Incorporating Historical Control Data When Comparing Tumor Incidence Rates.
Animal carcinogenicity studies, such as those conducted by the U.S. National Toxicology Program (NTP), focus on detecting trends in tumor rates across dose groups. Over time, the NTP has compiled vast amounts of data on tumors in control animals. Currently, this information is used informally, without the benefit of statistical tests for carcinogenicity that directly incorporate historical data on control animals. This article proposes a survival-adjusted test for detecting dose-related trends in tumor incidence rates, which incorporates data on historical control rates and formally accounts for variation in these rates among studies. An extensive simulation, based on a wide range of realistic situations, demonstrates that the proposed test performs well in comparison to the current NTP test, which does not incorporate historical control data. In particular, our test can aid in interpreting the occurrence of a few tumors in treated animals that are rarely seen in controls. One such example, which motivates our work, concerns the analysis of histiocytic sarcoma in the NTP's 2-year cancer bioassay of benzophenone. Whereas the occurrence of three histiocytic sarcomas in female rats was not significant according to the current NTP testing procedure (P = 0.074), it was highly significant (P = 0.004) when control data from six recent historical studies were included and our test was applied to the combined data.


Complex Regional Pain Syndrome (Sudeck Atrophy) Prevention Possibility and Accelerated Recovery in Patients with Distal Radius at the Typical Site Fracture Using Polarized, Polychromatic Light Therapy.
Objective: Distal radius fracture (DRF) is one of the most frequent population fracture mostly affecting women, and frequently leading to complex regional pain syndrome (CRPS). Management of DRF and CRPS in gerontology is complex. The aim was to evaluate the use of polarized, polychromatic, low-energy light therapy combined with conventional treatment after DRF in gerontology and to follow up patients for CRPS emergence. Materials and methods: After plaster removal, female patients (n = 52) were divided into two groups. Group 1 (n = 26) was treated with exercises and cryotherapy on the wrist and dorsal hand (control). Group 2 (n = 26) was additionally treated with light therapy (Bioptron). Results: While pain decreased and supination and pronation improved in all patients after 15 days of therapy, pain reduction was accelerated and supination enhanced in the light therapy-treated group (p < 0.05). None of the patients in the light therapy-treated group developed CRPS during the 6-month follow-up, compared with four patients (15.4%) in the control group (p < 0.05). Complete hand fist-forming capacity was achieved in 19 patients (73.1%) in the light therapy-treated group compared with 16 patients (61.5%) in the control group (p > 0.05). Conclusions: Bioptron light therapy combined with conventional therapy improves patient outcome after DRF in gerontology, compared with conventional treatment alone.


Deletion of many yeast introns reveals a minority of genes that require splicing for function.
Splicing regulates gene expression and contributes to proteomic diversity in higher eukaryotes. However, in yeast only 283 of the 6000 genes contain introns and their impact on cell function is not clear. To assess the contribution of introns to cell function, we initiated large-scale intron deletions in yeast with the ultimate goal of creating an intron-free model eukaryote. We show that about one-third of yeast introns are not essential for growth. Only three intron deletions caused severe growth defects, but normal growth was restored in all cases by expressing the intronless mRNA from a heterologous promoter. Twenty percent of the intron deletions caused minor phenotypes under different growth conditions. Strikingly, the combined deletion of all introns from the 15 cytoskeleton-related genes did not affect growth or strain fitness. Together, our results show that although the presence of introns may optimize gene expression and provide benefit under stress, a majority of introns could be removed with minor consequences on growth under laboratory conditions, supporting the view that many introns could be phased out of Saccharomyces cerevisiae without blocking cell growth.


Extension of a chromosome linkage group of Proteus mirabilis.
Mating procedures for detection of mobilization of the Proteus mirabilis chromosome were re-investigated. The chromosome was mobilized by plasmid D, the previously used hybrid between plasmids P-lac and R1drd19. About a 40-fold increase in recombinant recovery correlated with the absence of swarming during mating and a lower temperature of incubation. The modification introduced was that conjugation was allowed to proceed on a non-selective supplemented minimal medium at 30 degrees C before washing and plating on selective media. Final incubation was also at 30 degrees C. This technique enabled eight additional chromosomal markers to be mapped. Polarized transfer of the chromosome was shown by gradient of transmission experiments using a previously described marker as reference, by linkage analysis with reference to proximal and distal markers and (less successfully) by interrupted mating on solid medium. Markers of plasmid D transferred at high frequency to all recombinants. The plasmid was stable in recombinants and could transfer itself and chromosomal markers of the new hosts in further matings. Resulting recombination of markers occurred at usual frequencies. The marker order, his-1, ser-2, ura-2, pyrB1, trp-3, cysA1, ade-2, ilv-2, cysG1, gly-1, cysC1, argA2, metF2, nalA1, thr-1, leuB2, did not resemble the order of these markers in Escherichia coli.


Selection of antibody fragments specific for an alpha-helix region of acylphosphatase.
The native state of common-type acylphosphatase (AcP) elicits two alpha-helices spanning residues 22-32 and 55-67 in the protein sequence. A peptide corresponding to the second alpha-helix (helix-2) of the protein was used to select phage antibodies consisting of a single chain fragment variable. The selection was performed in the presence of trifluoroethanol, a cosolvent known to induce the formation of helical structure in peptides and proteins. Phage scFv antibodies capable of binding the peptide specifically in a trifluoroethanol-induced alpha-helical conformation were isolated by affinity selection (biopanning). Some of these scFvs were also able to bind the native protein but not the peptide in a non-helical unstructured state. This indicates that the structural determinant recognized by the selected antibodies is the alpha-helical conformation of this specific region, rather than simply its amino acid sequence. This study shows that phage display libraries can be used to raise antibodies one can use as reagents able to target regions of a protein with a specific native-like secondary structure.


ADHD and maturation of brain white matter: A DTI study in medication naive children and adults.
Several diffusion tensor imaging (DTI) studies in attention deficit hyperactivity disorder (ADHD) have shown a delay in brain white matter (WM) development. Because these studies were mainly conducted in children and adolescents, these WM abnormalities have been assumed, but not proven to progress into adulthood. To provide further insight in the natural history of WM maturation delay in ADHD, we here investigated the modulating effect of age on WM in children and adults. 120 stimulant-treatment naive male ADHD children (10-12 years of age) and adults (23-40 years of age) with ADHD (according to DSM-IV; all subtypes) were included, along with 23 age and gender matched controls. Fractional anisotropy (FA) values were compared throughout the WM by means of tract-based spatial statistics (TBSS) and in specific regions of interest (ROIs). On both TBSS and ROI analyses, we found that stimulant-treatment naive ADHD children did not differ in FA values from control children, whereas adult ADHD subjects had reduced FA values when compared to adult controls in several regions. Significant age × group interactions for whole brain FA (p = 0.015), as well as the anterior thalamic radiation (p = 0.015) suggest that ADHD affects the brain WM age-dependently. In contrast to prior studies conducted in medicated ADHD children, we did not find WM alterations in stimulant treatment naïve children, only treatment-naïve adults. Thus, our findings suggest that the reported developmental delay in WM might appear after childhood, and that previously reported differences between ADHD children and normal developing peers could have been attributed to prior ADHD medications, and/or other factors that affect WM development, such as age and gender.


How [FeFe]-Hydrogenase Facilitates Bidirectional Proton Transfer.
Hydrogenases are metalloenzymes that catalyze the conversion of protons and molecular hydrogen, H2. [FeFe]-hydrogenases show particularly high rates of hydrogen turnover and have inspired numerous compounds for biomimetic H2 production. Two decades of research on the active site cofactor of [FeFe]-hydrogenases have put forward multiple models of the catalytic proceedings. In comparison, our understanding of proton transfer is poor. Previously, residues were identified forming a hydrogen-bonding network between active site cofactor and bulk solvent; however, the exact mechanism of catalytic proton transfer remained inconclusive. Here, we employ in situ infrared difference spectroscopy on the [FeFe]-hydrogenase from Chlamydomonas reinhardtii evaluating dynamic changes in the hydrogen-bonding network upon photoreduction. While proton transfer appears to be impaired in the oxidized state (Hox), the presented data support continuous proton transfer in the reduced state (Hred). Our analysis allows for a direct, molecular unique assignment to individual amino acid residues. We found that transient protonation changes of glutamic acid residue E141 and, most notably, arginine R148 facilitate bidirectional proton transfer in [FeFe]-hydrogenases.


Awareness and practices of contraceptive use among university students in Botswana.
In Botswana, unplanned pregnancies, especially among the youth constitutes a growing health and social problem. Research in the field of contraceptive practices, and the causes of sexual practices in Botswana, remains scarce and relatively limited. The objectives of this study was to investigate the awareness and utilization of various contraceptive methods, among university students in Botswana. A descriptive, cross-sectional, research study was conducted among 346 randomly selected students, who completed confidential, self-administered questionnaires. The average age of the respondents was 21 years (SD = 2.8 years). The level of awareness among students regarding contraception was good (score ≥9). Both the male and the female students had almost similar awareness level of contraceptive use, as their mean scores were 8.79 and 8.72, respectively (p = .733). All the female students (100%) were 'aware' that the effectiveness of the contraceptives used, as compared to male students, being 93.7%. A greater proportion of the female students (90.6%) knew that using contraceptives irregularly would result in pregnancy, in contrast to 76.4% males. More than half (59.0%) of the students indicated that they had engaged in sexual acts. Significantly, more male students (68.5%) had sexual experiences prior to the study, compared to 54.5% of their female counterparts (p = .038).The majority of the students (76%) reported that they had always used contraceptive methods. The most commonly used contraceptive method was the condom (95.6%), followed by oral contraceptive pill (86.7%). There was no significant association found between the level of awareness and the use of contraceptives. Results suggested that many students still engaged in risky, contraceptive practices by engaging in unprotected sexual acts. Therefore, there is a need to educate the students about sexually transmitted infections, the different contraceptive methods and the regular use of the available contraceptives.


The good, the bad, and the ugly of calcium supplementation: a review of calcium intake on human health.
Calcium is an important integrative component of the human body and critical for human health. It has been well established that calcium intake is helpful in the prevention and treatment of osteoporosis, which has become one of the most serious public health problems across the world. However, community-dwelling adults with and without osteoporosis are rarely concerned or even not aware of the potential side effects of high or inappropriate doses of calcium intake. Some recent studies have revealed that excessive calcium intake might increase the risks of cardiovascular diseases. The purpose of this article was to review the health benefits, costs, and consequences of calcium supplementation on osteoporosis/osteoporotic fractures, cardiovascular events, kidney stones, gastrointestinal diseases, and other important diseases. In the end, we suggest that calcium supplementation should be prescribed and taken cautiously, accounting for individual patients' risks and benefits. Clearly, further studies are needed to examine the health effects of calcium supplementation to make any solid recommendations for people of different genders, ages, and ethnicities.


Transposon-Based Manufacturing of Human CAR-T Cells.
In this chapter, the methodologies are outlined for generating CAR-T from PBMCs using transposon engineering. Additionally, some methods and guidance related to basic functional and phenotypic analysis are described. This methodology can be applied to manufacture and assess chimeric antigen receptors for preclinical applications targeting a variety of molecules.


Facilitating microplastic quantification through the introduction of a cellulose dissolution step prior to oxidation: Proof-of-concept and demonstration using diverse samples from the Inner Oslofjord, Norway.
Identifying and quantifying microplastic in marine samples can be facilitated by removing natural organic matter (NOM). Cellulosic material, like chitin, however, are a type of NOM that is resistant to chemical digestion, and difficult to eliminate from samples. To address this, a two-step digestion method was developed to remove or reduce cellulosic materials in diverse marine media. This method was applied to reference microplastics, reference cellulosic materials, and diverse marine samples from the Inner Oslofjord Norway. This included plankton, seabed sediments near a water treatment plant and driftline sand. The method was developed and tested for plastic particles >45 μm. The first-step was to pre-dissolve cellulosic materials using a mixture of urea:thiourea:NaOH. This was followed by an oxidative digestion step, here using H2O2 and NaOH. Most reference plastics were unaffected, except minor effects for PET and nylon. After sufficient repetitions, cellulosic materials in both reference and marine samples were largely removed. This method was compared to other digestion methods used for microplastic quantification, including single-step oxidation, alkaline treatment, acid treatment and enzymatic treatment. The results indicate that the pre-dissolution step greatly facilitates NOM and cellulosic material digestion for the purpose of microplastic quantification.


The impact of collective efficacy on risks for adolescents' perpetration of dating violence.
Given prevalence rates and negative consequences that adolescents' perpetration of dating violence may have on an individual's well-being and future relationships, it is imperative to explore factors that may increase or reduce its occurrence. Thus, we aimed to identify how multiple contextual risk factors (individual, family, schools, and neighborhoods) were related to adolescents' perpetration of dating violence over a 6 year period. Then, we assessed how neighborhood collective efficacy, an important predictor of urban youths' well-being, buffered the relationship between each of the risk factors and adolescents' perpetration of dating violence. Three waves of data from the Welfare, Children, and Families: A Three-City Study were used (N = 765; Ages 16-20 at Wave 3). The sample is 53 % female, 42 % African-American, and 53 % Hispanic. For the total sample, drug and alcohol use, low parental monitoring, academic difficulties, and involvement with antisocial peers were significant early risk factors for perpetration of dating violence in late adolescence. Risk factors also varied by adolescents' race and sex. Finally, perceived neighborhood collective efficacy buffered the relationship between early academic difficulties and later perpetration of dating violence for Hispanic males. These results imply that multiple systems should be addressed in dating violence prevention programs.


Cerebrovascular Reactivity Measurement Using Magnetic Resonance Imaging: A Systematic Review.
Cerebrovascular reactivity (CVR) magnetic resonance imaging (MRI) probes cerebral haemodynamic changes in response to a vasodilatory stimulus. CVR closely relates to the health of the vasculature and is therefore a key parameter for studying cerebrovascular diseases such as stroke, small vessel disease and dementias. MRI allows in vivo measurement of CVR but several different methods have been presented in the literature, differing in pulse sequence, hardware requirements, stimulus and image processing technique. We systematically reviewed publications measuring CVR using MRI up to June 2020, identifying 235 relevant papers. We summarised the acquisition methods, experimental parameters, hardware and CVR quantification approaches used, clinical populations investigated, and corresponding summary CVR measures. CVR was investigated in many pathologies such as steno-occlusive diseases, dementia and small vessel disease and is generally lower in patients than in healthy controls. Blood oxygen level dependent (BOLD) acquisitions with fixed inspired CO2 gas or end-tidal CO2 forcing stimulus are the most commonly used methods. General linear modelling of the MRI signal with end-tidal CO2 as the regressor is the most frequently used method to compute CVR. Our survey of CVR measurement approaches and applications will help researchers to identify good practice and provide objective information to inform the development of future consensus recommendations.


An unusual case of isolated peritoneal metastases from lung adenocarcinoma.
Peritoneal metastases from lung cancer are a rare event. In this paper, we report the case of a patient with adenocarcinoma of the lungs who had isolated peritoneal metastases at the time of diagnosis. We report a 55-year-old female who presented with shortness of breath, decreased effort tolerance, cough, and weight loss. Her initial chest X-ray and subsequent chest CT showed a 12 × 9 × 8 cm mass in the middle lobe of the right lung. The histopathological examination of her biopsy material was consistent with a thyroid transcription factor-1 positive lung adenocarcinoma. In the abdomen, a 5.3-cm mass was identified. A biopsy and immunohistochemistry revealed a lung adenocarcinoma. The patient was administered chemotherapy based on carboplatin-paclitaxel-bevacizumab, but only with a partial response. Six months later, the patient showed brain metastases. Therefore, a second-line treatment based on pemetrexed was administered for 9 courses, and a clinical and radiological response was observed. The chemotherapy was stopped and the patient did not exhibit any symptoms of progression while waiting for a new evaluation. The incidence of peritoneal involvement of lung cancer without metastases in other parts of the body is scarcely encountered in clinical practice. Out of the different types of lung cancers, adenocarcinoma and large cell carcinoma are most likely to metastasize in the peritoneum. Immunohistochemical staining patterns were important in the differential diagnosis with the other etiologies for peritoneal metastasis and the mesothelioma. Peritoneal metastases are indicative of a disseminated disease and prognosis is extremely poor.


Efficacy of bronchoscopic lung volume reduction: a meta-analysis.
Over the last several years, the morbidity, mortality, and high costs associated with lung volume reduction (LVR) surgery has fuelled the development of different methods for bronchoscopic LVR (BLVR) in patients with emphysema. In this meta-analysis, we sought to study and compare the efficacy of most of these methods. ELIGIBLE STUDIES WERE RETRIEVED FROM PUBMED AND EMBASE FOR THE FOLLOWING BLVR METHODS: one-way valves, sealants (BioLVR), LVR coils, airway bypass stents, and bronchial thermal vapor ablation. Primary study outcomes included the mean change post-intervention in the lung function tests, the 6-minute walk distance, and the St George's Respiratory Questionnaire. Secondary outcomes included treatment-related complications. Except for the airway bypass stents, all other methods of BLVR showed efficacy in primary outcomes. However, in comparison, the BioLVR method showed the most significant findings and was the least associated with major treatment-related complications. For the BioLVR method, the mean change in forced expiratory volume (in first second) was 0.18 L (95% confidence interval [CI]: 0.09 to 0.26; P<0.001); in 6-minute walk distance was 23.98 m (95% CI: 12.08 to 35.88; P<0.01); and in St George's Respiratory Questionnaire was -8.88 points (95% CI: -12.12 to -5.64; P<0.001). The preliminary findings of our meta-analysis signify the importance of most methods of BLVR. The magnitude of the effect on selected primary outcomes shows noninferiority, if not equivalence, when compared to what is known for surgical LVR.


Discrepancies in the portrayal of the COVID-19 vaccine in Chinese and US international media outlets: A corpus-based discursive news values analysis.
This article compares the discursive construction of news values in English news reporting of China Daily and CNN about the COVID-19 vaccine, to reveal how the two media packaged the vaccine and improved the acceptance of the international community towards the vaccines made in the respective countries. Adopting corpus linguistic methods and Discursive news values analysis (DNVA) framework, this study examines news values through keywords, nomination strategies, and photographs. The results show that the two media outlets constructed the news value of Eliteness dominantly through a systematic combination of words and images, albeit in different ways. China Daily prominently consists of references to China's international communications in the production and application of the COVID-19 vaccine, at the same time packaging the COVID-19 vaccine as foreign aid to enhance diplomatic relations as well as protect and promote the order of the international community. In contrast, CNN chiefly demonstrates references to domestic medical experts and the well-known manufacturers of the COVID-19 vaccine, packaging the COVID-19 vaccine as the US' medical/commercial product. The respective ways in which they portray the COVID-19 vaccine have helped to bolster the acceptance of each country's vaccine by the international community.


Late and very late drug-eluting stent malapposition: serial 2-year quantitative IVUS analysis.
The long-term natural history of acquired malapposition continues to be the subject of debate. Using volumetric intravascular ultrasound analyses, we evaluated serial (poststenting, 6-month, and 2-year follow-up) changes in drug-eluting stent-treated vascular segments with acquired malapposition. External elastic membrane, stent, lumen, malapposition, and peristent plaque+media (P+M=external elastic membrane -stent- malapposition) areas were measured; and volumes were calculated and divided by stent length (normalized volume). Among 250 lesions in which complete serial intravascular ultrasound data were available, stent malapposition was identified in 19 lesions (7.6%) at 6 months, and an additional 13 malapposition lesions were newly detected at 2 years (5.2%). Because no malapposition sites resolved, the malapposition rate at 2 years was 12.8%. Malapposition areas and volumes were correlated to the increases in external elastic membrane (positive remodeling) throughout the study period, from immediately after stenting to 6 months and from 6 months to 2 years, both in the group that developed malapposition at 6 months and in the group that developed malapposition at 2 years. Clinical follow-up beyond the 2 year intravascular ultrasound study was done in all patients. Overall, there were 2 cardiac deaths and 1 noncardiac death. Two patients presented with acute myocardial infarction associated with very late stent thrombosis (1 definite stent thrombosis, 1 probable stent thrombosis). Three patients underwent repeat revascularization owing to in-stent restenosis developed after the 2-year follow-up. Expansive vascular remodeling may play a role in the development and dynamic progression of acquired drug-eluting stent malapposition, not only during the first 6 months after implantation but thereafter.


TRIP-1 regulates TGF-β1-induced epithelial-mesenchymal transition of human lung epithelial cell line A549.
Epithelial-mesenchymal transition (EMT) is a process by which epithelial cells undergo conversion to a mesenchymal phenotype contributing to wound repair by fibrosis and to cancer cell acquisition of invasive ability. Recently, we showed that type II TGF-β receptor interacting protein-1 (TRIP-1), a protein identified as a phosphorylation target of the TGF-β type II receptor kinase and as a functional component of eukaryotic translation initiator factor 3 (eiF3) multiprotein complex, is a novel modulator of fibroblast collagen contraction, an important step in wound repair stimulated by TGF-β1 action. TGF-β1 drives EMT, but it is not known whether TRIP-1 expression influences EMT induction. To investigate whether TRIP-1 plays a role in EMT induction we studied the effect of downregulating TRIP-1 expression in the well-characterized A549 model of TGF-β1 induction of EMT. Here we report that short hairpin RNA (shRNA)-mediated depletion of TRIP-1 gene transcripts in A549 cells promotes EMT as assessed by changes in phenotypic markers, morphology, and migrative ability. Knockdown of TRIP-1 dramatically increased A549 responsiveness to TGF-β1 induction of EMT. Mechanistically, a pathway involving increased TGF-β type II receptor level, enhanced Smad3 phosphorylation, and the transcription factor SLUG is implicated. Altogether, the findings point to regulation of endogenous TRIP-1 protein expression as a potential strategy to target EMT, and related invasive behavior, in cancer cells.


Intermittent Aeration Suppresses Nitrite-Oxidizing Bacteria in Membrane-Aerated Biofilms: A Model-Based Explanation.
Autotrophic ammonium oxidation in membrane-aerated biofilm reactors (MABRs) can make treatment of ammonium-rich wastewaters more energy-efficient, especially within the context of short-cut ammonium removal. The challenge is to exclusively enrich ammonium-oxidizing bacteria (AOB). To achieve nitritation, strategies to suppress nitrite-oxidizing bacteria (NOB) are needed, which are ideally grounded on an understanding of underlying mechanisms. In this study, a nitrifying MABR was operated under intermittent aeration. During eight months of operation, AOB dominated, while NOB were suppressed. On the basis of dissolved oxygen (DO), ammonium, nitrite, and nitrate profiles within the biofilm and in the bulk, a 1-dimensional nitrifying biofilm model was developed and calibrated. The model was utilized to explore the potential mechanisms of NOB suppression associated with intermittent aeration, considering DO limitation, direct pH effects on enzymatic activities, and indirect pH effects on activity via substrate speciation. The model predicted strong periodic shifts in the spatial gradients of DO, pH, free ammonia, and free nitrous acid, associated with aerated and nonaerated phases. NOB suppression during intermittent aeration was mostly explained by periodic inhibition caused by free ammonia due to periodic transient pH upshifts. Dissolved oxygen limitation did not govern NOB suppression. Different intermittent aeration strategies were then evaluated for nitritation success in intermittently aerated MABRs: both aeration intermittency and duration were effective control parameters.


The effect of visual cues on scoring of clinical word-recognition tests.
During routine clinical speech assessment, if the person being tested were to write down what he or she heard, it would not always match what the audiologist heard while scoring the listener's vocal responses (Nelson & Chaiklin, 1970). This study demonstrated a method to assess examiner accuracy and whether speechreading cues reduce writedown-talkback errors. Examiners were divided into 3 categories: normal hearing native speakers of English, normal hearing nonnative speakers of English, and native speakers with hearing loss. Each examiner assessed 4 normal-hearing listeners. Two NU-6 lists were presented to each listener; one was scored without visual cues and one with visual cues. Lists were presented at 50 dB HL in the presence of speech noise at 0 dB signal-to-noise ratio (SNR). Results analyzed by percentage of correct phonemes and words revealed fewer writedown-talkback discrepancies for all 3 examiner groups when visual cues were added, with a substantial improvement for examiners with hearing loss. The finding of errors between talkback versus writedown scoring of lists for all of the examiners, even with visual cues, suggests a need for modification of the clinical word-recognition procedure for applications that potentially affect diagnosis, rehabilitation choices, or financial compensation.


More Than a Tick Box: Medical Checklist Development, Design, and Use.
Despite improving patient safety in some perioperative settings, some checklists are not living up to their potential and complaints of "checklist fatigue" and outright rejection of checklists are growing. Problems reported often concern human factors: poor design, inadequate introduction and training, duplication with other safety checks, poor integration with existing workflow, and cultural barriers. Each medical setting-such as an operating room or a critical care unit-and different clinical needs-such as a shift handover or critical event response-require a different checklist design. One size will not fit all, and checklists must be built around the structure of medical teams and the flow of their work in those settings. Useful guidance can be found in the literature; however, to date, no integrated and comprehensive framework exists to guide development and design of checklists to be effective and harmonious with the flow of medical and perioperative tasks. We propose such a framework organized around the 5 stages of the checklist life cycle: (1) conception, (2) determination of content and design, (3) testing and validation, (4) induction, training, and implementation, and (5) ongoing evaluation, revision, and possible retirement. We also illustrate one way in which the design of checklists can better match user needs in specific perioperative settings (in this case, the operating room during critical events). Medical checklists will only live up to their potential to improve the quality of patient care if their development is improved and their designs are tailored to the specific needs of the users and the environments in which they are used.


Fluor-18-fluorodeoxyglucose positron emission tomography (FDG-PET) in malignant melanoma. Diagnostic comparison with conventional imaging methods.
To assess the diagnostic value of fluor-18-fluorodeoxyglucose positron emission tomography (FDG-PET) in screening for melanoma metastases. The case records of 94 melanoma patients who had been examined by whole-body FDG-PET between 1995 and 1999 were evaluated retrospectively. Forty patients showed evidence of lymphogenous and 42 of hematogenous metastasis. The maximal interval between PET and the diagnostic procedure under comparison was 2 weeks. Confirmation of the findings was based on histology or the clinical or radiological course. In 24 patients, all diagnostic examinations including CT had been performed within 2 weeks from PET. In no case did PET change the staging. In 13 patients, PET agreed with morphological diagnosis in the number of metastatically invaded organs. This included 3 patients without metastases. The estimated number of organs invaded by metastases was higher with PET in 5 patients and higher with morphological imaging techniques in 6 patients. Among the PET findings with higher or equivocal counts of organs with metastases there were 2 confirmed false-positive findings. In a selected patient population, FDG-PET was found to be inferior to CT for diagnosing lung and liver metastases. The supplementary use of FDG-PET is not generally of value once metastasis has been established.


Belowground Chemical Interactions: An Insight Into Host-Specific Behavior of Globodera spp. Hatched in Root Exudates From Potato and Its Wild Relative, Solanum sisymbriifolium.
Understanding belowground chemical interactions between plant roots and plant-parasitic nematodes is immensely important for sustainable crop production and soilborne pest management. Due to metabolic diversity and ever-changing dynamics of root exudate composition, the impact of only certain molecules, such as nematode hatching factors, repellents, and attractants, has been examined in detail. Root exudates are a rich source of biologically active compounds, which plants use to shape their ecological interactions. However, the impact of these compounds on nematode parasitic behavior is poorly understood. In this study, we specifically address this knowledge gap in two cyst nematodes, Globodera pallida, a potato cyst nematode and the newly described species, Globodera ellingtonae. Globodera pallida is a devastating pest of potato (Solanum tuberosum) worldwide, whereas potato is a host for G. ellingtonae, but its pathogenicity remains to be determined. We compared the behavior of juveniles (J2s) hatched in response to root exudates from a susceptible potato cv. Desirée, a resistant potato cv. Innovator, and an immune trap crop Solanum sisymbriifolium (litchi tomato - a wild potato relative). Root secretions from S. sisymbriifolium greatly reduced the infection rate on a susceptible host for both Globodera spp. Juvenile motility was also significantly influenced in a host-dependent manner. However, reproduction on a susceptible host from juveniles hatched in S. sisymbriifolium root exudates was not affected, nor was the number of encysted eggs from progeny cysts. Transcriptome analysis by using RNA-sequencing (RNA-seq) revealed the molecular basis of root exudate-mediated modulation of nematode behavior. Differentially expressed genes are grouped into two major categories: genes showing characteristics of effectors and genes involved in stress responses and xenobiotic metabolism. To our knowledge, this is the first study that shows genome-wide root exudate-specific transcriptional changes in hatched preparasitic juveniles of plant-parasitic nematodes. This research provides a better understanding of the correlation between exudates from different plants and their impact on nematode behavior prior to the root invasion and supports the hypothesis that root exudates play an important role in plant-nematode interactions.


No evidence that economic inequality moderates the effect of income on generosity.
A landmark study published in PNAS [Côté S, House J, Willer R (2015) Proc Natl Acad Sci USA 112:15838-15843] showed that higher income individuals are less generous than poorer individuals only if they reside in a US state with comparatively large economic inequality. This finding might serve to reconcile inconsistent findings on the effect of social class on generosity by highlighting the moderating role of economic inequality. On the basis of the importance of replicating a major finding before readily accepting it as evidence, we analyzed the effect of the interaction between income and inequality on generosity in three large representative datasets. We analyzed the donating behavior of 27,714 US households (study 1), the generosity of 1,334 German individuals in an economic game (study 2), and volunteering to participate in charitable activities in 30,985 participants from 30 countries (study 3). We found no evidence for the postulated moderation effect in any study. This result is especially remarkable because (i) our samples were very large, leading to high power to detect effects that exist, and (ii) the cross-country analysis employed in study 3 led to much greater variability in economic inequality. These findings indicate that the moderation effect might be rather specific and cannot be easily generalized. Consequently, economic inequality might not be a plausible explanation for the heterogeneous results on the effect of social class on prosociality.


Effect of methanol on the activity and conformation of acid phosphatase from the prawn Penaeus penicillatus.
Prawn (Penaeus penicillatus) acid phosphatase (EC 126.96.36.199) catalyzes the nonspecific hydrolysis of phosphate monoesters. The effects of some pollutants in sea water on the enzyme activity results in the loss of the biological function of the enzyme, which leads to disruption of phosphate metabolism in cells. This paper analyzes the effects of methanol on the activity and conformation of prawn acid phosphatase. The results show that low concentrations of methanol can lead to reversible inactivation. Inhibition of the enzyme by methanol is classified as non-competitive inhibition, and the inhibition constant (Ki) is 8.5%. Conformational changes of the enzyme molecule in methanol solutions of different concentrations were measured using fluorescence emission, differential UV-absorption, and circular dichroism spectra. Increased methanol concentrations caused the fluorescence emission intensity of the enzyme to increase. The ultraviolet difference spectra of the enzyme denatured with methanol had two negative peaks, at 222 and 270 nm, and a positive peak at 236 nm. The changes in the fluorescence and ultraviolet difference spectra reflected the changes of the microenvironments of tryptophan and tyrosine residues of the enzyme. The CD spectrum changes of the enzyme show that the secondary structure of the enzyme also changed some. These results suggest that methanol is a non-competitive inhibitor and the conformational integrity of the enzyme is essential for its activity.


A drop in Sahara dust fluxes records the northern limits of the African Humid Period.
Northern and eastern Africa were exposed to significantly wetter conditions relative to present during the early Holocene period known as the African Humid Period (AHP), although the latitudinal extent of the northward expansion of the tropical rain belt remains poorly constrained. New records of 230Thxs-normalized accumulation rates in marine sediment cores from the Red Sea and Gulf of Aden are combined with existing records of western Africa dust and terrestrial records across the Sahara Desert, revealing that fluxes of dust transported east from the Sahara decreased by at least 50% during the AHP, due to the development of wetter conditions as far north as ~22°N. These results provide the first quantitative record of sediment and dust accumulation rates in the Red Sea and the Gulf of Aden over the past 20 kyrs and challenge the paradigm of vast vegetative cover across the north and northeastern Sahara Desert during the AHP.


The comprehensive burn unit.
A burn unit is only as good as its staff. Trained, experienced nurses, therapists and surgeons accustomed to dealing with large open wounds are a major requisite for the care of burned patients, who have a multisystem disease. Equipment needs include monitors, hydrotherapy tank, ready access to the operating room and comprehensive rehabilitation facilities. Skilled anesthesia, consultative support in nephrology, respirology, pediatrics and infectious diseases, a blood bank, access to human allograft and good microbiology support are necessary. Ventilatory support for associated smoke inhalation injury may be provided on the unit or in a separate ventilatory intensive care unit with isolation capability. In 1982, 29.9 Canadians per 100 000 were hospitalized for burn care (approximately 20% to 25% in burn units). Burn care requires a high staff-to-patient ratio and a hospital budget to support this is mandatory.


Creatine deficiency syndromes and the importance of creatine synthesis in the brain.
Creatine deficiency syndromes, due to deficiencies in AGAT, GAMT (creatine synthesis pathway) or SLC6A8 (creatine transporter), lead to complete absence or very strong decrease of creatine in CNS as measured by magnetic resonance spectroscopy. Brain is the main organ affected in creatine-deficient patients, who show severe neurodevelopmental delay and present neurological symptoms in early infancy. AGAT- and GAMT-deficient patients can be treated by oral creatine supplementation which improves their neurological status, while this treatment is inefficient on SLC6A8-deficient patients. While it has long been thought that most, if not all, of brain creatine was of peripheral origin, the past years have brought evidence that creatine can cross blood-brain barrier, however, only with poor efficiency, and that CNS must ensure parts of its creatine needs by its own endogenous synthesis. Moreover, we showed very recently that in many brain structures, including cortex and basal ganglia, AGAT and GAMT, while found in every brain cell types, are not co-expressed but are rather expressed in a dissociated way. This suggests that to allow creatine synthesis in these structures, guanidinoacetate must be transported from AGAT- to GAMT-expressing cells, most probably through SLC6A8. This new understanding of creatine metabolism and transport in CNS will not only allow a better comprehension of brain consequences of creatine deficiency syndromes, but will also contribute to better decipher creatine roles in CNS, not only in energy as ATP regeneration and buffering, but also in its recently suggested functions as neurotransmitter or osmolyte.


Guidance for the Clinical Management of Impacted Maxillary Canines.
In this study of orthodontic and surgical management of impacted maxillary canines, the current literature is reviewed and a decision tree is presented to assist clinicians in determining the optimal treatment based on available evidence. Impacted canines have a prevalence of 2% and are more common in females. Palatal impactions are present in around 75% of cases. These trends are observed worldwide with small variations in different populations. Diagnosis through clinical examination and conventional imaging can be complemented with cone-beam computed tomography imaging when necessary. Early intervention by extraction of deciduous canines is indicated when the canine is impacted in sectors 2 or 3 and has an angle of 20 to 30 degrees in relation to the vertical line. Other early management approaches involve rapid palatal expansion or distalization of posterior teeth, when possible. Surgical orthodontic treatment is required when early intervention is unsuccessful. For buccal impactions, the canine position relative to the mucogingival junction determines the choice of surgical procedure; for palatal impactions, the open surgical procedure seems to be preferred. In some situations, however, a closed eruption has precise indications. Use of efficient orthodontic mechanics reduces treatment complications and may be complemented with the use of nitinol piggybacks, swinging gates, modified transpalatal arches, and temporary anchorage devices. Frequent complications with impactions include canine ankylosis, root resorption of the neighboring lateral or central incisor, and gingival esthetic differences between the impacted canine and the contralateral canine upon treatment completion.


Evaluation of Prenatal Exposure to Bisphenol Analogues on Development and Long-Term Health of the Mammary Gland in Female Mice.
Continued efforts to phase out bisphenol A (BPA) from consumer products have been met with the challenges of finding safer alternatives. This study aimed to determine whether early-life exposure to BPA and its related analogues, bisphenol AF (BPAF) and bisphenol S (BPS), could affect female pubertal mammary gland development and long-term mammary health in mice. Timed pregnant CD-1 mice were exposed to vehicle, BPA (0.5, 5, 50 mg/kg), BPAF (0.05, 0.5, 5 mg/kg), or BPS (0.05, 0.5, 5 mg/kg) via oral gavage between gestation days 10–17. Mammary glands were collected from resulting female offspring at postnatal day (PND) 20, 28, 35, and 56, and at 3, 8, and 14 months for whole mount, histopathological evaluation, and quantitative real-time polymerase chain reaction (qPCR); serum steroid concentrations were also measured at these time points. In the bisphenol-exposed mice, accelerated mammary gland development was evident during early puberty and persisted into adulthood. By late adulthood, mammary glands from bisphenol-exposed female offspring exhibited adverse morphology in comparison with controls; most prominent were undifferentiated duct ends, significantly more lobuloalveolar hyperplasia and perivascular inflammation, and various tumors, including adenocarcinomas. Effects were especially prominent in the BPAF 5 mg/kg and BPS 0.5 mg/kg groups. Serum steroid concentrations and mammary mRNA levels of Esr1, Pgr, Ar, and Gper1 were similar to controls. These data demonstrate that prenatal exposure of mice to BPAF or BPS induced precocious development of the mammary gland, and that siblings were significantly more susceptible to spontaneous preneoplastic epithelial lesions and inflammation, with an incidence greater than that observed in vehicle- and BPA-exposed animals. https://doi.org/10.1289/EHP3189.


Analysis of cell viability in intervertebral disc: Effect of endplate permeability on cell population.
Responsible for making and maintaining the extracellular matrix, the cells of intervertebral discs are supplied with essential nutrients by diffusion from the blood supply through mainly the cartilaginous endplates (CEPs) and disc tissue. Decrease in transport rate and increase in cellular activity may adversely disturb the intricate supply-demand balance leading ultimately to cell death and disc degeneration. The present numerical study aimed to introduce for the first time cell viability criteria into nonlinear coupled nutrition transport equations thereby evaluating the dynamic nutritional processes governing viable cell population and concentrations of oxygen, glucose and lactic acid in the disc as CEP exchange area dropped from a fully permeable condition to an almost impermeable one. A uniaxial model of an in vitro cell culture analogue of the disc is first employed to examine and validate cell viability criteria. An axisymmetric model of the disc with four distinct regions was subsequently used to investigate the survival of cells at different CEP exchange areas. In agreement with measurements, predictions of the diffusion chamber model demonstrated substantial cell death as essential nutrient concentrations fell to levels too low to support cells. Cells died away from the nutrient supply and at higher cell densities. In the disc model, the nucleus region being farthest away from supply sources was most affected; cell death initiated first as CEP exchange area dropped below approximately 40% and continued exponentially thereafter to depletion as CEP calcified further. In cases with loss of endplate permeability and/or disruptions therein, as well as changes in geometry and fall in diffusivity associated with fluid outflow, the nutrient concentrations could fall to levels inadequate to maintain cellular activity or viability, resulting in cell death and disc degeneration.


[Morphological characteristics of Peyronie's disease].
Morphological examinations of 40 operation preparations in Peyronie's disease were done by light and electron microscopy. The studies showed the main changes in this disease to localize in tunica albuginea which thickens considerably forming a plaque. The latter presents bundles of thickened collagen fibers with altered fibroblasts and perivascular round-cell infiltrates. Sometimes areas of formation of cartilage and bone tissue were found. The combination of Peyronie's disease with Dupuytren's contracture was confirmed.


You look familiar, but I don't care: Lure rejection in hybrid visual and memory search is not based on familiarity.
In "hybrid" search tasks, observers hold multiple possible targets in memory while searching for those targets among distractor items in visual displays. Wolfe (2012) found that, if the target set is held constant over a block of trials, reaction times (RTs) in such tasks were a linear function of the number of items in the visual display and a linear function of the log of the number of items held in memory. However, in such tasks, the targets can become far more familiar than the distractors. Does this "familiarity"- operationalized here as the frequency and recency with which an item has appeared-influence performance in hybrid tasks In Experiment 1, we compared searches where distractors appeared with the same frequency as the targets to searches where all distractors were novel. Distractor familiarity did not have any reliable effect on search. In Experiment 2, most distractors were novel but some critical distractors were as common as the targets while others were 4× more common. Familiar distractors did not produce false alarm errors, though they did slightly increase RTs. In Experiment 3, observers successfully searched for the new, unfamiliar item among distractors that, in many cases, had been seen only once before. We conclude that when the memory set is held constant for many trials, item familiarity alone does not cause observers to mistakenly confuse target with distractors.


Nanoparticle-mediated gene therapy strategies for mitigating inflammatory bowel disease.
Inflammatory bowel disease (IBD) is an autoimmune disorder of the gastrointestinal tract (GIT) where Ulcerative Colitis (UC) displays localized inflammation in the colon, and Crohn's Disease (CD) affects the entire GIT. Failure of current therapies and associated side-effects bring forth serious social, economic, and health challenges. The gut epithelium provides the best target for gene therapy delivery vehicles to combat IBD. Gene therapy involving the use of nucleic acid (NA) therapeutics faces major challenges due to the hydrophilic, negative-charge, and degradable nature of NAs. Recent success in the engineering of biomaterials for gene therapy and their emergence in clinical trials for various diseases is an inspiration for scientists to develop gene therapy vehicles that can be easily targeted to the desired tissues for IBD. Advances in nanotechnology have enabled the formulations of numerous nanoparticles for NA delivery to mitigate IBD that still faces challenges of stability in the GIT, poor therapeutic efficacy, and targetability. This review presents the challenges of gene therapeutics, gastrointestinal barriers, and recent advances in the engineering of nanoparticles for IBD treatment along with future directions for successful translation of nanoparticle-mediated gene therapeutics in clinics.


Peroxisome proliferator-activated receptor gamma activators downregulate angiotensin II type 1 receptor in vascular smooth muscle cells.
Peroxisome proliferator-activated receptor gamma (PPARgamma) activators, such as troglitazone (Tro), not only improve insulin resistance but also suppress the neointimal formation after balloon injury. However, the precise mechanisms have not been determined. Angiotensin II (Ang II) plays crucial roles in the pathogenesis of atherosclerosis, hypertension, and neointimal formation after angioplasty. We examined the effect of PPARgamma activators on the expression of Ang II type 1 receptor (AT(1)-R) in cultured vascular smooth muscle cells (VSMCs). AT(1)-R mRNA and AT(1)-R protein levels were determined by Northern blot analysis and radioligand binding assay, respectively. Natural PPARgamma ligand 15-deoxy-Delta(12,14)-prostaglandin J(2), as well as Tro, reduced the AT(1)-R mRNA expression and the AT(1)-R protein level. The PPARgamma activators also reduced the calcium response of VSMCs to Ang II. PPARgamma activators suppressed the AT(1)-R promoter activity measured by luciferase assay but did not affect the AT(1)-R mRNA stability, suggesting that the suppression occurs at the transcriptional level. PPARgamma activators reduced the AT(1)-R expression and calcium response to Ang II in VSMCs. Downregulation of AT(1)-R may contribute to the inhibition of neointimal formation by PPARgamma activators.


Dystonia.
Dystonia is a neurological condition characterized by abnormal involuntary movements or postures owing to sustained or intermittent muscle contractions. Dystonia can be the manifesting neurological sign of many disorders, either in isolation (isolated dystonia) or with additional signs (combined dystonia). The main focus of this Primer is forms of isolated dystonia of idiopathic or genetic aetiology. These disorders differ in manifestations and severity but can affect all age groups and lead to substantial disability and impaired quality of life. The discovery of genes underlying the mendelian forms of isolated or combined dystonia has led to a better understanding of its pathophysiology. In some of the most common genetic dystonias, such as those caused by TOR1A, THAP1, GCH1 and KMT2B mutations, and idiopathic dystonia, these mechanisms include abnormalities in transcriptional regulation, striatal dopaminergic signalling and synaptic plasticity and a loss of inhibition at neuronal circuits. The diagnosis of dystonia is largely based on clinical signs, and the diagnosis and aetiological definition of this disorder remain a challenge. Effective symptomatic treatments with pharmacological therapy (anticholinergics), intramuscular botulinum toxin injection and deep brain stimulation are available; however, future research will hopefully lead to reliable biomarkers, better treatments and cure of this disorder.


Diversity of Expression Types of Ht Genes Conferring Resistance in Maize to Exserohilum turcicum.
Northern corn leaf blight (NCLB) is an important leaf disease in maize (Zea mays) worldwide and is spreading into new areas with expanding maize cultivation, like Germany. Exserohilum turcicum, causal agent of NCLB, infects and colonizes leaf tissue and induces elongated necrotic lesions. Disease control is based on fungicide application and resistant cultivars displaying monogenic resistance. Symptom expression and resistance mechanisms differ in plants carrying different resistance genes. Therefore, histological studies and DNA quantification were performed to compare the pathogenesis of E. turcicum races in maize lines exhibiting compatible or incompatible interactions. Maize plants from the differential line B37 with and without resistance genes Ht1, Ht2, Ht3, and Htn1 were inoculated with either incompatible or compatible races (race 0, race 1 and race 23N) of E. turcicum. Leaf segments from healthy and inoculated plants were collected at five different stages of infection and disease development from penetration (0-1 days post inoculation - dpi), until full symptom expression (14-18 dpi). Symptoms of resistance responses conveyed by the different Ht genes considerably differed between Ht1 (necrotic lesions with chlorosis), Ht2 (chlorosis and small lesions), Ht3 (chlorotic spots) and Htn1 (no lesions or wilt-type lesions). In incompatible interactions, fungal DNA was only detected in very low amounts. At 10 dpi, DNA content was elevated in all compatible interactions. Histological studies with Chlorazol Black E staining indicated that E. turcicum formed appressoria and penetrated the leaf surface directly in both types of interaction. In contrast to incompatible interactions, however, the pathogen was able to penetrate into xylem vessels at 6 dpi in compatible interactions and strongly colonized the mesophyll at 12 dpi, which is considered the crucial process differentiating susceptible from resistant interactions. Following the distinct symptom expressions, resistance mechanisms conferred by Ht1, Ht2, Ht3, and Htn1 genes apparently are different. Lower disease levels and a delayed progress of infection in compatible interactions with resistant lines imply that maize R genes to E. turcicum are associated with or confer additional quantitative resistance.


[Rupture of the thoracic esophagus by compressed air].
A case of rupture of the oesophagus due to the accidental passage of compressed air through the mouth is reported. Two longitudinal lacerations were present in the thoracic oesophagus; they were treated by radical oesophagectomy cervical oesophagostomy and gastrostomy for feeding. Reconstruction was made by retrosternal coloplasty. The course of the patient was uneventful.


RNA Sequencing Provides Insights into the Regulation of Solanesol Biosynthesis in Nicotiana tabacum Induced by Moderately High Temperature.
Solanesol is a terpene alcohol composed of nine isoprene units that mainly accumulates in solanaceous plants, especially tobacco (Nicotiana tabacum). The present study aimed to investigate the regulation of solanesol accumulation in tobacco leaves induced by moderately high temperature (MHT). Exposure to MHT resulted in a significant increase in solanesol content, dry weight, and net photosynthetic rate in tobacco leaves. In MHT-exposed tobacco leaves, 492 and 1440 genes were significantly up- and downregulated, respectively, as revealed by RNA-sequencing. Functional enrichment analysis revealed that most of the differentially expressed genes (DEGs) were mainly related to secondary metabolite biosynthesis, metabolic pathway, carbohydrate metabolism, lipid metabolism, hydrolase activity, catalytic activity, and oxidation-reduction process. Moreover, 122 transcription factors of DEGs were divided into 22 families. Significant upregulation of N. tabacum 3-hydroxy-3-methylglutaryl-CoA reductase (NtHMGR), 1-deoxy-d-xylulose 5-phosphate reductoisomerase (NtDXR), geranylgeranyl diphosphate synthase (NtGGPS), and solanesyl diphosphate synthase (NtSPS) and significant downregulation of N. tabacum 1-deoxy-d-xylulose 5-phosphate synthase (NtDXS) and farnesyl diphosphate synthase (NtFPS) transcription upon MHT exposure were monitored by quantitative real-time PCR (qRT-PCR). This study indicated that solanesol accumulation in tobacco leaves can be manipulated through regulation of the environmental temperature and established a basis for further elucidation of the molecular mechanism of temperature regulation of solanesol accumulation.


[Acoustic evoked potentials and topical diagnosis in the central nervous system].
Acoustic stimulation evokes about 15 waves, the so-called auditory evoked potentials (AEP). According to their appearance in time there are three groups: early auditory evoked potentials, middle latency AEP and late latency AEP. The shorter the latency of a wave, the more precise the coordination to a definable structure in the CNS. Therefore only EAEP allow besides an evaluation of hearing threshold a differential diagnosis between peripheral, neural and central hearing disturbances. Still unclear are questions such as exact origin of waves II to V and the difference of response due to rarefaction and condensation stimuli. The test, however, is a sensitive indicator to evaluate hearing disturbances and brainstem disorders.


Characterization of a proteasome and TAP-independent presentation of intracellular epitopes by HLA-B27 molecules.
Nascent HLA-class I molecules are stabilized by proteasome-derived peptides in the ER and the new complexes proceed to the cell surface through the post-ER vesicles. It has been shown, however, that less stable complexes can exchange peptides in the Trans Golgi Network (TGN). HLA-B27 are the most studied HLA-class I molecules due to their association with Ankylosing Spondylitis (AS). Chimeric proteins driven by TAT of HIV have been exploited by us to deliver viral epitopes, whose cross-presentation by the HLA-B27 molecules was proteasome and TAP-independent and not restricted to Antigen-Presenting Cells (APC). Here, using these chimeric proteins as epitope suppliers, we compared with each other and with the HLA-A2 molecules, the two HLA-B*2705 and B*2709 alleles differing at residue 116 (D116H) and differentially associated with AS. We found that the antigen presentation by the two HLA-B27 molecules was proteasome-, TAP-, and APC-independent whereas the presentation by the HLA-A2 molecules required proteasome, TAP and professional APC. Assuming that such difference could be due to the unpaired, highly reactive Cys-67 distinguishing the HLA-B27 molecules, C67S mutants in HLA-B*2705 and B*2709 and V67C mutant in HLA-A*0201 were also analyzed. The results showed that this mutation did not influence the HLA-A2-restricted antigen presentation while it drastically affected the HLA-B27-restricted presentation with, however, remarkable differences between B*2705 and B*2709. The data, together with the occurrence on the cell surface of unfolded molecules in the case of C67S-B*2705 mutant but not in that of C67S-B*2709 mutant, indicates that Cys-67 has a more critical role in stabilizing the B*2705 rather than the B*2709 complexes.


Diabetes Study of Children of Diverse Ethnicity and Race: Study design.
Determining diabetes type in children has become increasingly difficult due to an overlap in typical characteristics between type 1 diabetes (T1D) and type 2 diabetes (T2D). The Diabetes Study in Children of Diverse Ethnicity and Race (DISCOVER) programme is a National Institutes of Health (NIH)-supported multicenter, prospective, observational study that enrols children and adolescents with non-secondary diabetes. The primary aim of the study was to develop improved models to differentiate between T1D and T2D in diverse youth. The proposed models will evaluate the utility of three existing T1D genetic risk scores in combination with data on islet autoantibodies and other parameters typically available at the time of diabetes onset. Low non-fasting serum C-peptide (<0.6 nmol/L) between 3 and 10 years after diabetes diagnosis will be considered a biomarker for T1D as it reflects the loss of insulin secretion ability. Participating centres are enrolling youth (<19 years old) either with established diabetes (duration 3-10 years) for a cross-sectional evaluation or with recent onset diabetes (duration 3 weeks-15 months) for the longitudinal observation with annual visits for 3 years. Cross-sectional data will be used to develop models. Longitudinal data will be used to externally validate the best-fitting model. The results are expected to improve the ability to classify diabetes type in a large and growing subset of children who have an unclear form of diabetes at diagnosis. Accurate and timely classification of diabetes type will help establish the correct clinical management early in the course of the disease.


Outcomes of ambulatory rehabilitation programmes following botulinum toxin for spasticity in adults with stroke.
To examine the benefits of high intensity ambulatory rehabilitation programmes over usual care following botulinum toxin A (BoNT-A) for post-stroke spasticity in Australian adults. Prospective single centre, controlled clinical trial. Fifty-nine adults, median 61 years old and 2.5 years following stroke. PARTICIPANTS were dichotomised into high intensity ambulatory rehabilitation programmes (≥ 3 × 1-h weekly sessions for approximately 10 weeks) or usual care programmes (≤ 2 × 1-h weekly sessions) following BoNT-A injections for spasticity. A blinded assessor completed outcomes at 0 (baseline), 6, 12 and 24 weeks. Primary endpoints: proportion of participants achieving ≥ 50% of their goals (using Goal Attainment Scaling: GAS) and GAS T-score change at 12 weeks. Modified Ashworth Scale (MAS), participant satisfaction, activity/participation measures and caregiver burden. Both groups showed significant improvement in goal attainment and participant satisfaction up to 24 weeks, with no overall between-group significant differences. There was, however, a statistical trend (p = 0.052) for participants to achieve more upper limb goals in the high intensity therapy group. GAS and satisfaction benefits persisted beyond the duration of spasticity reduction as measured by MAS. While patient-centred outcomes following BoNT-A injections for post-stroke spasticity were not influenced by intensity of ambulatory rehabilitation programmes, there was a trend for high intensity therapy to be associated with greater upper limb goal attainment. This suggests that the effects of more intensive therapy may be a modifier of the 'black box' of rehabilitation; however, further research is required to evaluate this effect and determine which elements of therapy programmes optimise post-BoNT-A outcomes.


Anaplastic Thyroid Carcinoma: A ceRNA Analysis Pointed to a Crosstalk between SOX2, TP53, and microRNA Biogenesis.
It has been suggested that cancer stem cells (CSC) may play a central role in oncogenesis, especially in undifferentiated tumours. Anaplastic thyroid carcinoma (ATC) has characteristics suggestive of a tumour enriched in CSC. Previous studies suggested that the stem cell factor SOX2 has a preeminent hierarchical role in determining the characteristics of stem cells in SW1736 ATC cell line. In detail, silencing SOX2 in SW1736 is able to suppress the expression of the stem markers analysed, strongly sensitizing the line to treatment with chemotherapeutic agents. Therefore, in order to further investigate the role of SOX2 in ATC, a competing endogenous RNA (ceRNA) analysis was conducted in order to isolate new functional partners of SOX2. Among the interactors, of particular interest are genes involved in the biogenesis of miRNAs (DICER1, RNASEN, and EIF2C2), in the control cell cycle (TP53, CCND1), and in mitochondrial activity (COX8A). The data suggest that stemness, microRNA biogenesis and functions, p53 regulatory network, cyclin D1, and cell cycle control, together with mitochondrial activity, might be coregulated.


[Dietary habits and food consumption in Spanish children and adolescents (1998-2000): socioeconomic and demographic factors].
Although children and adolescents have special nutritional requirements due to their physical development, little is known about the concept of a healthy diet. This study shows the food consumption of the Spanish population aged 2-24 years in relation to socio-economic and geographic factors. A representative sample of the Spanish population (n = 3.534 individuals, 1.905 female and 1.629 male) was studied. Both a 24-hours recall and a general questionnaire with socio-economic, demographic and life style items were administered. Most individuals consumed meals at home. The consumption of vegetables (90.4 g), cereals (181.1 g) and potatoes (69.7 g) was low, the consumption of red meat (71.6 g) and sausages (46.8 g) was high, and fish consumption was low (47.7 g). Girls had insufficient intakes of milk (280.9 g). We noticed geographical differences in food consumption which may be reflected in various health outcomes in adulthood. The familiar socioeconomic status and the educational level of the mother showed some influence on the intakes of meat, fish, fruits and vegetables, yoghurt and cheese. Nutritional education programs are needed to settle the observed nutritional inadequacies in the food habits of Spanish children and adolescents so that the future health of the population improves. It is also needed to reduce the inequalities linked to geographic and socio-economic factors.


[A Case of Advanced Gastric Cancer with Portosystemic Shunt Successfully Treated with Percutaneous Transvenous Coil Embolization].
A 57-year-old man with advanced gastric cancer and multiple liver metastases was referred to our hospital. He underwent a palliative gastrectomy to treat hemorrhage, and S-1 and cisplatin therapy was administered. After 7 courses of chemotherapy, a new liver metastatic lesion and a tumor thrombus in the right portal vein appeared. Moreover, the serum level of ammonia was elevated(296 mg/dL)following a consciousness disorder. Enhanced CT revealed an inferior mesenteric vein to left renal vein shunt, which led to the diagnosis of portal systemic encephalopathy due to portosystemic shunt. Percutaneous transvenous coil embolization was performed. The serum ammonia level decreased, and the encephalopathy disappeared. As a result, he was able to continue chemotherapy.


Repurposing Modular Polyketide Synthases and Non-ribosomal Peptide Synthetases for Novel Chemical Biosynthesis.
In nature, various enzymes govern diverse biochemical reactions through their specific three-dimensional structures, which have been harnessed to produce many useful bioactive compounds including clinical agents and commodity chemicals. Polyketide synthases (PKSs) and non-ribosomal peptide synthetases (NRPSs) are particularly unique multifunctional enzymes that display modular organization. Individual modules incorporate their own specific substrates and collaborate to assemble complex polyketides or non-ribosomal polypeptides in a linear fashion. Due to the modular properties of PKSs and NRPSs, they have been attractive rational engineering targets for novel chemical production through the predictable modification of each moiety of the complex chemical through engineering of the cognate module. Thus, individual reactions of each module could be separated as a retro-biosynthetic biopart and repurposed to new biosynthetic pathways for the production of biofuels or commodity chemicals. Despite these potentials, repurposing attempts have often failed owing to impaired catalytic activity or the production of unintended products due to incompatible protein-protein interactions between the modules and structural perturbation of the enzyme. Recent advances in the structural, computational, and synthetic tools provide more opportunities for successful repurposing. In this review, we focused on the representative strategies and examples for the repurposing of modular PKSs and NRPSs, along with their advantages and current limitations. Thereafter, synthetic biology tools and perspectives were suggested for potential further advancement, including the rational and large-scale high-throughput approaches. Ultimately, the potential diverse reactions from modular PKSs and NRPSs would be leveraged to expand the reservoir of useful chemicals.


Neoadjuvant chemotherapy versus cystectomy in management of stages II, and III urinary bladder cancer.
This phase III trial was de - signed to compare the survival benefit, surgical respectability, and toxicities among patients treated by neoadjuvant chemotherapy followed by radical cystectomy (arm A), with those treated by radical cystectomy (arm B) in the management of stage II, III urinary bladder cancer. For inclusion, patients should have pathologically proven urothelial carcinoma in urinary bladder, clinical stages from T2N0M0 to T4aN0M0, patient age less than 65 years, and performance state ≤ 2. Additionally, patients should have adequate hematological, renal, and liver functions. Arm A patients underwent 3 cycles of neoadjuvant cisplatin and gemcitabine followed by radical cystectomy, while arm B patients underwent radical cystectomy directly. Thirty patients had been enrolled in each arm between September 2009 and April 2014 in 3 educational institutes in Egypt. The 3 year OS (overall survival) for arm A, and B were 60% and 50% respectively. The median OS for arm A was 36+ months and that for arm B was 32.5 months. The 3 year progression-free survival (PFS) for arm A, and B were 57% and 43% respectively. The median PFS for arm A was 36+ months and for arm B was 28 months. A subgroup analysis was performed to correlate between 3 year OS and predetermined prognostic factors including age, tumor size, pathological stage, and the response to neoadjuvant chemotherapy. The later was performed only in arm A. Both treatment arms were tolerated well with mild toxicities profiles. Neoadjuvant chemotherapy achieved better survival, surgical respectability, with nearly equivalent toxicities when compared with radical cystectomy.


Prevalence of glucose-6-phosphate dehydrogenase deficiency in Northern Greece.
Glucose-6-phosphate dehydrogenase (G6PD) deficiency affects more than 400 million persons worldwide. Its distribution varies significantly among different geographic regions and different population groups. Purpose of our study was to estimate its prevalence in Northern Greece. The dataset comprised 5161 newborns and adults who were screened for G6PD deficiency between July 2001 and March 2007. G6PD deficiency was detected by the dye reduction method. In the screened group, 6.3% of subjects were G6PD deficient. Moderate enzyme deficiency was shown in 139 individuals (2.7%). Complete deficiency was identified in 3.7%. The prevalence of G6PD deficiency in Northern Greece is much higher compared with the general Greek population. Moreover, G6PD prevalence in the male sex is much higher - almost double - that in the female sex.


MnTnBuOE-2-PyP protects normal colorectal fibroblasts from radiation damage and simultaneously enhances radio/chemotherapeutic killing of colorectal cancer cells.
Manganese porphyrins have been shown to be potent radioprotectors in a variety of cancer models. However, the mechanism as to how these porphyrins protect normal tissues from radiation damage still remains largely unknown. In the current study, we determine the effects of the manganese porphyrin, MnTnBuOE-2-PyP, on primary colorectal fibroblasts exposed to irradiation. We found that 2 Gy of radiation enhances the fibroblasts' ability to contract a collagen matrix, increases cell size and promotes cellular senesence. Treating fibroblasts with MnTnBuOE-2-PyP significantly inhibited radiation-induced collagen contraction, preserved cell morphology and also inhibited cellular senescence. We further showed that MnTnBuOE-2-PyP enhanced the overall viability of the fibroblasts following exposure to radiation but did not protect colorectal cancer cell viability. Specifically, MnTnBuOE-2-PyP in combination with irradiation, caused a significant decrease in tumor clonogenicity. Since locally advanced rectal cancers are treated with chemoradiation therapy followed by surgery and non-metastatic anal cancers are treated with chemoradiation therapy, we also investigated the effects of MnTnBuOE-2-PyP in combination with radiation, 5-fluorouracil with and without Mitomycin C. We found that MnTnBuOE-2-PyP in combination with Mitomycin C or 5-fluorouracil further enhances those compounds' ability to suppress tumor cell growth. When MnTnBuOE-2-PyP was combined with the two chemotherapeutics and radiation, we observed the greatest reduction in tumor cell growth. Therefore, these studies indicate that MnTnBuOE-2-PyP could be used as a potent radioprotector for normal tissue, while at the same time enhancing radiation and chemotherapy treatment for rectal and anal cancers.


Whole abdominopelvic radiotherapy (WAPRT) using intensity-modulated arc therapy (IMAT): first clinical experience.
Whole abdominopelvic radiation therapy (WAPRT) is a treatment option in the palliation of patients with relapsed ovarian cancer. With conventional techniques, kidneys and liver are the dose- and homogeneity-limiting organs. We developed a planning strategy for intensity-modulated arc therapy (IMAT) and report on the treatment plans of the first 5 treated patients. Five consecutive patients with histologically proven relapsed ovarian cancer were sent to our department for WAPRT. The target volumes and organs at risk (OAR) were delineated on 0.5-cm-thick CT slices. The clinical target volume (CTV) was defined as the total peritoneal cavity. CTV and kidneys were expanded with 0.5 cm. In a preset range of 8 degrees interspaced gantry angles, machine states were generated with an anatomy-based segmentation tool. Machine states of the same class were stratified in arcs. The optimization of IMAT was done in several steps, using a biophysical objective function. These steps included weight optimization of machine states, leaf position optimization adapted to meet the maximal leaf speed constraint, and planner-interactive optimization of the start and stop angles. The final control points (machine states plus associated cumulative monitor unit counts) were calculated using a collapsed cone convolution/superposition algorithm. For comparison, two conventional plans (CONV) were made, one with two fields (CONV2), and one with four fields (CONV4). In these CONV plans, dose to the kidneys was limited by cerrobend blocks. The IMAT and the CONV plans were normalized to a median dose of 33 Gy to the planning target volume (PTV). Monomer/polymer gel dosimetry was used to assess the dosimetric accuracy of the IMAT planning and delivery method. The median volume of the PTV was 8306 cc. The mean treatment delivery time over 4 patients was 13.8 min. A mean of 444 monitor units was needed for a fraction dose of 150 cGy. The fraction of the PTV volume receiving more than 90% of the prescribed dose (V(90)) was 9% higher for the IMAT plan than for the CONV4 plan (89.9% vs. 82.5%). Outside a build-up region of 0.8 cm and 1 cm away from both kidneys, the inhomogeneity in the PTV was 15.1% for the IMAT plans and 24.9% for the CONV4 plans (for CONV2 plans, this was 34.9%). The median dose to the kidneys in the IMAT plans was lower for all patients. The 95th percentile dose for the kidneys was significantly higher for the IMAT plans than for the CONV4 and CONV2 plans (28.2 Gy vs. 22.2 Gy and 22.6 Gy for left kidney, respectively). No relevant differences were found for liver. The gel-measured dose was within clinical planning constraints. IMAT was shown to be deliverable in an acceptable time slot and to produce dose distributions that are more homogeneous than those obtained with a CONV plan, with at least equal sparing of the OARs.


The potential of chiroptical and vibrational spectroscopy of blood plasma for the discrimination between colon cancer patients and the control group.
Colorectal cancer is one of the most abundant causes of cancer deaths in the world. At an early stage, the established clinical procedures have low reliability and sensitivity. Therefore, we tested a novel approach based on chiroptical methods such as electronic circular dichroism (ECD) and Raman optical activity (ROA). These methods are suitable for detecting slight changes in the 3D structure of chiral biomolecules, some of which may be caused by pathological processes occurring during cancer growth. Fifty-five blood plasma samples were analyzed using the combination of ECD and ROA supplemented by conventional Raman and FT-IR spectroscopy. All obtained spectra were evaluated together by linear discriminant analysis. The accuracy of sample discrimination reached 100% and the subsequent leave-one-out cross-validation resulted in 93% sensitivity and 81% specificity. The achieved results indicate that chiroptical methods supplemented by Raman and FT-IR spectroscopy might be new supporting and minimally invasive tools in the clinical diagnosis of colon cancer.


Neuroanatomical voxel-based profile of schizophrenia and bipolar disorder.
Although schizophrenia (SCZ) and bipolar disorder (BD) share elements of pathology (Ellison-Wright and Bullmore, 2009), the neural mechanisms underlying these disorders are still under investigation. Up until now, many neuroimaging studies investigated the brain structural differences of SCZ and BD compared with healthy controls (HC), trying to identify the possible neuroanatomical markers for the two disorders. However, just a few studies focused on the brain structural changes between the two diagnoses. The present review summarises the findings of the voxel-based grey matter (GM) comparisons between SCZ and BD, with the objective to highlight the possible consistent anatomical differences between the two disorders. While the comparisons between patients and HC highlighted overlapping areas of GM reduction in insula and anterior cingulate cortex, the SCZ-BD comparisons suggest the presence of more generalised GM deficits in SCZ compared with BD. Indeed, in a number of studies, SCZ patients showed lower GM volumes than BD patients in fronto-temporal cortex, thalamus, hippocampus and amygdala. Conversely, only a couple of studies reported GM deficits in BD compared with SCZ, both at the level of cerebellum. In summary, the two disorders exhibit both common and specific neuroanatomical characteristics, whose knowledge is mandatory to develop innovative diagnostic and treatment strategies.


Carnosol and its analogues attenuate muscle atrophy and fat lipolysis induced by cancer cachexia.
Cancer cachexia is a multifactorial debilitating syndrome that directly accounts for more than 20% of cancer deaths while there is no effective therapeutic approach for treatment of cancer cachexia. Carnosol (CS) is a bioactive diterpene compound present in Lamiaceae spp., which has been demonstrated to have antioxidant, anti-inflammatory, and anticancer properties. But its effects on cancer cachexia and the possible mechanism remain a mystery. The in vitro cell models of C2C12 myotube atrophy and 3T3-L1 mature adipocyte lipolysis were used to check the activities of CS and its synthesized analogues. C26 tumour-bearing BALB/c mice were applied as the animal model to examine their therapeutic effects on cancer cachexia in vivo. Levels of related signal proteins in both in vitro and in vivo experiments were examined using western blotting to study the possible mechanisms. Carnosol and its analogues [dimethyl-carnosol (DCS) and dimethyl-carnosol-D6 (DCSD)] alleviated myotube atrophy of C2C12 myotubes and lipolysis of 3T3-L1 adipocytes in vitro. Interestingly, CS and its analogues exhibited stronger inhibitive effects on muscle atrophy induced by tumour necrosis factor-α (TNF-α) (CS, P < 0.001; DCS, P < 0.001; DCSD, P < 0.001) in C2C12 myoblasts than on muscle atrophy induced by IL-6 (CS, P < 0.05; DCS, P = 0.08; DCSD, P < 0.05). In a C26 tumour-bearing mice model, administration of CS or its analogue DCSD significantly prevented body weight loss without affecting tumour size. At the end of the experiment, the body weight of mice treated with CS and DCSD was significantly increased by 11.09% (P < 0.01) and 11.38% (P < 0.01) compared with that of the C26 model group. CS and DCSD also improved the weight loss of epididymal adipose tissue in C26 model mice by 176.6% (P < 0.01) and 48.2% (P < 0.05) increase, respectively. CS and DCSD treatment partly preserved gastrocnemius myofibres cross-sectional area. CS treatment decreased the serum level of TNF-α (-95.02%, P < 0.01) but not IL-6 in C26 tumour-bearing mice. Inhibition on NF-κB and activation of Akt signalling pathway were involved in the ameliorating effects of CS and its analogues on muscle wasting both in vitro and in vivo. CS and its analogues also alleviated adipose tissue loss by inhibiting NF-κB and AMPK signalling pathways both in vitro and in vivo. CS and its analogues exhibited anticachexia effects mainly by inhibiting TNF-α/NF-κB pathway and decreasing muscle and adipose tissue loss. CS and its analogues might be promising drug candidates for the treatment of cancer cachexia.


Mass-Tag Labeling Using Acyl-PEG Exchange for the Determination of Endogenous Protein S-Fatty Acylation.
The covalent coupling of fatty acids to proteins provides an important mechanism of regulation in cells. In eukaryotes, cysteine fatty acylation (S-fatty acylation) has been shown to be critical for protein function in a variety of cellular pathways as well as microbial pathogenesis. While methods developed over the past decade have improved the detection and profiling of S-fatty acylation, these are hampered in their ability to characterize endogenous protein S-fatty acylation levels under physiological conditions. Furthermore, understanding the contribution of specific sites and levels of S-fatty acylation remains a major challenge. To evaluate S-fatty acylation of endogenous proteins as well as to determine the number of S-fatty acylation events, we developed the acyl-PEG exchange (APE) that utilizes cysteine-specific chemistry to exchange S-fatty acylation sites with mass-tags of defined size, which can be readily observed by western blotting. APE provides a readily accessible approach to investigate endogenous S-fatty acylation from any sample source, with high sensitivity and broad applicability that complements the current toolbox of methods for thioester-based post-translational modifications. © 2017 by John Wiley & Sons, Inc.


[Risk factors of recurrence after radical prostatectomy for locally advanced prostate cancer].
We reviewed our retrospective surgical database and assessed the outcome after radical prostatectomy (RP) in patients with clinical T3 (cT3) prostate cancer (PC). Sixty four men underwent RP for cT3 PC in our hospital from 1995 to 2011. Clinical stage was diagnosed with MRI and rectal digital examination in all cases. We investigated the postoperative outcome, cancer specific survival and overall survival of all patients. We also investigated the risk factors of biochemical recurrence (BCR) in the patients without any adjuvant therapy. All survival was estimated using Kaplan-Meier plots. We performed univariate analysis by Mann-Whitney test, Fisher exact test and Log-Rank test, and multivariate analysis by Cox regression analysis. Median age at RP was 67 years (range: 48-74), and median initial PSA was 14.1 ng/ml (2.2-76.2). Sixty cases (93.8%) were classified into cT3a, and 4 cases (6.3%) into cT3b. Median follow-up period after RP was 62 months (3-172). Fifty three (83%) patients received neoadjuvant hormonal therapy. Median duration of neoadjuvant hormonal therapy was 7 months (3-31). Adjuvant therapy underwent in 20 cases. Of the 64 patients, overall survival and cancer specific survival rates at 10 years were 98% and 100%, respectively. Of the 44 patients who didn't receive any adjuvant therapy, BCR free survival rates at 5 and 10 years was 59% and 51%, respectively. Univariate analysis revealed that both PSA > or = 15 ng/ml and GS > or = 8 were associated with a significant risk of BCR. Any significant risk factor was not identified by multivariate analysis. In 16 patients who have cT3a, PSA < 15 ng/ml and GS < 8, BCR free survival rate at 5 years was 78%. On the other hand, that of the other patients was 37% (p = 0.009). It is suggested that RP is effective for some patients with locally advanced prostate cancer, especially who have cT3a diagnosed by MRI, PSA < 15 ng/ml and GS < 8.


Continuum beliefs and attitudes towards people with mental illness: Results from a national survey in France.
Whether mental disorders should be considered as categorical or dimensional has found increasing attention among mental health professionals. Only little is known about what the public thinks about this issue. First, to assess how prevalent the belief in a continuum of symptoms from mental health to mental illness is among the general public. Second, to examine how continuum beliefs are associated with attitudes towards people with mental disorder. In 2012, an on-line survey was conducted in France (N = 1,600). After the presentation of a case-vignette depicting a person with either schizophrenia or depression, belief in a continuum of symptoms, emotional reactions and desire for social distance related to the person in the vignette were assessed. While 58.2% of respondents agreed in a symptom continuum for depression, this percentage was only 28.5% for schizophrenia. In both disorders, continuum beliefs were associated with more pro-social reactions and less desire for social distance. Only in schizophrenia, there was an inverse relationship with the expression of anger. There is increasing evidence of an association between continuum beliefs and positive attitudes towards people with mental illness. Information on the continuous nature of psychopathological phenomena may usefully be included in anti-stigma messages.


Tibial cortical thickness: A dependable tool for assessing osteoporosis in the absence of dual energy X-ray absorptiopmetry.
Bone mineral density measurements with absorptiometry dual-energy X-ray absorptiometry (DXA) is the gold standard for diagnosing low bone mass and risk for fragility fractures. DXA is not available at every center, and physicians require an alternative method of diagnosis before referring patients. We conducted this study to assess and compare total cortical thickness (TCT) and its relation to the T score by DXA and its correlation-ship in the diagnosis of osteoporosis. Total cortical thickness was carried out in 50 Saudi Arabian females ≥ 45 years with DXA scans and 25 patients with age of ≤ 35 years whose radiographs of the upper tibia were available for analysis. Postero-medial cortical thickness of the tibia was measured 13 cm from the joint line and an average was calculated. The average T score of the spine and the hip was taken. A comparison was made between age, T score, and the TCT. Inter cortical distance (ICD) was measured and compared in both groups. Data were analyzed for predictive value for diagnosis of osteopenia and osteoporosis. There was a significant association between the T score and the TCT and age. As the age advanced the T score and TCT was very low (<0.05, 95% confidence interval [CI] <0.2). Forty patients were osteopenic and 10 osteoporotic. The T score in the former was - 1.33 ± 0.71 and the later was - 3.22 ± 0.56 (P < 0.0001 95% CI: <-1.67) and the TCT was 0.655 ± 0.06 versus 0.51 ± 0.05 (P < 0.0001 95% CI: <-0.17). In women ≤35 years the average TCT was 0.804 ± 0.155 cm and IMD was 3.34 ± 0.45 cm. We conclude that if TCT is less than the threshold value of ≤ 0.5 cm, patients should be referred for further investigations with DXA. We believe that further studies are needed to confirm our findings and in areas where DXA is not available, based on the TCT measurement anti-osteoporotic therapy could be initiated when other risk factors for osteoporosis is present.


Immunochemical studies on alpha-amylase. 3. Immunochemical relationships among amylases from various microorganisms.
Sirishinha, Stitaya (University of Rochester School of Medicine and Dentistry, Rochester, N.Y.), and Peter Z. Allen. Immunochemical studies on alpha-amylase. III. Immunochemical relationships among amylases from various microorganisms. J. Bacteriol. 90:1120-1128. 1965.-Immunochemical relationships among amylases obtained from a selected group of microorganisms were examined, and a cross-reaction was detected between the alpha-amylases of Bacillus stearothermophilus and B. subtilis. Immunodiffusion and quantitative precipitin studies, as well as cross-neutralization tests, indicate that B. stearothermophilus alpha-amylase reacts with a portion of antibody present in antisera to crystalline B. subtilis alpha-amylase. Amylases from these two species thus have some aspects of structure in common. Limited data obtained by immunodiffusion suggest that groupings which confer cross-reactivity to the B. stearothermophilus enzyme are lost after exposure to mercaptoethanol in the presence of ethylenediamine-tetraacetate, followed by treatment with iodoacetamide. With the antisera employed and within the concentration range examined, no immunochemical cross-reaction was observed among amylases from Aspergillus oryzae, B. subtilis, B. polymyxa, B. macerans, Pseudomonas saccharophila, and Euglena sanguinis. Immunoelectrophoresis of partially purified B. stearothermophilus alpha-amylase by use of antiserum to the crude enzyme, together with localization of amylase activity in immunoelectrophoretic plates, suggests that B. stearothermophilus alpha-amylase is antigenic in the rabbit.


The many faces of psoriatic arthritis: their genetic determinism.
In this review, we propose a model of PsA as a complex genetically determined autoimmune-mediated disease having a heterogeneous variety of subphenotypes, with each subphenotype under the control of a different susceptibility-associated HLA allele. Since the specific HLA molecules encoded by each susceptibility allele dominantly select a T cell repertoire with the property of recognizing different peptides, we hypothesize each subphenotype reflects a distinct adaptive autoimmune response directed to different target molecules that is mediated by T cells within each selected repertoire. The interaction among the patients' susceptibility alleles in the selection of their T cell repertoires determines a spectrum of overall clinical disease severity, varying from mild to severe. We further speculate that these different immune responses may result in activation of different immune effector pathways, which might therefore respond differently to various specific biologic agents.


A diagnostic approach to vomiting in severely retarded patients.
Vomiting is a considerable problem among severely retarded individuals. The majority have gastroesophageal reflux (GER). The incidence is increased in those who are nonambulatory or have scoliosis and/or spastic quadriplegia. In the absence of other symptoms, these persons should be kept in the upright position as much as possible. Persistent vomiting warrants a roentgenographic examination of the upper gastrointestinal tract. If GER is the only finding, upright positioning should be continued. The occurrence of complications attributable to GER is an indication for further diagnostic evaluation.


Smoking and the risk of diabetes in elderly Finnish men. Retrospective analysis of data from a 30-year follow-up study.
To assess the association of smoking with the risk of glucose intolerance (diabetes plus impaired glucose tolerance). A cohort consisting of 1,711 Finnish men born in 1900-1919 were followed up from 1959 to 1994. Smoking status was assessed in a similar way at each of the six surveys from 1959 to 1989, and subjects were classified as never, former, or current smokers. Diagnosis of diabetes and impaired glucose tolerance was made according to the oral glucose tolerance tests made in 1984 and 1989, and the 1985 World Health Organization criteria was applied. Association between smoking and glucose intolerance was estimated separately for 420 participants and 243 nonparticipants in 1989. Multiple logistic regression analyses show that odds ratios of glucose intolerance in 1984 for current smokers in 1984 were 0.36 (0.19-0.70) and 1.20 (0.52-2.78), respectively, in the participants and the nonparticipants in 1989. Among the nonparticipants in 1989, the odds ratio for current smokers in 1969 was 2.23 (1.00-4.96). A reduced risk of glucose intolerance in 1989 associated with smoking in the participants in 1989 was found to be significant from the beginning of the follow-up. The participants in 1989 were generally healthier and had a longer life expectancy than the nonparticipants in 1989. In a retrospective study of men, an increased risk of diabetes and impaired glucose tolerance in smokers was found among the nonparticipants, but a reduced risk was found among the participants in 1989. The difference observed might be attributed to the fact that the participants were constitutionally different from the nonparticipants.


[New 'targeted therapy' for lung cancer].
Patients with non-small cell lung cancer with specific mutations for which so-called 'targeted therapy' is available are likely to have a favourable tumour response. The first patient, a man aged 64 with an activating epidermal growth factor receptor (EGFR) mutation, had a longstanding tumour response on erlotinib, an EGFR tyrosine kinase inhibitor (TKI). After 16 months on treatment, there was still no progression of the disease. The next patient, a woman aged 78, also responded favourably to erlotinib After 2.5 years she discontinued the medication and the disease recurred. Remission was induced again with the use of erlotinib, but the recovery was of short duration and she died a few months later. A third patient, a 66-year-old man, developed resistance to erlotinib due to a T790M mutation in the EGFR protein. He responded well to a combination of the irreversible EGFR-TKI afatinib and the antibody to EGFR, cetuximab. The final patient, a 47-year-old woman, had an EML4-ALK translocation and responded remarkably well to an ALK inhibitor, crozotinib. Mutation analysis should be carried out in all patients with metastatic adenocarcinoma or large cell lung cancer, specifically for genes for which a targeted therapy is already available.


Hemodialysis-related changes in phenotypical features of monocytes.
Hemodialysis (HD) patients exhibit chronic inflammation and leukocyte activation. We investigated the surface-marker profile of monocytes by flow cytometry to assess the chronic effect of uremia and the acute effect of dialysis on their phenotypical and functional features in 16 healthy controls (CON) and 15 HD patients before and after a polysulfone-based dialysis session. Median fluorescence intensities were analyzed indicating expression of CD14, CD16, integrins (CD11b, CD18), chemokine receptors (CCR2, CX3CR1), scavenger receptors (CD36, CD163) and Toll-like receptor-2 (TLR2). Before and after dialysis, HD patients harbour 0.9-fold less CD14++CD16- (Mo1), 1.8-fold more CD14++CD16+ (Mo2) and CD14+CD16++ (Mo3) monocytes than CON. HD patients' Mo1 showed elevated expression of CD11b (1.7-fold), CD18 (1.2-fold) and CD36 (2.1-fold), whereas CD163 expression was reduced in Mo1 and Mo2 (0.6-fold) compared to CON. These markers remained unaffected by dialysis. CX3CR1 expression on Mo2 and Mo3 was lower in HD patients before (0.8-fold) and further diminished after dialysis (0.6-fold). Stimulation of monocytes resulted in diminished responses in HD patients compared to CON. In conclusion, a systematic analysis of the expression of particular surface markers on distinct monocyte subsets may help to distinguish between uremia and/or dialysis induced effects and to evaluate the functionality of monocytes and biocompatibility of HD.