Acclimation in plants - the Green Hub consortium.
Acclimation is the capacity to adapt to environmental changes within the lifetime of an individual. This ability allows plants to cope with the continuous variation in ambient conditions to which they are exposed as sessile organisms. Because environmental changes and extremes are becoming even more pronounced due to the current period of climate change, enhancing the efficacy of plant acclimation is a promising strategy for mitigating the consequences of global warming on crop yields. At the cellular level, the chloroplast plays a central role in many acclimation responses, acting both as a sensor of environmental change and as a target of cellular acclimation responses. In this Perspective article, we outline the activities of the Green Hub consortium funded by the German Science Foundation. The main aim of this research collaboration is to understand and strategically modify the cellular networks that mediate plant acclimation to adverse environments, employing Arabidopsis, tobacco (Nicotiana tabacum) and Chlamydomonas as model organisms. These efforts will contribute to 'smart breeding' methods designed to create crop plants with improved acclimation properties. To this end, the model oilseed crop Camelina sativa is being used to test modulators of acclimation for their potential to enhance crop yield under adverse environmental conditions. Here we highlight the current state of research on the role of gene expression, metabolism and signalling in acclimation, with a focus on chloroplast-related processes. In addition, further approaches to uncovering acclimation mechanisms derived from systems and computational biology, as well as adaptive laboratory evolution with photosynthetic microbes, are highlighted.


The effects of chloride dynamics on substantia nigra pars reticulata responses to pallidal and striatal inputs.
As a rodent basal ganglia (BG) output nucleus, the substantia nigra pars reticulata (SNr) is well positioned to impact behavior. SNr neurons receive GABAergic inputs from the striatum (direct pathway) and globus pallidus (GPe, indirect pathway). Dominant theories of action selection rely on these pathways' inhibitory actions. Yet, experimental results on SNr responses to these inputs are limited and include excitatory effects. Our study combines experimental and computational work to characterize, explain, and make predictions about these pathways. We observe diverse SNr responses to stimulation of SNr-projecting striatal and GPe neurons, including biphasic and excitatory effects, which our modeling shows can be explained by intracellular chloride processing. Our work predicts that ongoing GPe activity could tune the SNr operating mode, including its responses in decision-making scenarios, and GPe output may modulate synchrony and low-frequency oscillations of SNr neurons, which we confirm using optogenetic stimulation of GPe terminals within the SNr.


Fjord- and bay-region diol-epoxides investigated for stability, SOS induction in Escherichia coli, and mutagenicity in Salmonella typhimurium and mammalian cells.
The fjord-region diol-epoxides of benzo(c)phenanthrene combine high mutagenic and carcinogenic activity with low chemical reactivity. To study whether this is a unique property of these compounds or a more general characteristic of fjord-region diol-epoxides, we have synthesized the anti- and syn-diastereomers of r-9,t-10-dihydroxy-11,12-oxy-9,10,11,12-tetrahydrobenzo(c)chrysene and r-11-t-12-dihydroxy-13,14-oxy-11,12,13,14-tetrahydrobenzo(g)chrysene. These compounds as well as the anti- and syn-diastereomers of the fjord-region diol-epoxides of benzo(c)phenanthrene and of the bay-region diol-epoxides of phenanthrene, chrysene, and benzo(a)pyrene were investigated for their half-lives in a physiological buffer, for their mutagenicity in Salmonella typhimurium (reversion of the his- strains TA97, TA98, TA100, and TA104), for induction of SOS response in Escherichia coli (SOS chromotest in strain PQ37) and for their mutagenicity in V79 Chinese hamster cells (acquisition of resistance to 6-thioguanine). All six of the investigated fjord-region diol-epoxides were more stable in physiological buffer at 37 degrees C (t1/2 greater than 2 h) than the six bay-region diol-epoxides (t1/2 = 0.011 to 1.2 h). The half-lives correlated negatively with the calculated delta Edeloc values for the formation of the benzylic carbocations, and were consistently shorter for the syn- than for the corresponding anti-diastereomer. All fjord-region diol-epoxides showed extraordinarily high activity in all six genotoxicity assays used. In mammalian cells, the anti-diol-epoxide of benzo(c)chrysene was 8.6 and 12 times more active than the anti-diol-epoxides of benzo(c)phenanthrene and benzo(a)pyrene, respectively, which were the most potent mutagens among the reference compounds. The other three newly available fjord-region diol-epoxides were also markedly more mutagenic in mammalian cells than the reference compounds. Whereas the syn-diastereomers of the simple bay-region diolepoxides were clearly less mutagenic in mammalian cells than the corresponding anti-diastereomers, the differences in potency between diastereomers were small for the fjord-region diol-epoxides. In conclusion, the diol-epoxides of benzo(c)phenanthrene are not unique in their high biological activities. The two newly available diastereomeric pairs of fjord-region diol-epoxides of benzo(g)- and benzo(c)chrysene proved to be even more active. For one of them, the diol-epoxides of benzo(g)chrysene, the delta Edeloc value for the formation of the benzylic carbocation is lower than for the benzo(c)phenanthrene diol-epoxides, for the other it is higher.


Field testing of a multicriteria decision analysis (MCDA) framework for coverage of a screening test for cervical cancer in South Africa.
Systematic and transparent approaches to priority setting are needed, particularly in low-resource settings, to produce decisions that are sound and acceptable to stakeholders. The EVIDEM framework brings together Health Technology Assessment (HTA) and multi-criteria decision analysis (MCDA) by proposing a comprehensive set of decision criteria together with standardized processes to support decisionmaking. The objective of the study was to field test the framework for decisionmaking on a screening test by a private health plan in South Africa. Liquid-based cytology (LBC) for cervical cancer screening was selected by the health plan for this field test. An HTA report structured by decision criterion (14 criteria organized in the MCDA matrix and 4 contextual criteria) was produced based on a literature review and input from the health plan. During workshop sessions, committee members 1) weighted each MCDA decision criterion to express their individual perspectives, and 2) to appraise LBC, assigned scores to each MCDA criterion on the basis of the by-criterion HTA report.Committee members then considered the potential impacts of four contextual criteria on the use of LBC in the context of their health plan. Feedback on the framework and process was collected through discussion and from a questionnaire. For 9 of the MCDA matrix decision criteria, 89% or more of committee members thought they should always be considered in decisionmaking. Greatest weights were given to the criteria "Budget impact", "Cost-effectiveness" and "Completeness and consistency of reporting evidence". When appraising LBC for cervical cancer screening, the committee assigned the highest scores to "Relevance and validity of evidence" and "Disease severity". Combination of weights and scores yielded a mean MCDA value estimate of 46% (SD 7%) of the potential maximum value. Overall, the committee felt the framework brought greater clarity to the decisionmaking process and was easily adaptable to different types of health interventions. The EVIDEM framework was easily adapted to evaluating a screening technology in South Africa, thereby broadening its applicability in healthcare decision making.


Minimal residual disease status before allogeneic bone marrow transplantation is an important determinant of successful outcome for children and adolescents with acute lymphoblastic leukemia.
The efficacy of allografting in acute lymphoblastic leukemia (ALL) is heavily influenced by remission status at the time of transplant. Using polymerase chain reaction (PCR)-based minimal residual disease (MRD) analysis, we have investigated retrospectively the impact of submicroscopic leukemia on outcome in 64 patients receiving allogeneic bone marrow transplantation (BMT) for childhood ALL. Remission BM specimens were taken 6 to 81 days (median, 23) before transplant. All patients received similar conditioning therapy; 50 received grafts from unrelated donors and 14 from related donors. Nineteen patients were transplanted in first complete remission (CR1) and 45 in second or subsequent CR. MRD was analyzed by PCR of Ig or T-cell receptor delta or gamma rearrangements, electrophoresis, and allele-specific oligoprobing. Samples were rated high-level positive (clonal band evident after electrophoresis; sensitivity 10(-2) to 10(-3)), low-level positive (MRD detected only after oligoprobing; sensitivity 10(-3) to 10(-5)), or negative. Excluding 8 patients transplanted in CR2 for isolated extramedullary relapse (all MRD-), MRD was detected at high level in 12 patients, low level in 11, and was undetectable in 33. Two-year event-free survival for these groups was 0%, 36%, and 73%, respectively (P <.001). Follow-up in patients remaining in continuing remission is 20 to 96 months (median, 35). These results suggest that MRD analysis could be used routinely in this setting. This would allow identification of patients with resistant leukemia (who may benefit from innovative BMT protocols) and of those with more responsive disease (who may be candidates for randomized trials of BMT versus modern intensive relapse chemotherapy).


[Disease assessment by the pathologist].
Pathogenesis of the disease is discussed from the view-point of cell pathology and general pathology as a material basis of syndromes and nosology. When analyzing morphogenesis, the author focuses on alterations of intercellular interactions and antagonistic functions at various levels. The evaluation of such categories as nosology and nosological unity, pathomorphosis, iatrogenesis, diagnosis and prognosis is given.


The PRIME curriculum. Clinical research training during residency.
The Primary Medical Education (PRIME) program is an outpatient-based, internal medicine residency track nested within the University of California, San Francisco (UCSF) categorical medicine program. Primary Medical Education is based at the San Francisco Veteran's Affairs Medical Center (VAMC), 1 of 3 teaching hospitals at UCSF. The program accepts 8 UCSF medicine residents annually, who differentiate into PRIME after internship. In 2000, we implemented a novel research methods curriculum with the dual purposes of teaching basic epidemiology skills and providing mentored opportunities for clinical research projects during residency. Single academic internal medicine program. The PRIME curriculum utilizes didactic lecture, frequent journal clubs, work-in-progress sessions, and active mentoring to enable residents to "try out" a clinical research project during residency. Among 32 residents in 4 years, 22 residents have produced 20 papers in peer-reviewed journals, 1 paper under review, and 2 book chapters. Their clinical evaluations are equivalent to other UCSF medicine residents. While learning skills in evidence-based medicine, residents can conduct high-quality research. Utilizing a collaboration of General Internal Medicine researchers and educators, our curriculum affords residents the opportunity to "try-out" clinical research as a potential future career choice.


Operative start time may impact the quality of mesorectal excision in minimally invasive rectal surgery: retrospective analysis of 137 patients.
Timing of major elective operations is a potentially important outcome variable. This study examined the impact of operative start time (OST) on pathologic and short-term outcomes of minimally invasive rectal surgery (MIRS). All rectal tumors patients who underwent MIRS from May 2012 to April 2016 were identified. Peroperative outcomes and the oncological quality of surgical excision were compared between patients with OST before 13.00h and after. A total of 137 patients were included in the study (71 Romarobot-assisted and 66 conventional laparoscopic). Ninety-nine (72%) patients were operated before 13.00h and 38 after 13.00h. The majority of cases were low/middle rectal tumors (69%). Patient's baseline characteristics were quite similar in both groups. The rate of severe complication (p=0.460) or reoperation (p=0.614) was the same. Pathologic criteria (T or N stage, number of harvested lymph nodes, and presence of any positive margin) were the same between groups except for the quality of mesorectal excision (ME) that was significantly poorer for cases beginning after 13.00h (complete 91% vs 74%; p=0.016). The OST was found to be the only parameter associated with a poor quality of ME [OR 2.55 (1.08 - 6.36)]. Perioperative outcome after MIRS does not appear to be influenced by OST. Poorer quality of ME was observed and may thus raise important questions about the timing and sequence of case scheduling.


Attitudes of United Kingdom rheumatologists to musculoskeletal ultrasound practice and training.
This study was performed to describe what clinical rheumatologists currently use musculoskeletal ultrasound (MSUS) for, how they are currently training and is the first study to survey rheumatologists to determine their preferences for MSUS training implementation. 250 questionnaires were distributed at the British Society of Rheumatology Annual General Meeting (BSR AGM), 2005. 126 (50%) of questionnaires were completed by UK rheumatologists and were analysed. 117 (93%) of the respondents use MSUS imaging for patient management, with 41 (33%) indicating they perform MSUS themselves. Only two (2%) performed MSUS for >5 years. Rheumatologists use MSUS to image all peripheral joints-particularly the hands and feet-to assess joint and soft tissue inflammation and to guide joint injections. Lack of training in MSUS was the principal reason for not performing MSUS. Respondents expressed a preference for future training to be via a programme of regular sessions, with training delivered by either consultant radiologists or rheumatologists. Mentoring was the educational tool and assessment method of choice. The majority of respondents use MSUS in the management of their patients, with a third performing MSUS themselves. The report indicates rheumatologists' preferences on how training should be delivered in the future.


[Shigellosis related with the cause of death in children].
From a series of 4,147 postmortem studies, there were 2,280 cases of infectious processes as responsibility of death out of which, 647 corresponded to the digestive tract. Within the group of digestive tract infections, 283 were of bacterial nature and within this last group, there were 43 cases of shigellosis. Included in the fatal cases of shigellosis is the description of their description by ages and sexes; the types of enteropathogenic germs identified in the course of disease and at postmortem studies are mentioned and special reference is made to the type and localization of lesions within the digestive tract. Also, the type and localization of extraintestinal lesions, directly or indirectly related with shigellosis are described. Pathological processes considered as immediate cause of death are pointed out and from the group is extraintestinal infections, the germ identified in each as responsible of death is mentioned. Finally, a brief outline is made of the clinicopathological correlation.


Influence of combinations of cytokines on proliferation of isolated single cell-sorted human bone marrow hematopoietic progenitor cells in the absence and presence of serum.
Human mast cell growth factor (MGF, a c-kit ligand) and colony stimulating factors (Epo, GM-CSF, G-CSF, IL-3) were assessed in the absence or presence of serum for stimulation in semi-solid medium of single CD34 , CD34 HLA-DR+, or CD34 HLA-DR+CD33- cells sorted per microtiter well. The % of wells containing CFU-GM and erythroid containing (BFU-E and CFU-GEMM) colonies increased in proportion to the number of cytokines added. In the presence of serum, 1, to 4 cytokine combinations resulted in respective increases in cloning efficiencies of 10 to 21.0, 19.5 to 31.5, 35.8 to 42.9, and 46.3 to 60.0%. MGF had little effect by itself, but did act in combination with CSFs to enhance numbers and size of the colonies from isolated single cells. High cloning efficiencies were also obtained in the absence of serum when multiple cytokines were used. The results demonstrate that MGF and CSFs can act directly on the proliferation of single hematopoietic progenitor cells in the absence of accessory cells and serum.


[Antistreptococcal antibodies in the blood serum of glomerulonephritis patients].
To study humoral antistreptococcal immunity, 29 patients with acute glomerulonephritis (AGN), 211 patients with chronic glomerulonephritis (CGN) and 30 healthy donors were examined. According to EIA, blood sera of the indicated groups demonstrated antibodies (AB) to structural components of Streptococcus--A-polysaccharide (A-ps) and hyaluronic acid (HA) and to its extracellular products--streptokinase (SK) and streptolysin-O (ASLO). It has been shown that in the blood of AGN patients, the levels of AB to A-ps, SK and ASLO were high. The highest level of AB and SK was detected in 55% of the patients with the disease standing of up to half a year. In patients of all the clinical groups of CGN, the levels of AB to A-ps, SK and HA were elevated. The degree of the rise of the levels of all AB depended on the disease activity. Of prognostic importance in the chronicity of AGN and progression of CGN are high titers of AB and SK. The etiological role of streptococcus in glomerulonephritis and its importance in CGN exacerbation and prognosis are under discussion.


Mediation analysis of triple networks revealed functional feature of mindfulness from real-time fMRI neurofeedback.
The triple networks, namely the default-mode network (DMN), the central executive network (CEN), and the salience network (SN), play crucial roles in disorders of the brain, as well as in basic neuroscientific processes such as mindfulness. However, currently, there is no consensus on the underlying functional features of the triple networks associated with mindfulness. In this study, we tested the hypothesis that (a) the partial regression coefficient (i.e., slope): from the SN to the DMN, mediated by the CEN, would be one of the potential mindfulness features in the real-time functional magnetic resonance imaging (rtfMRI) neurofeedback (NF) setting, and (b) this slope level may be enhanced by rtfMRI-NF training. Sixty healthy mindfulness-naïve males participated in an MRI session consisting of two non-rtfMRI-runs, followed by two rtfMRI-NF runs and one transfer run. Once the regions-of-interest of each of the triple networks were defined using the non-rtfMRI-runs, the slope level was calculated by mediation analysis and used as neurofeedback information, in the form of a thermometer bar, to assist with participant mindfulness during the rtfMRI-NF runs. The participants were asked to increase the level of the thermometer bar while deploying a mindfulness strategy, which consisted of focusing attention on the physical sensations of breathing. rtfMRI-NF training was conducted as part of a randomized controlled trial design, in which participants were randomly assigned to either an experimental group or a control group. The participants in the experimental group received contingent neurofeedback information, which was obtained from their own brain signals, whereas the participants in the control group received non-contingent neurofeedback information that originated from matched participants in the experimental group. Our results indicated that the slope level from the SN to the DMN, mediated by the CEN, was associated with mindfulness score (rtfMRI-NF runs: r = 0.53, p = 0.007; p-value was corrected from 10,000 random permutations) and with task-performance feedback score (rtfMRI-NF run: r = 0.61, p = 0.001) in the experimental group only. In addition, during the rtfMRI-NF runs the level of the partial regression coefficient feature was substantially increased in the experimental group compared to the control group (p < 0.05 from the paired t-test; the p-value was corrected from 10,000 random permutations). To the best of our knowledge, this is the first study to demonstrate a partial regression coefficient feature of mindfulness in the rtfMRI-NF setting obtained by triple network mediation analysis, as well as the possibility of enhancement of the partial regression coefficient feature by rtfMRI-NF training.


Can Customizing an Avatar Motivate Exercise Intentions and Health Behaviors Among Those with Low Health Ideals?
Studies have shown that self-resembling avatars in health games and other applications can heighten exercise intentions, but objective self-awareness (OSA) theory suggests that this effect is likely to be true only for those who believe in the ideal of a healthy self. How can avatars be used to motivate those who do not hold this ideal and may not be motivated by avatars to pursue healthy activities? One possibility is to afford individuals the ability to customize their avatar, so they are not only more self-aware but also feel in control of their persona, both of which are necessary conditions for behavior change according to OSA. In order to test this prediction, participants in an online virtual environment created an avatar of the same sex or opposite sex by choosing among a small or large number of possible traits, then completed a series of items measuring self-awareness, sense of control, health-focused behavior, and ideal internalization. Results show that customizing a same-sex avatar can overcome differences in health intentions and behaviors between individuals with high and low levels of prior health-ideal internalization.


A multicenter trial of two dexamethasone regimens in ventilator-dependent premature infants.
Ventilator-dependent premature infants are often treated with dexamethasone. However, the optimal timing of therapy is unknown. We compared the benefits and hazards of initiating dexamethasone therapy at two weeks of age and at four weeks of age in 371 ventilator-dependent very-low-birth-weight infants (501 to 1500 g) who had respiratory index scores (mean airway pressure x the fraction of inspired oxygen) of 52.4 at two weeks of age. One hundred eighty-two infants received dexamethasone for two weeks followed by placebo for two weeks, and 189 infants received placebo for two weeks followed by either dexamethasone (those with a respiratory-index score of > or =2.4 on treatment day 14) or additional placebo for two weeks. Dexamethasone was given at a dose of 0.25 mg per kilogram of body weight twice daily intravenously or orally for five days, and the dose was then tapered. The median time to ventilator independence was 36 days in the dexamethasone-placebo group and 37 days in the placebo-dexamethasone group. The incidences of chronic lung disease (defined as the need for oxygen supplementation at 36 weeks' postconceptional age) were 66 percent and 67 percent, respectively. Dexamethasone was associated with an increased incidence of nosocomial bacteremia (relative risk, 1.5; 95 percent confidence interval, 1.1 to 2.1) and hyperglycemia (relative risk, 1.9; 95 percent confidence interval, 1.2 to 3.0) in the dexamethasone-placebo group, elevated blood pressure (relative risk, 2.9; 95 percent confidence interval, 1.2 to 6.9) in the placebo-dexamethasone group, and diminished weight gain and head growth (P< 0.001) in both groups. Treatment of ventilator-dependent premature infants with dexamethasone at two weeks of age is more hazardous and no more beneficial than treatment at four weeks of ages.


Rationale and clinical results of multi-target treatments in oncology.
During the last 10 years, the concept of targeted biological therapy for the treatment of cancer has emerged. Targeted agents entered clinical practice only recently, and the first drugs with demonstrated clinical efficacy were mainly inhibitors of the ErbB family of receptors (i.e., EGFR and HER-2), either monoclonal antibodies (MAbs) or tyrosine kinase inhibitors (TKIs). After the proof of concept for the clinical efficacy and tolerability of these selective agents, it was conceived that most tumors will depend on more than one signaling pathway for their growth and survival. As a consequence, different strategies were pursued to inhibit multiple signaling pathways or multiple steps in the same pathway, either by the development of multi-targeted agents or the combination of single targeted drugs. The recent FDA and EMEA approval of sorafenib and sunitinib, both multi-targeted TKIs, marked the coming of age of this new generation of drugs. Now a whole new wave of multi-targeted compounds is moving into clinical trials, raising in the minds of investigators important questions about the best strategies to pursue in their use and many doubts about their differences and the seeming redundancies in the pipelines of pharmaceutical companies. This review will deal with the rationale underlying the multi-targeted approach and with the available clinical experience with multi-targeted agents, especially focusing on molecules with anti- EGFR mechanisms of action.


Dietary sodium and arterial pressure: problems of studies within a single population.
The nature of the relationship between dietary sodium and arterial pressure remains uncertain, largely because of the difficulty of investigating this relationship within a single population. There are two main hypotheses: one requires that hypertensive and normotensive patients differ in their sodium intake, the other that they differ in their susceptibility to dietary sodium. Neither hypothesis has been fully explored. In this paper the types of study required to test each hypothesis are considered and published work is used to illustrate the problems of interpreting studies in this field.


Proximity ligation assays: a recent addition to the proteomics toolbox.
An essential skill for every researcher is to learn how to select and apply the most appropriate methods for the questions they are trying to answer. With the extensive variety of methods available, it is increasingly important to scrutinize the advantages and disadvantages of these techniques prior to making a decision on which to use. In this article, we describe an approach to evaluate methods by reducing them into subcomponents. This is exemplified by a brief description of some commonly used proteomics methods. The same approach can also be used in method development by rearranging subcomponents in order to create new methods, as demonstrated with the development of proximity ligation assays (PLAs). PLA is a method as designed in our laboratory for detection of proteins, protein-protein interactions and post-translational modifications. Fundamentally, protein-recognition events are converted into detectable DNA molecules. The technique uses protein-DNA conjugates as binders for the targets of interest. Binding of two or more conjugates to the target results in assembly of an assay-specific DNA molecule. Subsequent amplification of the DNA molecule generates a signal that can be detected using PCR, for detection of minute amounts of proteins in serum, or standard fluorescence microscopy for detection of protein-protein interactions in tissue sections. Lastly, we apply the approach of recombining subcomponents to develop a few novel hypothetical methods hoping this might stimulate the readers to utilize this approach themselves.


Diamonds in the Rough: Harnessing Tumor-Associated Myeloid Cells for Cancer Therapy.
Therapeutic approaches that engage immune cells to treat cancer are becoming increasingly utilized in the clinics and demonstrated durable clinical benefit in several solid tumor types. Most of the current immunotherapies focus on manipulating T cells, however, the tumor microenvironment (TME) is abundantly infiltrated by a heterogeneous population of tumor-associated myeloid cells, including tumor-associated macrophages (TAMs), tumor-associated dendritic cells (TADCs), tumor-associated neutrophils (TANs), and myeloid-derived suppressor cells (MDSCs). Educated by signals perceived in the TME, these cells often acquire tumor-promoting properties ultimately favoring disease progression. Upon appropriate stimuli, myeloid cells can exhibit cytoxic, phagocytic, and antigen-presenting activities thereby bolstering antitumor immune responses. Thus, depletion, reprogramming or reactivation of myeloid cells to either directly eradicate malignant cells or promote antitumor T-cell responses is an emerging field of interest. In this review, we briefly discuss the tumor-promoting and tumor-suppressive roles of myeloid cells in the TME, and describe potential therapeutic strategies in preclinical and clinical development that aim to target them to further expand the range of current treatment options.


Replication landscape of the human genome.
Despite intense investigation, human replication origins and termini remain elusive. Existing data have shown strong discrepancies. Here we sequenced highly purified Okazaki fragments from two cell types and, for the first time, quantitated replication fork directionality and delineated initiation and termination zones genome-wide. Replication initiates stochastically, primarily within non-transcribed, broad (up to 150 kb) zones that often abut transcribed genes, and terminates dispersively between them. Replication fork progression is significantly co-oriented with the transcription. Initiation and termination zones are frequently contiguous, sometimes separated by regions of unidirectional replication. Initiation zones are enriched in open chromatin and enhancer marks, even when not flanked by genes, and often border 'topologically associating domains' (TADs). Initiation zones are enriched in origin recognition complex (ORC)-binding sites and better align to origins previously mapped using bubble-trap than λ-exonuclease. This novel panorama of replication reveals how chromatin and transcription modulate the initiation process to create cell-type-specific replication programs.


Growth in fossil and extant deer and implications for body size and life history evolution.
Body size variation within clades of mammals is widespread, but the developmental and life-history mechanisms by which this variation is achieved are poorly understood, especially in extinct forms. An illustrative case study is that of the dwarfed morphotypes of Candiacervus from the Pleistocene of Crete versus the giant deer Megaloceros giganteus, both in a clade together with Dama dama among extant species. Histological analyses of long bones and teeth in a phylogenetic context have been shown to provide reliable estimates of growth and life history patterns in extant and extinct mammals. Similarity of bone tissue types across the eight species examined indicates a comparable mode of growth in deer, with long bones mainly possessing primary plexiform fibrolamellar bone. Low absolute growth rates characterize dwarf Candiacervus sp. II and C. ropalophorus compared to Megaloceros giganteus displaying high rates, whereas Dama dama is characterized by intermediate to low growth rates. The lowest recorded rates are those of the Miocene small stem cervid Procervulus praelucidus. Skeletal maturity estimates indicate late attainment in sampled Candiacervus and Procervulus praelucidus. Tooth cementum analysis of first molars of two senile Megaloceros giganteus specimens revealed ages of 16 and 19 years whereas two old dwarf Candiacervus specimens gave ages of 12 and 18 years. There is a rich histological record of growth across deer species recorded in long bones and teeth, which can be used to understand ontogenetic patterns within species and phylogenetic ones across species. Growth rates sensu Sander & Tückmantel plotted against the anteroposterior bone diameter as a proxy for body mass indicate three groups: one with high growth rates including Megaloceros, Cervus, Alces, and Dama; an intermediate group with Capreolus and Muntiacus; and a group showing low growth rates, including dwarf Candiacervus and Procervulus. Dwarf Candiacervus, in an allometric context, show an extended lifespan compared to other deer of similar body size such as Mazama which has a maximum longevity of 12 years in the wild. Comparison with other clades of mammals reveals that changes in size and life history in evolution have occurred in parallel, with various modes of skeletal tissue modification.


Primary genome scan for complex body shape-related traits in the common carp Cyprinus carpio.
To identify quantitative trait loci (QTL) that affect body shape in common carp Cyprinus carpio, a linkage map, 2159·23 cM long, was constructed with a total of 307 markers covering 51 linkage groups (LG). The map included 167 new single nucleotide polymorphism (SNP) markers derived from expressed sequence tags (EST) together with 140 microsatellite markers reported earlier. A primary genome scan was conducted for QTL for standard length (L(S)), head length (L(H)), body height (H(B)), body width (W(B)) and tail length (L(TAIL)) in an F1 line containing 92 offspring. A total of 15 suggestive QTL on six LGs were found to associate with L(S), L(H), H(B), W(B) and L(TAIL) which explained 10·7-17·4% of the variance. Five significant QTL were detected for body-shape related traits and located for LGs (lg1, 12 and 20). These QTL included: one associated with L(S) (21·1% variance explained), three for H(B) (almost 20% variance explained) and one for W(B) (20·7% variance explained).


The impact of the COVID-19 pandemic on people with rheumatic and musculoskeletal diseases: insights from patient-generated data on social media.
During the COVID-19 pandemic, much communication occurred online, through social media. This study aimed to provide patient perspective data on how the COVID-19 pandemic impacted people with rheumatic and musculoskeletal diseases (RMDs), using Twitter-based patient-generated health data (PGHD). A convenience sample of Twitter messages in English posted by people with RMDs was extracted between 1 March and 12 July 2020 and examined using thematic analysis. Included were Twitter messages that mentioned keywords and hashtags related to both COVID-19 (or SARS-CoV-2) and select RMDs. The RMDs monitored included inflammatory-driven (joint) conditions (ankylosing spondylitis, RA, PsA, lupus/SLE and gout). The analysis included 569 tweets by 375 Twitter users with RMDs across several countries. Eight themes emerged regarding the impact of the COVID-19 pandemic on people with RMDs: (i) lack of understanding of SARS-CoV-2/COVID-19; (ii) critical changes in health behaviour; (iii) challenges in healthcare practice and communication with healthcare professionals; (iv) difficulties with access to medical care; (v) negative impact on physical and mental health, coping strategies; (vi) issues around work participation; (vii) negative effects of the media; and (viii) awareness-raising. The findings show that Twitter serves as a real-time data source to understand the impact of the COVID-19 pandemic on people with RMDs. The platform provided 'early signals' of potentially critical health behaviour changes. Future epidemics might benefit from the real-time use of Twitter-based PGHD to identify emerging health needs, facilitate communication and inform clinical practice decisions.


Conformational control of nonplanar free base porphyrins: towards bifunctional catalysts of tunable basicity.
For the first time, free base and N-methylated porphyrins have been utilized as bifunctional organocatalysts in Michael additions and it was found that distortion of the macrocycle is a vital prerequisite for their catalytic activity. Conformational design has been used to tailor the properties of nonplanar porphyrins with regards to availability of the N-H units for hydrogen bonding (distortion-dependent hydrogen bonding) and the basicity of the heterocyclic groups. NMR spectroscopic- and catalyst screening studies provided insight into the likely mode of catalyst action. This unprecedented use of free base and N-substituted porphyrins as organocatalysts opens a new functional role for porphyrins.


Vital role of chest CT in diagnosis of coronavirus disease 2019 (COVID-19).
In December 2019, a new virus called coronavirus disease 2019 (COVID-19) causing severe acute respiratory syndrome emerged in Wuhan, China, and rapidly spread to other areas of China and other regions of the world. Since it was a discovery, COVID-19 has spread to several countries and to this date, affecting about 2,329,651 people and caused about 160,721 deaths. Since most COVID-19 infected cases were diagnosed with pneumonia and characteristic chest computed tomography (CT) scan patterns, radiological examinations have become an important tool in early diagnosis. Nowadays, CT findings combined with normal blood cells (WBCs), lymphopenia and a history of epidemiological exposure have been used as criteria for clinical diagnosis of COVID-19. It is noteworthy that reverse transcription polymerase chain reaction (RT-PCR) test is still gold standard for the diagnosis. This review focuses on role of chest CT in the clinical evaluation of disease progression and more accurate diagnosis.


Effects and Mechanism of SO2 Inhalation on Rat Myocardial Collagen Fibers.
BACKGROUND This study investigates the effects and mechanism of sulfur dioxide (SO2) inhalation and exercise on rat myocardial collagen fiber. MATERIAL AND METHODS The rats were randomly divided into 4 groups: a control group (RG), an exercise group (EG), an SO2 pollution group (SRG), and an SO2 pollution and exercise group (SEG). Body weight, cardiac index, and left ventricular index in each group were compared. The myocardial hydroxyproline (Hyp) concentration was determined by pepsin acid hydrolysis. The interstitial myocardial collagen expression was measured by Sirius Red F3B in saturated carbazotic acid. The local myocardial angiotensin II type 1 receptor (AT1R) and connective tissue growth factor (CTGF) expression was tested by immunohistochemistry SABC method. RESULTS Compared with RG, the weight growth rate of EG, SRG, and SEG decreased significantly (P<0.01). Compared with EG, the body weight growth rate of SEG significantly decreased (P<0.01) and cardiac index and left ventricular index decreased but without a significant difference. Compared with EG, myocardial Hyp and collagen concentration, myocardial collagen volume fraction (CVF), perivascular collagen area (PVCA), and the expression of AT1R and CTGF in myocardium of SEG increased significantly (P<0.01). CONCLUSIONS SO2 inhalation and exercise will not only offset beneficial health effects of movement on the cardiovascular system, but also produce more unfavorable influences. People should pay attention to their environment when exercising, and try to avoid exercising in environments with SO2 pollution.


The Use of ß-Elemene to Enhance Radio Sensitization of A375 Human Melanoma Cells.
Melanoma is the most malignant and severe type of skin cancer. It is a tumor with a high risk of metastasis and resistant to conventional treatment methods (surgery, radiotherapy, and chemotherapy). β-elemene is the most active constituent of Curcuma wenyujin which is a non-cytotoxic antitumor drug, proved to be effective in different types of cancers. The study aimed to investigate the therapeutic effects of β-elemene in combination with radiotherapy on A375 human melanoma. In this experimental study, human melanoma cells were grown in the monolayer culture model. The procedure of the treatment was performed by the addition of different concentrations of β-elemene to the cells. Then, the cells were exposed to 2 and 4 Gy X-ray in different incubation times (24, 48, and 72 hours). The MTT assay was used for the determination of the cell viability. To study the rate of apoptosis response to treatments, the Annexin V/PI assay was carried out. The results of the MTT assay showed β-elemene reduced the cell proliferation in dose- and time-dependent manners in cells exposed to radiation. Flow cytometry analysis indicated that β-elemene was effective in the induction of apoptosis. Furthermore, the combination treatment with radiation remarkably decreased the cells proliferation ability and also enhanced apoptosis. For example, cell viability in a group exposed to 40 μg/ml of β-elemene was 80%, but combination treatment with 6 MV X beam at a dose of 2 Gy reduced the viability to 61%. Our results showed that β-elemene reduced the proliferation of human melanoma cancer cell through apoptosis. Also, the results demonstrated that the radio sensitivity of A375 cell line was significantly enhanced by β-elemene. The findings of this study indicated the efficiency of β-elemene in treating melanoma cells and the necessity for further research in this field.


Cisapride for gastroesophageal reflux disease: a placebo-controlled, double-blind study.
To evaluate the safety and efficacy of cisapride in patients with gastroesophageal reflux disease. Patients (N = 177) were randomized to double-blind treatment with cisapride (10 or 20 mg q.i.d.) or placebo for 12 wk. Efficacy was determined by pre- and poststudy endoscopies, symptom assessments by patient and physician, and Maalox consumption. Safety evaluations included vital signs, electrocardiograms, clinical laboratory tests, and reports of adverse events. Cisapride 10 mg significantly reduced daytime and nighttime heartburn at 4 wk compared with placebo. Cisapride 20 mg reduced both daytime and nighttime heartburn at 4, 8, and 12 wk, compared with placebo, and was also significantly superior to the 10-mg dose at 12 wk. The percent of patients with endoscopic healing was significantly higher with cisapride 20 mg than with placebo [healing: 51 vs 36% (p < or = 0.044)]. Maalox usage declined significantly with cisapride 20 mg compared with placebo. No clinically significant changes in safety variables occurred with cisapride. The most frequently reported adverse events in the cisapride group were diarrhea, headache, and sinusitis. Cisapride 10 and 20 mg q.i.d. were safe and well tolerated in a population of patients with mild-to-moderate gastroesophageal reflux disease. Both symptoms and endoscopic grade improved after 12 wk of treatment with cisapride 20 mg q.i.d.


Effect of combined haloperidol-lithium treatment on vitro RBC lithium uptake in patients with affective disorders.
Combined treatment with haloperidol and lithium is a frequently employed strategy for the treatment of acute psychoses. Although this combination regime is safe in most clinical situations, under certain circumstances it has resulted in neurotoxicity, with organic brain syndrome, and ultimately, in some patients, irreversible brain damage and death. Plasma lithium levels in these neurotoxic patients are generally within the clinically acceptable range of 0.7 - 1.5 mEq/l, but RBC-lithium levels, when reported are abnormally elevated. To account for these observations we hypothesized that in vivo haloperidol will alter the transport of lithium across the RBC membrane and thus cause an increase in RBC lithium levels. We report preliminary results from a study that tested this hypothesis by measuring RBC lithium transport in vitro, in patients treated with a) haloperidol only, b) haloperidol, followed by haloperidol and lithium, c) combined haloperidol and lithium. In eight manic depressive patients in vivo haloperidol alone, or in combination with lithium resulted in a statistically significant (p less than 0.0001) reduction of the in vitro RBC Li+ uptake values. These results are interpreted as supportive of our hypothesis, that in vivo haloperidol alters the transport of lithium across the RBC membrane, and this effect can be detected by the use of a sensitive in vitro test. Work is currently in progress to evaluate, whether the RBC Li+ transport alteration is due to a direct effect of the drug on the cell membrane or secondary to some circulating factor, and to extend these findings to a larger sample of patients.


Diet composition and activity level of at risk and metabolically healthy obese American adults.
Obesity often clusters with other major cardiovascular disease risk factors, yet a subset of the obese appears to be protected from these risks. Two obesity phenotypes are described, (i) "metabolically healthy" obese, broadly defined as body mass index (BMI) ≥ 30 kg/m(2) and favorable levels of blood pressure, lipids, and glucose; and (ii) "at risk" obese, BMI ≥ 30 with unfavorable levels of these risk factors. More than 30% of obese American adults are metabolically healthy. Diet and activity determinants of obesity phenotypes are unclear. We hypothesized that metabolically healthy obese have more favorable behavioral factors, including less adverse diet composition and higher activity levels than at risk obese in the multi-ethnic group of 775 obese American adults ages 40-59 years from the International Population Study on Macro/Micronutrients and Blood Pressure (INTERMAP) cohort. In gender-stratified analyses, mean values for diet composition and activity behavior variables, adjusted for age, race, and education, were compared between metabolically healthy and at risk obese. Nearly one in five (149/775 or 19%) of obese American INTERMAP participants were classified as metabolically healthy obese. Diet composition and most activity behaviors were similar between obesity phenotypes, although metabolically healthy obese women reported higher sleep duration than at risk obese women. These results do not support hypotheses that diet composition and/or physical activity account for the absence of cardiometabolic abnormalities in metabolically healthy obese.


Bisphenol A exposure in relation to altered lipid profile and dyslipidemia among Chinese adults: A repeated measures study.
Animal experiments suggest that bisphenol A (BPA) could potentially induce lipid abnormalities. However, whether BPA exposure associates with altered lipid metabolism in humans has not been fully elucidated. We thus comprehensively investigated the relationship of BPA exposure and its change with lipid profile and development of incident dyslipidemia among Chinese adults. We initially included 1872 participants aged 40 years or older who were free of dyslipidemia at baseline in 2009, and followed them for 4 years. Urinary BPA and serum lipids including total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG) were determined at baseline and follow-up. Linear mixed models were used for repeated measures analyses and linear and logistic regression models were used to evaluate longitudinal changes in lipid profile and risk of incident dyslipidemia. In repeated measures analyses, per doubling of urinary BPA concentrations was associated with higher serum levels of LDL-C, non-HDL-C, TC to HDL-C ratio, and lower levels of HDL-C and TG. In longitudinal change analyses, participants with high BPA at both baseline and follow-up showed an additional 2.94% increase in LDL-C (95% CI: 0.02%, 5.95%) and 6.12% increase in TG (95% CI: 0.74%, 11.8%), as compared with those who maintained low BPA. Furthermore, participants with sustained high BPA at two time points had increased odds of developing hyper-LDL cholesterolemia (odds ratio = 1.93, 95% CI: 1.02, 3.66). Our results suggested that high BPA exposure, especially maintained a long time period apart, was associated with deterioration of lipid profiles among middle-aged and elderly adults, supporting a detrimental role of BPA in lipid metabolism.


What is the optimal protocol to decontaminate a dropped custom polyethylene component?
With advancements in manufacturing technology, custom orthopedic implants have become commercially available. A new concern with these implants is what to do when custom heat-sensitive components are contaminated. While intraoperative decontamination protocols for dropped autograft tissue have been described, no literature describes an intraoperative protocol for decontaminating one-of-a-kind polyethylene implants. The purpose of this work is to describe and evaluate polyethylene decontamination protocols using materials found in the average operating suite that could be used intraoperatively. Sixteen custom polyethylene inserts were contaminated with potting soil and processed in one of four protocols: 1) hydrogen peroxide, 2) chlorhexidine gluconate, 3) povidone-iodine, or 4) control. Following processing, the implants were cultured with swabs or sonication. Each implant was evaluated with one aerobic, one anaerobic, and one fungal culture. All cultures from implants processed with both the chlorhexidine and povidone-iodine protocols were negative. One colony of Ralstonia species was isolated on the aerobic culture from one of the implants processed with hydrogen peroxide. The remainder of the cultures from implants processed with the hydrogen peroxide protocol were negative. All of the cultures for each culture modality from all of the control implants were positive with florid proliferation. In the rare situation that a custom polyethylene insert becomes contaminated intraoperatively, the surgeon should consider all salvage options. Chlorhexidine and povidone-iodine decontamination protocols eliminated bacterial growth following culture swabs or sonicate taken from the contaminated polyethylene inserts while hydrogen peroxide failed in one case to completely eradicate growth.


Detection and management of atrial fibrillation after cryptogenic stroke or embolic stroke of undetermined source.
Cryptogenic stroke (CS) and embolic stroke of unknown source (ESUS) represent a major challenge to healthcare systems worldwide. Atrial fibrillation (AF) is commonly found after CS or ESUS. Independent of the mechanism of the index CS or ESUS, detection of AF in these patients offers the opportunity to reduce the risk of stroke recurrence by prescribing an anticoagulant instead of aspirin. The detection of AF may be pursued with different monitoring strategies. Comparison of monitoring strategies should take into account that AF detection rates reported in published studies, and then pooled in meta-analyses, are not only a function of the monitoring strategy itself, but also depend on patient-related, device-related, and study design-related factors. Once AF is found, the decision to anticoagulate a patient should be made on the basis of AF burden and the baseline risk of the patient. Empirical anticoagulation in patients with ESUS and no evidence of AF is an intriguing but still-unproven strategy and therefore should not be adopted outside of randomized clinical trials.


New insights into the upregulation and function of the salivary Na+-K+-2Cl- cotransporter.
In many exocrine epithelia, the Na+-K+-2Cl- cotransporter is the main provider of cellular chloride entry during transepithelial salt and water secretion. Because of its accessibility and hormonal responsiveness, the salivary gland has recently emerged as a convenient preparation in which to study the regulation and characteristics of this transport protein. In this review, we summarize recent findings from our laboratory which demonstrate that muscarinic, alpha1-adrenergic and peptidergic stimulation of rat parotid acinar cells induce a dramatic (up to twenty-fold) upregulation of Na+-K+-2Cl- cotransporter activity. Our results indicate that this effect is dependent on the rise in intracellular calcium concentration ([Ca2+]i) that accompanies stimulation, and is not a consequence of the KCl loss and the concomitant cell shrinkage associated with fluid secretion. In addition, we show that the effect of muscarinic stimulation on the cotransporter can be blocked by inhibitors of phospholipase A2, by a general inhibitor of arachidonic acid metabolism, and by specific inhibitors of the cytochrome P450 pathway. These data argue strongly for the involvement of a product of the cytochrome P450 pathway of arachidonic acid metabolism in upregulation of the salivary Na+-K+-2Cl- cotransporter.


Factors affecting healing and survival after finger amputations in patients with digital artery occlusive disease.
Finger amputations are typically performed as distal as possible to preserve maximum finger length. Failure of primary amputation leads to additional procedures, which could potentially be avoided if a more proximal amputation was initially performed. The effect of single versus multiple procedures on morbidity and mortality is not known. We evaluated factors that predicted primary healing and the effects of secondary procedures on survival. Patients undergoing finger amputations from 1995 to 2011 were evaluated for survival with uni- and multivariate analysis of demographic data and preoperative vascular laboratory studies to assess factors influencing primary healing. Seventy-six patients underwent 175 finger amputations (range 1 to 6 fingers per patient). Forty-one percent had diabetes, 33% had nonatherosclerotic digital artery disease, and 29% were on dialysis. Sex distribution was equal. Primary healing occurred in 78.9%, with the remainder requiring revisions. By logistic regression analysis, nonatherosclerotic digital artery disease was associated with failure of primary healing (odds ratio = 7.5; 95% confidence interval, 1.03 to 54; P = .047). Digital photoplethysmography did not predict primary healing. The overall healing of primary and secondary finger amputations was 96.0%. The mean survival after the initial finger amputation was 34.3 months and did not differ between patients undergoing single (35.6 months) versus multiple procedures (33.6 months). Dialysis dependence was associated with decreased survival (hazard ratio = 2.9; 95% confidence interval, 1.13 to 7.25; P = .026). Failure of primary healing is associated with the presence of nonatherosclerotic digital artery disease and is not predicted by digital photoplethysmographic studies. Dialysis dependence is associated with decreased survival in patients with finger amputations, but failure of primary healing does not adversely affect survival. A strategy of aggressive preservation of finger length is appropriate for most patients.


Compared performance of Spot and SW800 photoscreeners on Chinese children.
To evaluate the effectiveness of Spot photoscreener and SW800 vision screener in detecting amblyopia risk factors in Chinese children between 4 and 6 years of age. One hundred and thirteen children (226 eyes) underwent complete ophthalmologic examination, cycloplegic retinoscopy refraction, prism cover tests and photoscreen using both Spot (v2.1.4) and SW800 (v22.214.171.124) photoscreeners. The agreement of results obtained from photoscreener and retinoscopy was evaluated by paired t-test as well as Pearson correlation test. The sensitivity and specificity of detecting amblyopia risk factors were calculated based on the American Association of Pediatric Ophthalmology and Strabismus 2013 guidelines. The overall effectiveness of detecting amblyopia risk factors by using either photoscreener was analysed by receiver operating characteristic (ROC) curves. A strong linear agreement was observed between Spot and retinoscopy (p<0.01) in aspects of spherical equivalent (SE, Pearson's r=0.95), dioptre sphere (DS, r=0.97), dioptre cylinder (DC, r=0.84) and horizontal deviation (Hdev, r=0.91), with overall -0.17 D myopic shift of SE. Significant correlation was also shown between SW800 and retinoscopy (p<0.01) in aspects of SE (r=0.90), DS (r=0.93), DC (r=0.82) and Hdev (r=0.80), with overall -0.12 D myopic shift of SE. The overall sensitivity and specificity in detecting amblyopia risk factors were 94.0% and 80.0% for Spot and 88.8% and 81.1% for SW800. The measurements of Spot and SW800 photoscreener showed a strong agreement with cycloplegic retinoscopy refraction and prism cover tests. The performance of both screeners in detecting individual amblyopia risk factors is satisfactory. ROC analysis indicates that the Spot and SW800 performed very similarly in detecting amblyopia risk factors.


Does increased aromatase activity in adipose fibroblasts cause low sexual desire in patients with HIV lipodystrophy?
There is evidence from our own unit and other workers that many patients who have lipodystrophy on HAART given for HIV disease also have raised oestrogen levels and complain of low sexual desire. This hypothesis paper discusses a possible pathological mechanism for these changes--an increase in the number of fibroblasts and macrophages present in lipoatrophic areas that could convert testosterone to oestrogen by intracellular aromatisation. This process is known to be enhanced by increased levels of tumour necrosis factor, interleukin 6 (IL-6), and hydroxycorticosteroids present in many patients with HIV lipodystrophy. Treatment options are discussed, including aromatase inhibitors and testosterone.


Mediterranean diet adherence during pregnancy and fetal growth: INMA (Spain) and RHEA (Greece) mother-child cohort studies.
Dietary intake of specific nutrients or food groups during pregnancy could influence fetal growth, but scant evidence is available on effects of dietary patterns. The aim of this study was to evaluate the impact of Mediterranean diet (MD) adherence during pregnancy on fetal growth in two population-based mother-child cohorts in Spain and Greece. We studied 2461 mother-newborn pairs from the Spanish multi-centre 'INMA' study (Atlantic area: INMA-Atlantic; Mediterranean area: INMA-Mediterranean), and 889 pairs from the 'RHEA' study in Crete, Greece. Maternal diet during pregnancy was assessed by FFQ and MD adherence was evaluated through an a priori score. Fetal growth restriction was based on a customised model, and multivariate log-binomial and linear regression models were used to adjust for several confounders. MD scores differ significantly between the cohorts with women in INMA-Atlantic reporting higher intakes of fish and dairy products, while women in the Mediterranean area reported higher intakes of cereals, vegetables and fruits. Women with high MD adherence had a significantly lower risk of delivering a fetal growth-restricted infant for weight (risk ratios: 0·5; 95 % CI 0·3, 0·9) in the INMA-Mediterranean cohort. Stratified analysis by smoking revealed that higher MD adherence increased birth weight and birth length in smoking mothers, whereas this effect was not apparent in non-smoking mothers. The results of the present study show that several types of MD exist across European Mediterranean regions. High MD adherence may modify the detrimental effect of smoking on birth size, but overall effects of diet were not universal for the studies in this analysis.


The newly graduated Canadian urologist: Over-trained and underemployed?
There are two prevailing perceptions among urology residents (1) fellowship training is becoming a requirement after residency, and (2) there are few job opportunities after graduation. In this study, we examine postgraduate training patterns and employment choices of urology residents. All Canadian urology program directors provided a summary of fellowship training and employment of Canadian residents graduating between 1998 and 2009. Logistic regression models were used to detect linear trends. In total, 258 Canadian urology residents graduated over the study period, with a median of 22 (interquartile range 21-22) graduating per year. Of these, 72% completed a fellowship. Of these fellowships, 62% included protected research time. The most common subspecialty area was minimally invasive surgery (MIS)/endourology (39% of fellowships). There was a significant increase in fellowship training over time (p < 0.0001); this was mostly due to an increase in MIS/endourology fellowships. The number of urologists obtaining graduate degrees after medical school has increased significantly over the study period. Almost all graduates are employed. Of the employed graduates in total, 34% are academic urologists. Among all graduates, 50% are practicing within 100 km of their residency site, 16% are practicing in the United States and 22% are in rural practice. There has been no significant change over time in the proportion of residents practicing within 100 km of their training program, practicing rurally, leaving their province of training, practicing in the United States, or choosing academic practice. Fellowship training, especially in MIS/endourology, has become significantly more common. Graduate degrees are more frequently being obtained. We did not find evidence that there has been a significant change in a urology resident's ultimate ability to obtain employment upon graduation.


Paclitaxel in the treatment of hormone-refractory prostate cancer.
Prostate cancer is the most frequently diagnosed cancer and the second leading cause of cancer death in men in the United States. In 1997 it was estimated that more than 41,000 men died of this disease. Treatment of metastatic disease remains palliative, with androgen ablation used as first-line therapy. After failure of androgen ablation, chemotherapy can now be used to induce a remission in many men. Treatment regimens that include paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) have been particularly successful in treating hormone-refractory prostate cancer in the phase II setting. We have conducted a trial of estramustine 280 mg orally three times per day for 14 days combined with etoposide 50 mg/m2/d (in general, one 50-mg tablet twice a day) for 14 days, with paclitaxel 135 mg/m2 over 1 hour on day 2. This regimen is repeated every 21 days for a maximum of six cycles. Patients responding to therapy are then given a break and re-treated at physician discretion. On preliminary analysis, 24 of 38 patients demonstrated a decline in pretreatment prostate-specific antigen of more than 50% (63%). The regimen was well-tolerated and only seven patients demonstrated grade 3 or 4 neutropenia. Further analysis is ongoing.


Picosecond kinetics of the initial photochemical electron-transfer reaction in bacterial photosynthetic reaction centers.
The absorption changes that occur in reaction centers of the photosynthetic bacterium Rhodopseudomonas sphaeroides during the initial photochemical electron-transfer reaction have been examined. Measurements were made between 740 and 1300 nm at 295 and 80 K by using a pulse-probe technique with 610-nm, 0.8-ps flashes. An excited singlet state of the bacteriochlorophyll dimer P* was found to give rise to stimulated emission with a spectrum similar to that determined previously for fluorescence from reaction centers. The stimulated emission was used to follow the decay of P*; its lifetime was 4.1 +/- 0.2 ps at 295 K and 2.2 +/- 0.1 ps at 80 K. Within the experimental uncertainty, the absorption changes associated with the formation of a bacteriopheophytin anion, Bph-, develop in concert with the decay of P* at both temperatures, as does the absorption increase near 1250 nm due to the formation of the cation of P, P+. No evidence was found for the formation of a bacteriochlorophyll anion, Bchl-, prior to the formation of Bph-. This is surprising, because in the crystal structure of the Rhodopseudomonas viridis reaction center [Deisenhofer, J., Epp, O., Miki, K., Huber, R., & Michel, H. (1984) J. Mol. Biol. 180, 385-398] a Bchl is located approximately in between P and the Bph. It is possible that Bchl- (or Bchl+) is formed but, due to kinetic or thermodynamic constraints, is never present at a sufficient concentration for us to observe. Alternatively, a virtual charge-transfer state, such as P+Bchl-Bph or PBchl+Bph-, could serve to lower the energy barrier for direct electron transfer between P* and the Bph.


Researchers on research integrity: a survey of European and American researchers.
Reports of questionable or detrimental research practices (QRPs) call into question the reliability of scientific evidence and the trustworthiness of research. A critical component of the research ecosystem is the organization within which research takes place. We conducted a survey to explore the attitudes and beliefs of European and American researchers about the organisations in which they work, their own research practices and their attitudes towards research integrity and research integrity policies. We administered an online survey (International Research Integrity Survey (IRIS)) to 2,300 active researchers based in the US and 45,000 in Europe (including UK, Norway, Iceland and Switzerland). We employed a stratified probability sample of the authors of research articles published between 2016 and 2020 included in Clarivate's Web of Science citation database. Coverage includes researchers in the humanities, social sciences, natural sciences and medical sciences, who hold at least a master's level degree. In comparison to researchers in the US, European researchers admit to more QRPs and are less confident in maintaining high research integrity (RI) standards. In the US and Europe, many researchers judge their organization to fall short of best RI practice. All researchers recognize the benefits of RI, reliable knowledge and the trust of colleagues and the public, and there is support for RI training particularly among Europeans. To create and maintain a culture of integrity in scientific research, a collective commitment from researchers, their institutions and funders is needed. Researchers rely on many channels of communication about research integrity and thus the involvement of many different participants in the research system is required to make improvements. Policies must be developed to reinforce best practice rather than being seen as an irrelevance to the real business of research.


Chaos in blood flow control in genetic and renovascular hypertensive rats.
Hydrostatic pressure and flow in renal proximal tubules oscillate at 30-40 mHz in normotensive rats anesthetized with halothane. The oscillations originate in tubuloglomerular feedback, a mechanism that provides local blood flow regulation. Instead of oscillations, spontaneously hypertensive rats (SHR) have aperiodic tubular pressure fluctuations; the pattern is suggestive of deterministic chaos. Normal rats made hypertensive by clipping one renal artery had similar aperiodic tubular pressure fluctuations in the unclipped kidney, and the fraction of rats with irregular fluctuations increased with time after the application of the renal artery clip. Statistical measures of deterministic chaos were applied to tubular pressure data. The correlation dimension, a measure of the dimension of the phase space attractor generating the time series, indicated the presence of a low-dimension strange attractor, and the largest Lyapunov exponent, a measure of the rate of divergence in phase space, was positive, indicating sensitivity to initial conditions. These time series therefore satisfy two criteria of deterministic chaos. The measures were the same in SHR as in rats with renovascular hypertension. Since two different models of hypertension displayed similar dynamics, we suggest that chaotic behavior is a common feature of renal vascular control in the natural history of the disease.


Socioeconomic inequality in catastrophic health expenditure in Brazil.
To analyze the evolution of catastrophic health expenditure and the inequalities in such expenses, according to the socioeconomic characteristics of Brazilian families. Data from the National Household Budget 2002-2003 (48,470 households) and 2008-2009 (55,970 households) were analyzed. Catastrophic health expenditure was defined as excess expenditure, considering different methods of calculation: 10.0% and 20.0% of total consumption and 40.0% of the family's capacity to pay. The National Economic Indicator and schooling were considered as socioeconomic characteristics. Inequality measures utilized were the relative difference between rates, the rates ratio, and concentration index. The catastrophic health expenditure varied between 0.7% and 21.0%, depending on the calculation method. The lowest prevalences were noted in relation to the capacity to pay, while the highest, in relation to total consumption. The prevalence of catastrophic health expenditure increased by 25.0% from 2002-2003 to 2008-2009 when the cutoff point of 20.0% relating to the total consumption was considered and by 100% when 40.0% or more of the capacity to pay was applied as the cut-off point. Socioeconomic inequalities in the catastrophic health expenditure in Brazil between 2002-2003 and 2008-2009 increased significantly, becoming 5.20 times higher among the poorest and 4.17 times higher among the least educated. There was an increase in catastrophic health expenditure among Brazilian families, principally among the poorest and those headed by the least-educated individuals, contributing to an increase in social inequality.


The Local and Systemic Immune Response to Intrauterine LPS in the Prepartum Mouse.
Inflammation plays a key role in human term and preterm labor (PTL). Intrauterine LPS has been widely used to model inflammation-induced complications of pregnancy, including PTL. It has been shown to induce an intense myometrial inflammatory cell infiltration, but the role of LPS-induced inflammatory cell activation in labor onset and fetal demise is unclear. We investigated this using a mouse model of PTL, where an intrauterine injection of 10 μg of LPS (serotype 0111:B4) was given at E16 of CD1 mouse pregnancy. This dose induced PTL at an average of 12.7 h postinjection in association with 85% fetal demise. Flow cytometry showed that LPS induced a dramatic systemic inflammatory response provoking a rapid and marked leucocyte infiltration into the maternal lung and liver in association with increased cytokine levels. Although there was acute placental inflammatory gene expression, there was no corresponding increase in fetal brain inflammatory gene expression until after fetal demise. There was marked myometrial activation of NFκB and MAPK/AP-1 systems in association with increased chemokine and cytokine levels, both of which peaked with the onset of parturition. Myometrial macrophage and neutrophil numbers were greater in the LPS-injected mice with labor onset only; prior to labor, myometrial neutrophils and monocytes numbers were greater in PBS-injected mice, but this was not associated with an earlier onset of labor. These data suggest that intrauterine LPS induces parturition directly, independent of myometrial inflammatory cell infiltration, and that fetal demise occurs without fetal inflammation. Intrauterine LPS provokes a marked local and systemic inflammatory response but with limited inflammatory cell infiltration into the myometrium or placenta.


What COVID-19 Reveals about the Neglect of WASH within Infection Prevention in Low-Resource Healthcare Facilities.
The highly infectious nature of the SARS-CoV-2 virus requires rigorous infection prevention and control (IPC) to reduce the transmission of COVID-19 within healthcare facilities, but in low-resource settings, the lack of water access creates a perfect storm for low-handwashing adherence, ineffective surface decontamination, and other environmental cleaning functions that are critical for IPC compliance. Data from the WHO/UNICEF Joint Monitoring Programme show that one in four healthcare facilities globally lacks a functional water source on premises (i.e., basic water service); in sub-Saharan Africa, half of all healthcare facilities have no basic water services. But even these data do not tell the whole story, other water, sanitation, and hygiene (WASH) assessments in low-resource healthcare facilities have shown the detrimental effects of seasonal or temporary water shortages, nonfunctional water infrastructure, and fluctuating water quality. The rapid spread of COVID-19 forces us to reexamine prevailing norms within national health systems around the importance of WASH for quality of health care, the prioritization of WASH in healthcare facility investments, and the need for focused, cross-sector leadership and collaboration between WASH and health professionals. What COVID-19 reveals about infection prevention in low-resource healthcare facilities is that we can no longer afford to "work around" WASH deficiencies. Basic WASH services are a fundamental prerequisite to compliance with the principles of IPC that are necessary to protect patients and healthcare workers in every setting.


Characterization of the N-oligosaccharides attached to the atypical Asn-X-Cys sequence of recombinant human epidermal growth factor receptor.
The extracellular domain of human EGF receptor (sEGFR) produced by CHO cells has been used in various biophysical studies to elucidate the molecular mechanism of EGF-induced receptor activation. We have found that the CHO sEGFR contains one oligosaccharide chain attached to an atypical N-glycosylation consensus sequence, Asn(32 )-X( 33 )-Cys(34 ). The oligosaccharide structure at Asn(32 ) is a mixture of the monosialo and asialo forms of a core fucosylated biantennary complex-type oligosaccharide. Deletion of this atypical glycosylation site by replacement of Asn(32 ) with lysine changed neither the expression nor function of the full length EGFR in CHO cells. The glycosylation at Asn(32 ) in CHO sEGFR was incomplete: 20% of Asn(32 ) remained unmodified. Thus, CHO sEGFR itself is heterogeneous with respect to the glycosylation at Asn(32 ), which may cause problems in biophysical studies. An attempt to remove the oligosaccharide at Asn(32 ) enzymatically did not succeed under nondenaturing conditions. Therefore, sEGFR with the mutation of Asn(32) -> Lys(32 )is useful for biophysical and biochemical studies, and, particularly, for X-ray crystallography.


A prospective three-year cohort study of the epidemiology and virology of acute respiratory infections of children in rural India.
Acute respiratory infection (ARI) is a major killer of children in developing countries. Although the frequency of ARI is similar in both developed and developing countries, mortality due to ARI is 10-50 times higher in developing countries. Viruses are common causes of ARI among such children, yet the disease burden of these infections in rural communities is unknown. A prospective longitudinal study was carried out in children enrolled from two rural Indian villages at birth and followed weekly for the development of ARI, classified as upper respiratory infection, acute lower respiratory infection (ALRI), or severe ALRI. Respiratory syncytial virus (RSV), influenza, parainfluenza viruses and adenoviruses in nasopharyngeal aspirates were detected by direct fluorescent antibody testing (DFA) and, in addition, centrifugation enhanced culture for RSV was done. 281 infants enrolled in 39 months and followed until 42 months. During 440 child years of follow-up there were 1307 ARIs, including 236 ALRIs and 19 severe ALRIs. Virus specific incidence rates per 1000 child years for RSV were total ARI 234, ALRI 39, and severe ALRI 9; for influenza A total ARI 141, ALRI 39; for INF B total ARI 37; for PIV1 total ARI 23, for PIV2 total ARI 28, ALRI 5; for parainfluenza virus 3 total ARI 229, ALRI 48, and severe ALRI 5 and for adenovirus total ARI 18, ALRI 5. Repeat infections with RSV were seen in 18 children. RSV, influenza A and parainfluenza virus 3 were important causes of ARI among children in rural communities in India. These data will be useful for vaccine design, development and implementation purposes.


Quantum mechanically derived AMBER-compatible heme parameters for various states of the cytochrome P450 catalytic cycle.
Molecular mechanics (MM) methods are computationally affordable tools for screening chemical libraries of novel compounds for sites of P450 metabolism. One challenge for MM methods has been the absence of a consistent and transferable set of parameters for the heme within the P450 active site. Experimental data indicate that mammalian P450 enzymes vary greatly in the size, architecture, and plasticity of their active sites. Thus, obtaining X-ray-based geometries for the development of accurate MM parameters for the major classes of hepatic P450 remains a daunting task. Our previous work with preliminary gas-phase quantum mechanics (QM)-derived atomic partial charges greatly improved the accuracy of docking studies of raloxifene to CYP3A4. We have therefore developed and tested a consistent set of transferable MM parameters based on gas-phase QM calculations of two model systems of the heme-a truncated (T-HM) and a full (F-HM) for four states of the P450 catalytic cycle. Our results indicate that the use of the atomic partial charges from the F-HM further improves the accuracy of docked predictions for raloxifene to CYP3A4. Different patterns for substrate docking are also observed depending on the choice of heme model and state. Newly parameterized heme models are tested in implicit and explicitly solvated MD simulations in the absence and presence of enzyme structures, for CYP3A4, and appear to be stable on the nanosecond simulation timescale. The new force field for the various heme states may aid the community for simulations of P450 enzymes and other heme-containing enzymes.


Type I Interferon Receptor Signaling in Astrocytes Regulates Hippocampal Synaptic Plasticity and Cognitive Function of the Healthy CNS.
Type I interferon receptor (IFNAR) signaling is a hallmark of viral control and host protection. Here, we show that, in the hippocampus of healthy IFNAR-deficient mice, synapse number and synaptic plasticity, as well as spatial learning, are impaired. This is also the case for IFN-β-deficient animals. Moreover, antibody-mediated IFNAR blocking acutely interferes with neuronal plasticity, whereas a low-dose application of IFN-β has a positive effect on dendritic spine structure. Interfering with IFNAR signaling in different cell types shows a role for cognitive function and synaptic plasticity specifically mediated by astrocytes. Intriguingly, levels of the astrocytic glutamate-aspartate transporter (GLAST) are reduced significantly upon IFN-β treatment and increase following inhibition of IFNAR signaling. These results indicate that, besides the prominent role for host defense, IFNAR is important for synaptic plasticity as well as cognitive function. Astrocytes are at the center stage of this so-far-unknown signaling cascade.


Deactivation of Left Ventricular Assist Devices: Differing Perspectives of Cardiology and Hospice/Palliative Medicine Clinicians.
Beliefs around deactivation of a left ventricular assist device (LVAD) vary substantially among clinicians, institutions, and patients. Therefore, we sought to understand perspectives regarding LVAD deactivation among cardiology and hospice/palliative medicine (HPM) clinicians. We administered a 41-item survey via electronic mail to members of 3 cardiology and 1 HPM professional societies. A convergent parallel mixed-methods design was used. From October through November 2011, 7168 individuals were sent the survey and 440 responded. Three domains emerged: (1) LVAD as a life-sustaining therapy; (2) complexities of the process of LVAD deactivation; and (3) legal and ethical considerations of LVAD deactivation. Most respondents (cardiology 92%; HPM 81%; P = .15) believed that an LVAD is a life-sustaining treatment for patients with advanced heart failure; however, 60% of cardiology vs 2% of HPM clinicians believed a patient should be imminently dying to deactivate an LVAD (P < .001). Additionally, 87% of cardiology vs 100% of HPM clinicians believed the cause of death following LVAD deactivation was from underlying disease (P < .001), with 13% of cardiology clinicians considering it to be a form of euthanasia or physician-assisted suicide. Cardiology and HPM clinicians have differing perspectives regarding LVAD deactivation. Bridging the gaps and engaging in dialog between these 2 specialties is a critical first step in creating a more cohesive approach to care for LVAD patients.


Metabolome and gut microbiota variation with long-term intake of Panax ginseng extracts on rats.
Ginseng, a widely used functional food and food additive, has been proven to have promotion effects of health on the body. However, whether the long-term intake of Ginseng is beneficial or has side effects on an organism is still unclear. In this study, untargeted GC-TOFMS metabolomic analysis of serum, cecum and ileum intestinal contents was conducted to understand the effect of the long-term intake of Ginseng extracts. 16S rRNA microbial sequencing technology was applied to investigate the effect of Ginseng extracts on the structure of gut microbiota. Cytokines in spleen were detected to determine the effect of Ginseng extracts on the immune system. Compared to control groups, the metabolites in serum, cecum and ileum, such as amino acids, amines and other metabolites related to carbohydrate metabolism, significantly varied between the C and GS groups. Ginseng extracts affected the structure of gut microbiota with a decreased abundance of TM7, while the abundance of Proteobacteria, Methylobacteriaceae, Parasutterella, Sutterella increased in the GS group. The increased abundance of Bifidobacterium and Lactobacillus demonstrated that Ginseng extracts contribute to probiotic amplification. Highly correlated with Bifidobacterium and Lactobacillus, interleukin 4 (IL4), IL10 and immunoglobulin A (IgA) levels were significantly elevated after the long-term intake of Ginseng extracts. These results indicated that the long-term administration of Ginseng extracts positively affected the host-gut metabolism, immune system, the anti-inflammation process and the gut intestinal microbiota structure.


Effect of interferon-gamma on ACNU-induced DNA damage and cytotoxicity in human glioblastoma cells.
Interferons (IFNs) are a natural body defense with powerful effects on tumor growth, including gliomas. The direct effects of IFN-gamma on (1-4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3-nitrosourea hydrochloride (ACNU)-induced deoxyribonucleic acid (DNA) damage and cytotoxicity were investigated in two human glioblastoma cell lines, A-172 and T98G, using a single cell microgel electrophoresis technique and a microculture tetrazolium assay. The results demonstrated a synergistic effect of IFN-gamma with ACNU on intracellular damage in both cell lines. 10 micrograms/ml ACNU induced a cell inhibition rate of 23.9% in A-172 cells, and almost no effect on T98G cells. 1000 U/ml IFN-gamma and 10 micrograms/ml ACNU caused a significant increase in cell inhibition, 51.2% for A-172 and 72.3% for T98G cells. DNA damage in individual A-172 and T98G cells exposed to ACNU was enhanced significantly by IFN-gamma (p < 0.001). The findings suggest a direct effect of IFN-gamma on ACNU-induced cell damage in human glioma, in addition to its effect on immunomodulation.


Myopathy associated with hyperadrenocorticism in the dog.
Naturally occurring or iatrogenic hyperadrenocorticism was associated with myopathy in six dogs. One dog had muscle weakness and muscle atrophy but normal electromyographic findings. Five dogs had muscle stiffness, proximal appendicular muscle enlargement, and myotonic discharges on electromyography. Histologic, electron microscopic, and histochemical findings in the musculature of dogs that were examined were characteristic of noninflammatory degenerative myopathy. Clinical signs of the myopathy improved to varying degrees in five dogs that were treated for the hyperadrenocorticism.


Accelerator mass spectrometry in pharmaceutical research and development--a new ultrasensitive analytical method for isotope measurement.
Accelerator mass spectrometry (AMS) permits the measurement of elemental isotopes at the individual atom level. The main application of AMS in drug discovery and development will be in the analysis of 14-carbon (14C). The principle behind AMS is the separation of individual positively charged atoms through mass, charge and momentum differences. In order to obtain the high-energy charge state required for separation, negative atoms are accelerated through a high voltage field (up to 10 million volts) generated by a tandem Van de Graaff accelerator. In the middle of the accelerator, the outer valency electrons are stripped from the atom and the resulting charged species are separated and counted. For 14C, AMS counts the number of individual atoms rather than measuring radioactive decays. The result is that AMS is up to one million times more sensitive than decay counting. Radioactivity levels as low 0.0001 dpm can be detected using AMS. The exquisite sensitivity of AMS analysis means that much lower amounts of 14C can be used than for conventional counting methods. This makes it easier to use 14C for in vitro, preclinical and clinical research programmes. As 14C poses both a biological and environmental hazard, AMS permits much lower doses to be used. Human drug mass balance studies have been conducted with doses of 50 nanoCuries and below. Radioactive HPLC metabolite profiles of plasma extracts from subjects given nanoCurie doses of 14C-labelled drug have been obtained by injecting as little as 0.25 dpm onto an HPLC column. In studies of biologics, biosynthetically 14C-labelled recombinant protein has been produced with a specific radioactivity sufficient to conduct human clinical studies with AMS analysis. For one human recombinant protein an increase in sensitivity of 2,000-fold over ELISA was obtained with AMS measurement. AMS is an enabling technology that should prove of value in increasing human and environmental safety as well as allowing new research directions to be followed.


Electrochemical Ion Transfer with Thin Films of Poly(3-octylthiophene).
We report on the limiting conditions for ion-transfer voltammetry between an ion-exchanger doped and plasticized poly(vinyl chloride) (PVC) membrane and an electrolyte solution that was triggered via the oxidation of a poly(3-octylthiophene) (POT) solid-contact (SC), which was unexpectedly related to the thickness of the POT SC. An electropolymerized 60 nm thick film of POT coated with a plasticized PVC membrane exhibited a significant sodium transfer voltammetric signal whereas a thicker film (180 nm) did not display a measurable level of ion transfer due to a lack of oxidation of thick POT beneath the membrane film. In contrast, this peculiar phenomenon was not observed when the POT film was in direct contact with an organic solvent-based electrolyte. This evidence is indicative of three key points: (i) the coated membrane imposes a degree of rigidity to the system, which restricts the swelling of the POT film and its concomitant p-doping; (ii) this phenomenon is exacerbated with thicker POT films due to an initial morphology (rougher comprising a network of large POT nanoparticles), which gives rise to a diminished surface area and electrochemical reactivity in the POT SC; (iii) the rate of sodium transfer is higher with a thin POT film due to a smoother surface morphology made up of a network of smaller POT nanoparticles with an increased surface area and electrochemical reactivity. A variety of techniques including cyclic voltammetry (CV), electrochemical impedance spectroscopy (EIS), ellipsometry, scanning electron microscopy (SEM), atomic force microscopy (AFM), and synchrotron radiation-X-ray photoelectron spectroscopy (SR-XPS) were used to elucidate the mechanism of the POT thickness/POT surface roughness dependency on the electrochemical reactivity of the PVC/POT SC system.


Behavioral heterogeneity in an animal model of neuropsychiatric lupus.
Various psychiatric manifestations of unknown etiology are common in systemic autoimmune disease lupus erythematosus (SLE). Profound heterogeneity at clinical and neuropathological levels suggests distinct subpopulations of SLE patients and multiple mechanisms in the pathogenesis of aberrant behavior. Using inbred mice prone to SLE-like condition, we presently examine whether subpopulations of diseased mice can be identified on the basis of their behavioral performance. Hierarchical cluster analysis was used to classify 105 MRL-lpr males into clusters. Multivariate analysis of variance (MANOVA) and discriminant function analysis were used to detect overall differences and identify discriminative variables. Cluster 1 was characterized by blunted responsiveness to palatable stimulation, as well as increased spleen mass and serum levels of interleukin-1. Cluster 2 comprised of animals with reduced ambulation speed and enlarged spleen. Mice from cluster 3 showed profound dilatation of brain ventricles, reduced brain mass, impaired nutrition and performance in task reflective of emotional reactivity. Present results suggest that systemic autoimmunity compromises brain function via non-Mendelian mechanisms. Although neuroactive cytokines may impair reward systems, brain atrophy seems to underlie deficits in ingestive behavior and emotional reactivity. This study supports the hypothesis that multiple neuroimmunological pathways are involved in the etiology of aberrant behavior during SLE-like disease.


Detection of IgM and IgG complexes provides new insight into immune regulation of patients with malignancies: a randomized controlled trial.
Ig/Ig two-component-determined circulating immune complex (TCIC) may reveal alteration in immune regulation in patients. In the current study, IgM and IgG-TCIC was investigated in sera of patients suffering from esophagus, intestine, lung, nasopharyngeal, ovarian, breast, uterine and thyroid cancers, and hepatocellular carcinoma, Hodgkins lymphoma, non-Hodgkins lymphoma. This investigation was performed by detection of IgM/IgG-TCIC and IgG/IgM-TCIC with the use of ELISA by the reciprocal use of coating and detecting antibodies. The current study was carried out in 979 patients with these cancers and 401 healthy controls. We found that down-regulated IgM/IgG-TCIC was a common feature in these patients, whereas levels of IgG/IgM-TCIC showed significantly higher, lower or no difference with respect to the control. In summary, our results suggest that IgM and IgG-TCIC may play an important role in immune regulation during the course of malignancies and may be a hallmark for cancer pathogenesis. Decreased IgM/IgG-TCIC, accompanied by diverse IgG/IgM-TCIC, forms a peculiar trait in malignancies. Our findings thus provide new insights into immune regulation in patients with malignancies.


Treatment patterns, risk factor control and functional capacity in patients with cardiovascular and chronic kidney disease in the cardiac rehabilitation setting.
Chronic kidney disease (CKD) is a frequent comorbidity among elderly patients and those with cardiovascular disease. CKD carries prognostic relevance. We aimed to describe patient characteristics, risk factor management and control status of patients in cardiac rehabilitation (CR), differentiated by presence or absence of CKD. Data from 92,071 inpatients with adequate information to calculate glomerular filtration rate (GFR) based on the Cockcroft-Gault formula were analyzed at the beginning and the end of a 3-week CR stay. CKD was defined as estimated GFR <60 ml/min/1.73 m(2). Compared with non-CKD patients, CKD patients were significantly older (72.0 versus 58.0 years) and more often had diabetes mellitus, arterial hypertension, and atherothrombotic manifestations (previous stroke, peripheral arterial disease), but fewer were current or previous smokers had a CHD family history. Exercise capacity was much lower in CKD (59 vs. 92 Watts). Fewer patients with CKD were treated with percutaneous coronary intervention (PCI), but more had coronary artery bypass graft (CABG) surgery. Patients with CKD compared with non-CKD less frequently received statins, acetylsalicylic acid (ASA), clopidogrel, beta blockers, and angiotensin converting enzyme (ACE) inhibitors, and more frequently received angiotensin receptor blockers, insulin and oral anticoagulants. In CKD, mean low density lipoprotein cholesterol (LDL-C), total cholesterol, and high density lipoprotein cholesterol (HDL-C) were slightly higher at baseline, while triglycerides were substantially lower. This lipid pattern did not change at the discharge visit, but overall control rates for all described parameters (with the exception of HDL-C) were improved substantially. At discharge, systolic blood pressure (BP) was higher in CKD (124 versus 121 mmHg) and diastolic BP was lower (72 versus 74 mmHg). At discharge, 68.7% of CKD versus 71.9% of non-CKD patients had LDL-C <100 mg/dl. Physical fitness on exercise testing improved substantially in both groups. When the Modification of Diet in Renal Disease (MDRD) formula was used for CKD classification, there was no clinically relevant change in these results. Within a short period of 3-4 weeks, CR led to substantial improvements in key risk factors such as lipid profile, blood pressure, and physical fitness for all patients, even if CKD was present.


Preliminary Analysis of Brain Footprints in Multiple Sclerosis Females With Detrusor Sphincter Dyssynergia: A Concurrent Urodynamic and Functional Magnetic Resonance Imaging Study.
This study evaluates the grey and white brain matter characteristics in women with multiple sclerosis (MS) and detrusor sphincter dyssynergia (DSD). Grey matter is assessed via the functional connectivity (FC) of brain regions activated during voiding, using functional magnetic resonance imaging (fMRI). Two white matter tracts involved in bladder function, the anterior thalamic radiation (ATR) and superior longitudinal fasciculus (SLF), were evaluated using diffusion tensor imaging. Twenty-seven women with MS (2 groups: no-DSD [n=23] or DSD [n=4]), and 8 healthy controls (HCs) underwent concurrent urodynamic-fMRI evaluation with 4 cycles of bladder filling and emptying. A FC similarity measure (FC_sim) was calculated for each subject to express the similarity of individual FC at voiding initiation compared to all FC patterns. ATR and SLF tracts were traced and their fractional anisotropy (FA) and mean diffusivity (MD) were recorded. Mean FC_sim values were significantly different among the 3 groups indicating distinct FC patterns; however, no significant difference was found between DSD and no-DSD groups. DSD group showed trends of lower FA and higher MD- indicating loss of coherence-in all tracts compared to HCs, and in the left and right ATR when compared to MS women with neither DSD nor voiding dysfunction (VD), suggesting more damage in these tracts for MS women with DSD. Women with MS show distinctly different FC patterns compared to HCs. There are trends showing more damage in the ATR in women with MS and DSD compared to those with neither DSD nor VD.


Limiting systemic endocrine overtreatment in postmenopausal breast cancer patients with an ultralow classification of the 70-gene signature.
Guidelines recommend endocrine treatment for estrogen receptor-positive (ER+) breast cancers for up to 10 years. Earlier data suggest that the 70-gene signature (MammaPrint) has potential to select patients that have an excellent survival without chemotherapy and limited or no tamoxifen treatment. The aim was to validate the 70-gene signature ultralow-risk classification for endocrine therapy decision making. In the IKA trial, postmenopausal patients with non-metastatic breast cancer had been randomized between no or limited adjuvant tamoxifen treatment without receiving chemotherapy. For this secondary analysis, FFPE tumor material was obtained of ER+HER2- patients with 0-3 positive lymph nodes and tested for the 70-gene signature. Distant recurrence-free interval (DRFI) long-term follow-up data were collected. Kaplan-Meier curves were used to estimate DRFI, stratified by lymph node status, for the three predefined 70-gene signature risk groups. A reliable 70-gene signature could be obtained for 135 patients. Of the node-negative and node-positive patients, respectively, 20% and 13% had an ultralow-risk classification. No DRFI events were observed for node-negative patients with an ultralow-risk score in the first 10 years. The 10-year DRFI was 90% and 66% in the low-risk (but not ultralow) and high-risk classified node-negative patients, respectively. These survival analyses indicate that the postmenopausal node-negative ER+HER2- patients with an ultralow-risk 70-gene signature score have an excellent 10-year DRFI after surgery with a median of 1 year of endocrine treatment. This is in line with published results of the STO-3-randomized clinical trial and supports the concept that it is possible to reduce the duration of endocrine treatment in selected patients.


Evaluation of Syringomas by In Vivo Reflectance Confocal Microscopy: A Report of Two Cases.
Syringomas are benign adnexal tumors that are characterized histologically by the presence of small solid and cystic epithelial structures in the upper half of the reticular dermis. Reflectance confocal microscopy is a noninvasive diagnostic method that enables in vivo visualization of tissues with a resolution that approximates that of conventional histopathology. The use of this method in skin imaging over the past several years has improved dermatological diagnoses, creating the potential for its wide application in such diagnoses, especially for benign and malignant skin tumors. We describe its use in the diagnosis of syringoma in 2 patients and correlate the resulting clinical, histopathological, and digital reflectance confocal microscopy images.