may rely on bacterial symbionts (commonly Clostridium spp.). Such enrichment approaches represent a useful intermediary between maker-gene detection and isolation, allowing us to broaden our understanding of methanogen physiological ecology while potentially providing valuable sequence data.


Primary Sjogren's syndrome presenting as an isolated severe autonomic dysfunction treated with steroids.
Primary Sjogren's syndrome (pSS) is an autoimmune connective tissue disorder with multisystem manifestations. We here report a previously healthy woman who presented with autonomic dysfunction in the form of severe dizziness without any apparent sensory neuropathy. Detailed history and examination revealed the signs and symptoms of Sjogren's syndrome such as constipation and dry eyes and mouth, following which anti-SSA and SSB antibodies were found to be positive. Finally, a diagnosis of pSS was established after ruling out all the other causes of autonomic dysfunction in addition to the clinical and laboratory evidence. The patient was treated with the maximum doses of midodrine and fludrocortisone, yet no progress was noticed. Hence, a trial of steroids was started and she showed a significant clinical improvement. Our patient presented with pure autonomic failure associated with Sjogren's syndrome, making it an extremely rare entity.


CpG island arrays: an application toward deciphering epigenetic signatures of breast cancer.
CpG island hypermethylation is a frequent epigenetic event in cancer. We have recently developed an array-based method, called differential methylation hybridization (DMH), allowing for a genome-wide screening of CpG island hypermethylation in breast cancer cell lines (T. H-M. Huang et al., Hum. Mol. Genet., 8: 459-470, 1999). In the present study, DMH was applied to screen 28 paired primary breast tumor and normal samples and to determine whether patterns of specific epigenetic alterations correlate with pathological parameters in the patients analyzed. Amplicons, representing a pool of methylated CpG DNA derived from these samples, were used as hybridization probes in an array panel containing 1104 CpG island tags. Close to 9% of these tags exhibited extensive hypermethylation in the majority of breast tumors relative to their normal controls, whereas others had little or no detectable changes. Pattern analysis in a subset of CpG island tags revealed that CpG island hypermethylation is associated with histological grades of breast tumors. Poorly differentiated tumors appeared to exhibit more hypermethylated CpG islands than their moderately or well-differentiated counterparts (P = 0.041). This early finding lays the groundwork for a population-based DMH study and demonstrates the need to develop a database for examining large-scale methylation data and for associating specific epigenetic signatures with clinical parameters in breast cancer.


Preoperative Trapped Lung Is Associated With Increased Mortality After Orthotopic Liver Transplantation.
Trapped lung, characterized by atelectatic lung unable to reexpand and fill the thoracic cavity due to a restricting fibrous visceral pleural peel, is occasionally seen in patients with end-stage liver disease complicated by hepatic hydrothorax. Limited data suggest that trapped lung prior to orthotopic liver transplantation may be associated with poor outcomes. What is the clinical significance of trapped lung in patients receiving orthotopic liver transplantation? We performed a retrospective analysis of patients who underwent liver transplantation over an 8-year period. Baseline clinical characteristics and postoperative outcomes of adult patients with trapped lung were analyzed and compared to the overall cohort of liver transplant recipients and controls matched 3:1 based on age, sex, Model for End-Stage Liver Disease (MELD) score, and presence of pleural effusion. Of the 1193 patients who underwent liver transplantation, we identified 20 patients (1.68%) with trapped lung. The probability of 1 and 2-year survival were 75.0% and 57.1%, compared to 85.6% and 80.4% (p = 0.02) in all liver transplant recipients and 87.9% and 81.1% (p = 0.03) in matched controls respectively. Patients with trapped lung had a longer hospital length of stay compared to the total liver transplant population (geometric mean 54.9 ± 8.4 vs. 27.2 ± 0.7 days, p ≤ 0.001), when adjusted for age and MELD score. Patients with trapped prior to orthotopic liver transplantation have increased probability of mortality as well as increased health care utilization. This is a small retrospective analysis, and further prospective investigation is warranted.


Properties of complexes formed by Na(+), Mg(2+), and Fe(2+) binding with benzene molecules.
A theoretical investigation was performed to study cation-π interactions in complexes of benzene (Bz) with cations, that is, M(z+)(Bz)n for M(z+) = Na(+), Mg(2+), Fe(2+) and n = 1-3, using MP2 theory with the 6-31+G* and 6-311++G** basis sets and the DFT/(B3LYP and B3LYP-D)/6-311++G** methods. Binding energies and structures of the complexes are reported. The splitting between the quintet and single states of the Fe(2+) complexes was found to depend on the number of benzene molecules in the complex and the complex's structure. All of the M(z+)(Bz) complexes prefer a half-sandwich geometry. A geometry with the cation sandwiched between the two benzene rings was found for the M(z+)(Bz)2 complexes, with the benzene rings either in an eclipsed or staggered conformation. An approximate cyclic structure, with the cation at its center, was found for three benzene molecules interacting with the cation. The cation-benzene binding energy is substantial and equal to 22, 108, and 151 kcal/mol for the Na(+)(Bz), Mg(2+)(Bz), and Fe(2+)(Bz) complexes, respectively. The strength of the interaction of the cation with an individual benzene molecule decreases as the number of benzene molecules bound to the cation increases; for example, it is 108 kcal/mol for Mg(2+)(Bz), but only 71 kcal/mol for Mg(2+)(Bz)3. There is a range of values for the M(z+)(Bz)n intermolecular vibrational frequencies; for example, they are ∼230-360 and ∼10-330 cm(-1) for the Mg(2+)(Bz) and Mg(2+)(Bz)3 complexes, respectively. Binding of the cation to benzene both red and blue shifts the benzene vibrational frequencies. This shifting is larger for the Mg(2+) and Fe(2+) complexes, as compared to those for Na(+), as a result of the former's stronger cation-benzene binding. The present study is an initial step to understand the possible importance of cation-π interactions for polycyclic aromatic hydrocarbon aggregation processes during soot formation.


Ozone Gas Effect on Mineral Content of Dentin exposed to Streptococcus mutans Biofilm: An Energy-dispersive X-ray Evaluation.
This study aims to assess the effect of ozone gas on dentin exposed to Streptococcus mutans biofilm by evaluation of mineral content [log calcium-to-phosphorus (Ca/P)] using energy-dispersive X-ray (EDX) spectroscopy. Five human third molars were sectioned into four slices of dentin and distributed in four groups: I - control (no treatment); II - ozone therapy; III - biofilm development; IV - ozone therapy followed by biofilm development. Mineral content (log Ca/P) was evaluated by EDX. Data were analyzed by analysis of variance and Tukey's test (p < 0.05). Results showed that the mineral content of control group (I) was similar to ozone group (II), and was statistically higher than biofilm (III) and ozone + biofilm (IV). The lowest log Ca/P was determined in biofilm group (III). It can be concluded that ozone gas did not grant preventive effects of demineralization by S. mutans biofilm on dentin surface. Ozone gas therapy may be an alternative noninvasive treatment aiming to reduce the levels of caries-associated microorganisms. This therapy may, thereby, be an alternative and/or complementary treatment strategy in preventive dentistry.


An Interactive Timeline Visualization for Patient Cohorts in the Oncological Routine: A Use Case on Multiple Myeloma.
With the growing interdisciplinarity of cancer treatment and increasing amounts of data and patients, it is getting increasingly difficult for physicians to capture a patient's medical history as a basis for adequate treatment and to compare different medical histories of similar patients to each other. Furthermore, in order to tackle the etiological mechanisms of cancer, it is crucial to identify patients exhibiting a different disease course than their corresponding cohort. Several timeline visualizations have already been proposed. However, the functions and design of such visualizations are always use case dependent. We constructed a cohort timeline prototype mock-up for a specific oncological use case involving multiple myeloma, where the chronological monitoring of various parameters is crucial for patient diagnosis and treatment. Our proposed cohort timeline is a synthesis between elements described in the literature and our own approaches regarding function and design.


Mechanisms of soluble beta-amyloid impairment of endothelial function.
Alzheimer's disease (AD) has been recently associated with vascular risk factors. beta-amyloid peptides (AbetaP), the main component of senile plaques typical of AD, circulate in soluble globular form in bloodstream. Interestingly, AbetaP is able to induce endothelial dysfunction, and this effect may represent the link between vascular and neuronal pathophysiological factors involved in AD. We aimed to clarify the molecular mechanisms underlying globular AbetaP-induced vascular toxicity. Using several methodological approaches, we have observed that in vascular tissues globular AbetaP is unable to induce oxidative stress, one of the mechanisms hypothesized involved in beta-amyloid toxicity. More important, we have demonstrated that globular AbetaP is able to localize on vascular endothelium, where it inhibits eNOS enzymatic activity. In particular, AbetaP enhances eNOS phosphorylation on threonine 495 and serine 116 and reduces acetylcholine-induced phosphorylation on serine 1177. Such an effect depends on a PKC signaling pathway, as suggested by its phosphorylation on serine 660. In fact, selective inhibition of the calcium-dependent group of PKC is able to rescue beta-amyloid-induced alteration of eNOS phosphorylation, NO production, and endothelial vasorelaxation. The activation of these Ca(2+)-dependent pathways is probably due to the ability of AbetaP to evoke Ca(2+) leakage from inositol 1,4,5-triphosphate receptors on endoplasmic reticulum. Our data demonstrate that globular AbetaP-induced endothelial NO dysfunction can be attributed to an alteration of intracellular Ca(2+) homeostasis, which could lead to the activation of calcium-dependent group of PKC with a consequent change of the eNOS phosphorylation pattern. These mechanisms could contribute to shed further light on the toxic effect of beta-amyloid in vascular tissues.


Brain oxygen, CO2, pH, and temperature monitoring: evaluation in the feline brain.
Currently, no ideal method exists for monitoring the injured brain. Recently, a single, compact, fiberoptic sensor has become available for measuring oxygen, CO2, pH and temperature in blood. We have adapted this instrument for continuous use in brain tissue to measure oxygen tension, carbon dioxide tension (pCO2), pH, and temperature. To evaluate this new technique, we produced hypercapnia, hypocapnia, intracranial pressure increase, and hypoxemia in seven normal cats. In an additional six animals, sensors were placed within a zone of focal brain ischemia induced by occluding the left middle cerebral artery. The sensor readings were compared with cerebral blood flow measurements, intracranial pressure, and brain histological findings. An in vitro experiment was also performed using human blood to test the accuracy of the sensor over a wide range of pCO2 and oxygen tension values. After careful precalibration and rigid cranium fixation, stable measurements could be obtained throughout the 6- to 8-hour experiments. In normal animals, brain oxygen was 42 +/- 9 mm Hg, brain CO2 was 59 +/- 14 mm Hg, brain pH was 7.0 +/- 0.2, and brain temperature was 36.7 +/- 0.7 degrees C. Hypocapnia and hypoxemia produced a significant decline in tissue oxygen (< or = 30 +/- 3 mm Hg; P < 0.001), whereas hypercapnia caused by hypoventilation and intracranial pressure increase produced a significant increase in tissue CO2 (> or = 74 +/- 4 mm Hg; P < 0.001). Focal ischemia produced a rapid 42% decline in brain oxygen (25 +/- 7 mm Hg) and a 25% increase in tissue pCO2 (71 +/- 23 mm Hg). Brain oxygen further decreased to 19 +/- 6 mm Hg toward the end of the experiment, 4 hours later. After middle cerebral artery occlusion, the regional cerebral blood flow decreased to 10 +/- 5 ml per 100 g per minute, within the 1st hour, from a baseline value of 65 +/- 15 ml per 100 g per minute. It then gradually increased to 15 +/- 5 ml per 100 g per minute by the end of the 4-hour experiment. Brain pH was closely and inversely related to brain CO2. The brain temperature in the focally ischemic tissue decreased from 36.7 +/- 0.7 to 35.5 +/- 1.6 degrees C by the end of the experiment. The in vitro experiment demonstrated good linear correlation between the sensor readings and the blood gas analysis. Continuous monitoring of oxygen, CO2, pH, and temperature in damaged or at-risk brain tissue using a single sensor is now feasible and will, thus, allow improved continuous monitoring of neurosurgical patients who are at risk of significant secondary brain damage.


Extrapolating evidence of antiepileptic drug efficacy in adults to children ≥2 years of age with focal seizures: The case for disease similarity.
Expediting pediatric access to new antiseizure drugs is particularly compelling, because epileptic seizures are the most common serious neurological symptom in children. Analysis of antiepileptic drug (AED) efficacy outcomes of randomized controlled trials, conducted during the past 20 years in different populations and a broad range of study sites and countries, has shown considerable consistency for each drug between adult and pediatric populations. Historically, the majority of regulatory approvals for AEDs have been for seizure types and not for specific epilepsy syndromes. Available data, both anatomical and neurophysiological, support a similar pathophysiology of focal seizures in adults and young children, and suggest that by age 2 years the structural and physiological milieu upon which seizures develop is similar. Although the distribution of specific etiologies and epilepsy syndromes is different in children from in adults, this should not impact approvals of efficacy based on seizure type, because the pathophysiology of focal seizures and the drug responsiveness of these seizure types are quite similar. Safety and pharmacokinetics cannot be extrapolated from adults to children. The scientific rationale, clinical consensus, and published data support a future approach accepting efficacy data from adult trials and focusing exclusively on prospective pharmacokinetic, tolerability, and safety studies and long-term follow-up in children. Whereas tolerability studies can be compared easily in children and adults, safety studies require large numbers of patients followed for many years.


[Cytochemical study of the cysts of the sarcosporidian Sarcocystis bovicanis. I. Nucleic acids, polysaccharides, lipids and proteins].
A light microscopic study of S. bovicanis cysts and cyst stages has been carried out, in addition to morphological characterization of cysts. At least two types of cyst stages could be distinguished--merozoites and metrocytes. The light microscopic differentiation of the third type--the intermediate cells--from merozoites seems to be rather difficult especially when non-dividing cells are examined. Merozoites (zoites) much varied in size, and besides the usual parasitic cells with the terminal nuclei, cells with the central ones were recognized. Since the classical Feulgen reaction did not give sufficient results when establishing DNA distribution, its modification with a fluorescent agent Auramin O was used. The latter provided excellent results showing numerous chromatin granules in the nucleus, no distinct nucleoli being determined. Gallocyanin--chromalum method and methyl green--pyronin staining for DNA and RNA demonstrated a poor staining of the nucleus contrasting with an intensive coloration of cytoplasmic RNA and associated high level protein synthesis. The PAS reaction revealed numerous polysaccharide granules in the cytoplasm of zoites. On cryostat sections a certain PAS positive layer was distinguished around the cyst in the muscle tissue which did not disappear even after a long term amylase treatment. Even more intensively stained was the pre-cystic muscle after cytochemical test for general protein using amido black and coomassie blue. It does not seem unlikely that some metabolic changes may occur in the host cell harbouring the cyst. Several methods for lipid detection in cyst stages with Fat red, Oil red O and Sudan black B were used with negative results.(ABSTRACT TRUNCATED AT 250 WORDS)


Liquiritigenin ameliorates memory and cognitive impairment through cholinergic and BDNF pathways in the mouse hippocampus.
Liquiritigenin (LQ), a flavonoid extracted from the radix of Glycyrrhiza, has anti-inflammatory and neuroprotective properties. In this study, we evaluated the cognitive enhancing effects of LQ on learning and memory impairments induced by scopolamine (0.5 mg/kg, i.p.), a muscarinic antagonist, using the Y-maze, passive avoidance, and novel object recognition tests. A single administration of LQ significantly improved scopolamine-induced cognitive impairments in these behavioral tests. In addition, LQ dramatically inhibited acetylcholinesterase and thiobarbituric acid reactive substance activities in the hippocampus of scopolamine-induced mice in a dose-dependent manner. Furthermore, LQ markedly increased the protein level of brain-derived neurotrophic factor (BDNF) and phosphorylation of extracellular signal-regulated kinase (ERK) and cAMP response element binding (CREB) in the hippocampus of scopolamine-induced mice. Taken together, our results indicate that LQ may be useful for the treatment of learning and memory impairments, and that the beneficial effects of LQ are mediated, in part, by cholinergic and BDNF/ERK/CREB signaling enhancement and/or protection.


Cast versus functional brace in the rehabilitation of patients treated for an ankle fracture: protocol for the UK study of ankle injury rehabilitation (AIR) multicentre randomised trial.
Each year in the UK over 120 000 people fracture their ankle. It is not known what the best rehabilitation strategy is for these people. Traditionally standard care has involved immobilisation in a plaster cast but an alternative is a functional brace, which can be removed to allow early movement. This paper details the protocol for a multicentre randomised trial of plaster cast immobilisation versus functional bracing for patients with an ankle fracture. We will recruit adults with a fractured ankle, for which the treating clinician would consider plaster cast to be a reasonable management option. Randomisation will be on a 1:1 basis, stratified by centre, operative or non-operative management and age. Participants will be allocated to either plaster cast or a functional brace, both treatments are widely used. To have 90% power to detect a difference of 10 points on the primary outcome (Olerud and Molander Ankle Score) at the primary outcome time point (16 weeks), we need to randomise a minimum of 478 people. Quality of life and resource use will be collected at 6, 10, 16, 24 weeks and 12, 18, 24 months. The differences between treatment groups will be assessed on an intention-to-treat basis. The economic evaluation will adhere to the recommendations of the National Institute for Health and Care Excellence reference case. National Research Ethic Committee approved this study on 4 July 2017 (17/WM/0239). The first site opened to recruitment 9 October 2017. The results of this trial will be submitted to a peer-reviewed journal and will inform clinical practice. ISRCTN15537280; Pre-results.


[Temperature dependence of the transmembrane distribution of non-electrolytes in human erythrocytes].
Influence of temperature on the behaviour of non-electrolytes n-alcohol series distribution between intra- and extracellular environment of human red blood cells was studied by means of 1H-NMR technique. It was shown, that the temperature dependences of the distribution coefficients Q of the non-electrolytes solutions between erythrocytes and medium in the range of T = +4(-)+37 degrees C could not be describe by Arrhenius equation. There was supposed that the absorbtion-phase theory may be used for the description of non-electrolyte absorbtion and non-electrolyte distribution between human erythrocytes and intercellular medium.


Tobacco use among the elderly: The first Brazilian National Survey (BNAS).
This study describes the prevalence and pattern of tobacco use among the elderly in Brazil and establishes its association with socio-demographic characteristics, other substance use and depression. The analyses were performed in 400 individuals aged 60 years and over who participated in the first Brazilian national alcohol survey (BNAS) in 2000. Nearly 60% of the sample had ever smoked, of them one in three were still smoking at the time of the interview. Most (94.3%) of the tobacco users were smoking everyday and 34.3% consuming more than 20 cigarettes a day. Only 1% of the former smokers had received support to quit. Over half of the current users (65%) would use free treatment to quit if it existed in Brazil, and just under half of them (47.4%) would consider quitting if cigarettes' price were higher. Currently, tobacco users were more likely to be men and alcohol abusers. Prevalence of depression was high regardless participant smoking status (33.0% among non-smokers, 34.7% among current smokers and 39.3% among former smokers). There was no significant association between smoking and depression. This study found a disturbingly high proportion of tobacco users among the elderly in Brazil. According to the Global Burden of Disease project, tobacco has the highest mortality risk of all substance use categories, especially for the elderly. This study shows there is an urgent need to develop smoking cessation interventions targeted specifically to the elderly.


Decreased STAT4 indicates poor prognosis and enhanced cell proliferation in hepatocellular carcinoma.
To investigate the role of signal transduction and activation of transcription 4 (STAT4) in the development and progression of human hepatocellular carcinoma (HCC). Recent genetic investigations have identified that a genetic variant of STAT4 is associated with hepatitis B virus (HBV)-related HCC. The level of STAT4 in 90 HCC patients was examined via Western blot and immunohistochemical analyses. The correlation between STAT4 expression and the clinicopathological characteristics of the patients was analyzed. The level of STAT4 expression in the HCC liver tissues was significantly lower than that in the non-HCC liver tissues and correlated with tumor size, histological grade of HCC and serum hepatitis B surface antigen level in HCC patients. The data were statistically analyzed using SPSS. Furthermore, siRNA oligos targeting STAT4 were employed to investigate the influence of STAT4 RNA interference on HCC cell physiology. Based on Cell Counting Kit-8 and flow cytometric assays, we found that depletion of STAT4 expression significantly enhanced the proliferation of L02 cells. STAT4 protein expression was significantly lower in HCC tissues than in normal liver tissues. Immunohistochemistry followed by statistical analysis revealed that the expression of STAT4 negatively correlated with Ki67 expression (r = 0.851; P < 0.05) and positively correlated with maximal tumor size (P < 0.05), HBV (P = 0.012) and histological grade (P < 0.05). Kaplan-Meier analysis revealed significant differences in the survival curves between HCC patients expressing low and high levels of STAT4 and Ki67 (P < 0.05). Based on a multivariate Cox proportional hazard model, STAT4 expression was an independent prognostic indicator for HCC patients who underwent curative resection. In vitro, following the release of L02 cell lines from serum starvation, the expression of STAT4 was downregulated, and transfection of L02 cells with siRNA targeting STAT4 inhibited cell proliferation. Our data indicate that STAT4 may inhibit HCC development by modulating HCC cell proliferation.