Involvement of interferon-system in the regulation of cell growth and differentiation.
In this report we review the current knowledge on the involvement of the interferon (IFN) system in the regulation of cell growth and differentiation. We also summarize our own data which provide evidence for the strong correlation between IFN-mediated growth-arrest of transformed cells and the elevated enzymatic activity of an IFN-induced protein. Similarly, it is demonstrated that elevated levels of IFN-induced proteins accompany the early phases of in-vitro cell differentiation. IFN-treatment of NIH/3T3 mouse fibroblasts transformed by Moloney-murine sarcoma virus (MSV) resulted in a significant reduction in the rates of cell growth, protein synthesis and cloning efficiency. In parallel, 2-5A-synthetase activity was induced ten-fold above the background level. Treatment of these cells for 3 days with 450 international units (IU)/ml of IFN followed by its removal, resulted in a gradual increase in all parameters associated with cell growth while the 2-5A-synthetase activity was reduced to its normal level. However, almost no recovery occurred when cells were treated with 1,800 IU/ml. In parallel, 2-5A-synthetase activity remained highly elevated even at 3 days after the removal of IFN. In these cells, the expression of both c-myc and v-mos was reduced rapidly following IFN treatment. Upon removal of IFN after 24 h of treatment, the expression of both genes was resumed but with a different kinetics, suggesting that different mechanisms are responsible for the reduction in gene expression. In rat skeletal muscle cultures which differentiate to form myotubes, the level of both 2-5A-synthetase and protein kinase activities was transiently elevated, reaching a peak at 3 days followed by a decrease to background levels. This peak activity precedes the appearance of the major muscle differentiating proteins.


[Prediction of microorganism resistance to the immobilization process in polyacrylamide gel].
It is shown that the immobilization of bacterial cells in polyacrylamide gel or their exposure to monomer acrylamide results in a quantitatively similar decrease of their viability. It is indicated that acrylamide treatment may be used as a test for measuring the resistance of microbial populations to polyacrylamide gel immobilization and predicting the survival rate of microorganisms incorporated.


Searching for Cross-Diagnostic Convergence: Neural Mechanisms Governing Excitation and Inhibition Balance in Schizophrenia and Autism Spectrum Disorders.
Recent theoretical accounts have proposed excitation and inhibition (E/I) imbalance as a possible mechanistic, network-level hypothesis underlying neural and behavioral dysfunction across neurodevelopmental disorders, particularly autism spectrum disorder (ASD) and schizophrenia (SCZ). These two disorders share some overlap in their clinical presentation as well as convergence in their underlying genes and neurobiology. However, there are also clear points of dissociation in terms of phenotypes and putatively affected neural circuitry. We highlight emerging work from the clinical neuroscience literature examining neural correlates of E/I imbalance across children and adults with ASD and adults with both chronic and early-course SCZ. We discuss findings from diverse neuroimaging studies across distinct modalities, conducted with electroencephalography, magnetoencephalography, proton magnetic resonance spectroscopy, and functional magnetic resonance imaging, including effects observed both during task and at rest. Throughout this review, we discuss points of convergence and divergence in the ASD and SCZ literature, with a focus on disruptions in neural E/I balance. We also consider these findings in relation to predictions generated by theoretical neuroscience, particularly computational models predicting E/I imbalance across disorders. Finally, we discuss how human noninvasive neuroimaging can benefit from pharmacological challenge studies to reveal mechanisms in ASD and SCZ. Collectively, we attempt to shed light on shared and divergent neuroimaging effects across disorders with the goal of informing future research examining the mechanisms underlying the E/I imbalance hypothesis across neurodevelopmental disorders. We posit that such translational efforts are vital to facilitate development of neurobiologically informed treatment strategies across neuropsychiatric conditions.


Genetic variation in organisms with sexual and asexual reproduction.
The genetic variation in a partially asexual organism is investigated by two models suited for different time scales. Only selectively neutral variation is considered. Model 1 shows, by the use of a coalescence argument, that three sexually derived individuals per generation are sufficient to give a population the same pattern of allelic variation as found in fully sexually reproducing organisms. With less than one sexual event every third generation, the characteristic pattern expected for asexual organisms appear, with strong allelic divergence between the gene copies in individuals. At intermediary levels of sexuality, a complex situation reigns. The pair-wise allelic divergence under partial sexuality exceeds, however, always the corresponding value under full sexuality. These results apply to large populations with stable reproductive systems. In a more general framework, Model 2 shows that a small number of sexual individuals per generation is sufficient to make an apparently asexual population highly genotypically variable. The time scale in terms of generations needed to produce this effect is given by the population size and the inverse of the rate of sexuality.


Severity of Depression and Anxiety in Patients with Alopecia Areata in Bandar Abbas, Iran.
Alopecia areata (AA) is a chronic disease which esthetic outcomes may result in deep effects on mental disorders of patients. In this case-control study, we compared the mental health of 68 patients diagnosed with AA with 68 healthy individuals using Hamilton anxiety and depression rating scales. There were significant differences between the case and control groups regarding the prevalence of anxiety and depression. The means of anxiety scores in cases and control group were 12.76±7.21 vs 8.54±6.37, P=0.003. Likewise, the means of depression scores for the groups were 12.84±4.03 vs 6.22±4.95, P=0.001. Further-more, patients with AA were exposed to depression approximately five times and to anxiety about three times more than normal people. Our study revealed a high prevalence of anxiety and depression in AA patients. Dermatologists should pay more attention on psychological effect of the disease on the patients.


Smoking prevalence and beliefs on smoking cessation among members of the Japanese Cancer Association in 2006 and 2010.
Smoking is a significant contributing factor to disease-related deaths worldwide. Members of the Japanese Cancer Association (JCA) can play a leading role in helping people to live tobacco-free through social action. In 2010, this study assessed smoking prevalence among JCA members and their attitudes toward smoking, smoking cessation, and their responsibilities. Results of the 2010 survey were compared with those of a 2006 survey. Final response rates were 60.8% in the 2006 survey and 47.4% in the 2010 survey, and the current smoking rates were 9.0% and 5.3%, respectively. Regarding concern by current smokers over smoking cessation, the percentage of smokers who were ready to quit smoking within the next month increased from 4.9% to 6.3% between 2006 and 2010. Most JCA members agreed with antismoking actions such as smoking bans in all workplaces, public places, or while walking in the street, regulation restricting the sale and distribution of tobacco to children, tobacco education at school, use of tobacco tax for health, provision of information on tobacco, and smoking cessation support. Approximately 30% of responders disagreed on actions to raise the price of tobacco, regulations restricting the sale of tobacco, health warnings on tobacco packaging, bans on tobacco advertisement, and antismoking campaigns. Barriers to smoking cessation interventions identified were physician's time required to provide interventions, resistance of patients to smoking cessation advice, and lack of education on tobacco control. Not only antismoking actions but also support of smokers by health professionals through adequate education on smoking cessation treatment is needed in the future.


Gimme shelter--the relative sensitivity of parasitic nematodes with direct and indirect life cycles to climate change.
Climate change is expected to alter the dynamics of host-parasite systems globally. One key element in developing predictive models for these impacts is the life cycle of the parasite. It is, for example, commonly assumed that parasites with an indirect life cycle would be more sensitive to changing environmental conditions than parasites with a direct life cycle due to the greater chance that at least one of their obligate host species will go extinct. Here, we challenge this notion by contrasting parasitic nematodes with a direct life cycle against those with an indirect life cycle. Specifically, we suggest that behavioral thermoregulation by the intermediate host may buffer the larvae of indirectly transmitted parasites against temperature extremes, and hence climate warming. We term this the 'shelter effect'. Formalizing each life cycle in a comprehensive model reveals a fitness advantage for the direct life cycle over the indirect life cycle at low temperatures, but the shelter effect reverses this advantage at high temperatures. When examined for seasonal environments, the models suggest that climate warming may in some regions create a temporal niche in mid-summer that excludes parasites with a direct life cycle, but allows parasites with an indirect life cycle to persist. These patterns are amplified if parasite larvae are able to manipulate their intermediate host to increase ingestion probability by definite hosts. Furthermore, our results suggest that exploiting the benefits of host sheltering may have aided the evolution of indirect life cycles. Our modeling framework utilizes the Metabolic Theory of Ecology to synthesize the complexities of host behavioral thermoregulation and its impacts on various temperature-dependent parasite life history components in a single measure of fitness, R0 . It allows quantitative predictions of climate change impacts, and is easily generalized to many host-parasite systems.


Kinesin-II recruits Armadillo and Dishevelled for Wingless signaling in Drosophila.
Wingless (Wg)/Wnt signaling is fundamental in metazoan development. Armadillo (Arm)/β-catenin and Dishevelled (Dsh) are key components of Wnt signal transduction. Recent studies suggest that intracellular trafficking of Wnt signaling components is important, but underlying mechanisms are not well known. Here, we show that Klp64D, the Drosophila homolog of Kif3A kinesin II subunit, is required for Wg signaling by regulating Arm during wing development. Mutations in klp64D or RNAi cause wing notching and loss of Wg target gene expression. The wing notching phenotype by Klp64D knockdown is suppressed by activated Arm but not by Dsh, suggesting that Klp64D is required for Arm function. Furthermore, klp64D and arm mutants show synergistic genetic interaction. Consistent with this genetic interaction, Klp64D directly binds to the Arm repeat domain of Arm and can recruit Dsh in the presence of Arm. Overexpression of Klp64D mutated in the motor domain causes dominant wing notching, indicating the importance of the motor activity. Klp64D shows subcellular localization to intracellular vesicles overlapping with Arm and Dsh. In klp64D mutants, Arm is abnormally accumulated in vesicular structures including Golgi, suggesting that intracellular trafficking of Arm is affected. Human KIF3A can also bind β-catenin and rescue klp64D RNAi phenotypes. Taken together, we propose that Klp64D is essential for Wg signaling by trafficking of Arm via the formation of a conserved complex with Arm.


Membrane permeability and regulation of drug "influx and efflux" in enterobacterial pathogens.
In Enterobacteriaceae, membrane permeability is a key in the level of susceptibility to antibiotics. Modification of the bacterial envelope by decreasing the porin production or increasing the expression of efflux pump systems has been reported. These phenomena are frequently associated with other resistance mechanisms such as alteration of antibiotics or modification of the drug targets, in various clinical isolates showing a Multi Drug Resistant phenotype (MDR). In Escherichia coli, Enterobacter aerogenes, Klebsiella pneumoniae and Salmonella enterica several genes and external factors are involved in the emergence of MDR isolates. These bacterial isolates exhibit a noticeable reduction of functional porins per cell due to a decrease, a complete shutdown of synthesis, or the expression of an altered porin and a high expression of efflux systems (e.g. overexpression of the pump). The combined action of these mechanisms during an infection confers a significant decrease in bacterial sensitivity to antibiotherapy ensuring dissemination and colonization of the patient and favours the acquisition of additional mechanisms of resistance. MarA and ramA are involved in a complex regulation cascade controlling membrane permeability and actively participate in the triggering of the MDR phenotype. Mutations in regulator genes have been shown to induce the overproduction of efflux and the down-regulation of porin synthesis. In addition, various compounds such as salicylate, imipenem or chloramphenicol are able to activate the MDR response. This phenomenon has been observed both in vitro during culture of bacteria in the presence of drugs and in vivo during antibiotic treatment of infected patients. These effectors activate the expression of specific global regulators, marA, ramA, or target other genes located downstream in the regulation cascade.


Trickling filters for upgrading low technology wastewater plants for nitrogen removal.
Previous work through the 1990s in the Thames Water region in the UK has demonstrated the ability of the trickling filter process to produce fully nitrified effluents, reliably throughout the year. The original data used for the nitrification model derivations have been reanalysed, to investigate the degree of nitrogen removal across the process. Removals of total nitrogen ranging from 0% to over 50% were observed across the trickling filter process and calculated total nitrogen removals of 26-63% were obtained when primary treatment was included. The degree of nitrogen removal and biological denitrification (excluding cellular assimilation) was found to be strongly influenced by BOD load, irrigation velocity and media size. Regression models were produced which gave good predictive relationships for the data ranges used. The models produced worked for filters used with and without a recirculation of effluent nitrate which suggests that a significant degree of nitrification occurred in areas of high heterotroph activity (BOD removal). The simplicity and energy efficiency of the trickling filter process, combined with its capacity for full nitrification and partial denitrification, make the process attractive as a combined process used with pond systems in developing countries where nitrogen removal may be required. Some of these synergies have already been developed with the PETRO process in South Africa.


Prognostic indicators in peritoneal carcinomatosis from gastrointestinal cancer.
Peritoneal carcinomatosis from gastrointestinal cancer has new treatment options for surgical management. The approach uses cytoreductive surgery which combines peritonectomy and visceral resection in an effort to remove all visible cancer within the abdomen and pelvis. Then the peritoneal cavity is flooded with chemotherapy solution in an attempt to eradicate residual disease. In order to select patients for this approach the quantitative prognostic indicators for carcinomatosis were reviewed, compared and contrasted. Prognostic indicators to be used to select patients for this aggressive approach at the initiation of surgery and after completion of cytoreduction were studied. Four quantitative assessments to be used at the time of abdominal exploration were the Gilly staging, Japanese gastric cancer P score, peritoneal cancer index (PCI), and the simplified peritoneal cancer index (SPCI). All have value with the PCI being the most validated and most precise. Preoperative assessments include the tumor histopathology and the prior surgical score. The completeness of cytoreduction score is an assessment of residual disease after a maximal surgical effort. An opportunity for long-term survival following treatment for carcinomatosis requires a complete cytoreduction in all reports for gastrointestinal cancer. Quantitative prognostic indicators need to be knowledgeably employed when patients with carcinomatosis are being treated. Improved patient selection with greater benefit and reduced morbidity and mortality should result.


Disclosure of information to patients in medical care.
It is generally agreed that patients have a right to be adequately informed. However, little is known about the extent to which doctors and patients agree about information that should be disclosed. We studied what patients want to know, as contrasted with what physicians report actually disclosing, in a population of physicians who treat seizures and patients or parents of patients who have this disorder. In general, it was found that patients or parents of patients who have this disorder. In general, it was found that patients prefer far more detailed disclosures than physicians routinely offer and that the two groups have widely different beliefs about the consequences of detailed disclosures. Patients and parents preferred extensive disclosures, particularly regarding risks and alternative therapy. Physicians were likely to disclose only risks with a relatively high probability of occurrence and they provided little information about alternative therapies. Patients and parents were also much more likely than physicians to believe that the final decision concerning therapy should rest with the patient. The data suggest that a better empirical understanding of the consequences of detailed disclosures may help resolve differences of opinion regarding how much information should be provided to patients.


Incidence of intracerebral and subarachnoid haemorrhage in southern Sweden.
Spontaneous intracranial haemorrhage-that is, mainly subarachnoid haemorrhage (SAH) and primary intracerebral haemorrhage (PICH)-constitutes an important part of all strokes. As previous epidemiological studies have demonstrated highly variable incidence rates, we conducted a large prospective investigation of all haemorrhagic strokes during a 1 year period. Twelve hospitals serving a defined population of 1.14 million in southern Sweden registered all cases with spontaneous intracranial haemorrhage, including those found dead outside hospitals, during 1996. All patients were examined with CT of the brain or underwent necropsy. Incidence rates adjusted to the Swedish population for age and sex, as well as location of haematoma and prevalence of risk factors were calculated. A total of 106 patients with SAH and 341 patients with PICH were identified. The annual incidence/100 000 was 10.0 (6.4 for men and 13.5 for women) for SAH and 28.4 (32.2 for men and 24.7 for women) for PICH when adjusted to the Swedish population. Subarachnoid haemorrhage affected twice as many women as men. The incidence of both types of haemorrhage increased with advancing age, but in particular, this was the case for supratentorial PICH. Lobar haematomas were the most common (51.6%) type of PICH. Among patients with PICH, 37% had hypertension, 41% other vascular disease, and 12% were on oral anticoagulation. Among patients with SAH, 28% had hypertension and 18% vascular disease before the haemorrhage but no one was on treatment with oral anticoagulation. The incidence of PICH was high, especially for the older age groups. PICH was, on average, three times as common as SAH. The study underscores the importance of PICH and SAH as significant stroke subgroups.


Disk diffusion testing with polymyxin and amikacin for differentiation of Mycobacterium fortuitum and Mycobacterium chelonei.
Disk diffusion is one method of susceptibility testing of the Mycobacterium fortuitum complex to antibacterial agents. We utilized disks of polymyxin B (300 U), amikacin, and kanamycin to determine whether they could also be used for species identification when compared with standard biochemical methods. With the polymyxin disk, 100% of 75 M. fortuitum strains produced zones of inhibition, whereas none (0%) of 58 Mycobacterium chelonei subspecies abscessus and chelonei strains had any zone of inhibition. With the amikacin disk, 99% of M. fortuitum biovariant fortuitum had zones of greater than or equal to 30 mm compared with 6% of M. chelonei. The rare M. chelonei-like organisms gave variable results, and 42% of the unnamed "third group" biovariant of M. fortuitum exhibited an unusual but diagnostic pattern of small zone sizes to amikacin and no zone to kanamycin. The kanamycin disk was otherwise not helpful, although it resulted in larger zone sizes for M. chelonei than did amikacin. Thus, disk diffusion susceptibilities which include these disks (especially polymyxin) will provide presumptive evidence of species as well as susceptibility data.


Detection and analysis of nucleic acid in various biological samples of COVID-19 patients.
COVID-19 (corona virus disease 2019) is a kind of acute severe pneumonia caused by 2019-nCoV (2019-nCoV) infection. Since December 2019, it has been found in Wuhan, Hubei Province, and then spread to the whole country. Some parts of the world also showed an outbreak trend [1-3]. Real-time fluorescence quantitative reverse transcriptase polymerase chain reaction (reverse transcriptase-polymerase chain reaction,RT-PCR) and viral gene sequencing are the gold standard for the diagnosis of COVID-19. At present, upper respiratory tract nasopharyngeal swabs are mostly used as nucleic acid detection samples in China, but the positive rate is low. However, there are few reports on clinical application of 2019-nCoV nucleic acid detection in other biological samples. | The East Section of Renmin Hospital of Wuhan University is a designated COVID-19 hospital in Wuhan City, Hubei Province, China. This observation study included 132 patients diagnosed with COVID-19 in the infectious disease areas of the East Section of Renmin Hospital of Wuhan University from 2020.1.31 to 2020.2.29. COVID-19 diagnostic criteria: according to China's ⟪pneumonia diagnosis and treatment Program of novel coronavirus infection (trial version 7) ⟫, in accordance with the relevant epidemiological and clinical manifestations, nasopharyngeal swabs real-time fluorescence RT-PCR detection of 2019-nCoV nucleic acid positive, COVID-19 cases were divided into mild, ordinary, severe and severe [1]. The nasopharyngeal swabs of 132 cases of COVID-19 were positive for 2019-nCoV nucleic acid on admission, including 72 males and 60 females, with an average age of 66.7 ± 9.1 years, including 80 cases of common type, 44 cases of severe type and 8 cases of critical type. During the period of admission, under the condition of tertiary protection, nasopharyngeal swabs, sputum, blood, feces and anal swabs of COVID-19 cases were collected many times in the isolation ward for 2019-nCoV nucleic acid detection. All biological samples are sealed and transferred to the laboratory in strict accordance with the standard process. The RT-PCR test kits (BioGerm) were recommended by the Chinese Center for Disease Control and Prevention. The same technician and brand of test kit was used for all RT-PCR testing reported; both internal controls and negative controls were routinely performed with each batch of tests. | 132 the results of 2019-nCoV nucleic acid test of various biological samples during the treatment of confirmed COVID-19 cases are as follows: the positive rate of 2019-nCoV nucleic acid test of nasopharyngeal swab is 38.13% (180/472 times), the positive rate of 2019-nCoV nucleic acid test of sputum is 48.68% (148/304 times), the positive rate of blood 2019-nCoV nucleic acid test is 3.03% (4/132 times), and the positive rate of 2019-nCoV nucleic acid test of feces is 9.83% (24/244 times). The positive rate of 2019-nCoV nucleic acid detection in anal swabs is 10.00% (12/120 times). In this study, it was found that the positive rate of 2019-nCoV nucleic acid in sputum of 132 patients with COVID-19 was higher than that of nasopharyngeal swabs, and viral nucleic acids were also detected in blood and digestive tract (fecal/anal swabs). Simple detection of nasopharyngeal swab 2019-nCoV nucleic acid detection positive rate is not high, multi-sample 2019-nCoV nucleic acid detection can improve the accuracy, reduce the false negative rate, better guide clinical treatment and evaluate the therapeutic effect.


Slow light on Gbit/s differential-phase-shift-keying signals.
We demonstrate, via simulation and experiment, slowing down of a phase-modulated optical signal. A 10.7-Gb/s NRZ-DPSK signal can be delayed by as much as 42 ps while still achieving error free via broadband SBS-based slow light. We further analyze the impact of slow-light-induced data-pattern dependence on both constructive and destructive demodulated ports. By detuning the SBS gain profile, we achieve 3-dB Q-factor improvement by the reduction of pattern dependence. Performance comparison between NRZ-DPSK and RZ-DPSK shows that robustness to slow-light-induced pattern dependence is modulation format dependent.


Mutation, multilevel selection, and the evolution of propagule size during the origin of multicellularity.
Evolutionary transitions require the organization of genetic variation at two (or more) levels of selection so that fitness heritability may emerge at the new level. In this article, we consider the consequences for fitness variation and heritability of two of the main modes of reproduction used in multicellular organisms: vegetative reproduction and single-cell reproduction. We study a model where simple cell colonies reproduce by fragments or propagules of differing size, with mutations occurring during colony growth. Mutations are deleterious at the colony level but can be advantageous or deleterious at the cell level ("selfish" or "uniformly deleterious" mutants). Fragment size affects fitness in two ways: through a direct effect on adult group size (which in turn affects fitness) and by affecting the within- and between-group variances and opportunity for selection on mutations at the two levels. We show that the evolution of fragment size is determined primarily by its direct effects on group size except when mutations are selfish. When mutations are selfish, smaller propagule size may be selected, including single-cell reproduction, even though smaller propagule size has a direct fitness cost by virtue of producing smaller organisms, that is, smaller adult cell groups.


Impact of qualified (indeterminate) diagnoses on the accuracy of renal, thyroid, and breast fine-needle aspiration biopsy.
A qualified (indeterminate) diagnosis (QD), such as "suggestive of malignancy," is thought to complicate patient management by heightening clinical uncertainty. We report that QDs increase the overall effectiveness of renal, thyroid, and breast fine-needle aspiration (FNA) biopsy and that the probability that a qualified diagnosis is negative (QDN) can be predicted by the formula QDN = number of QDs x (proportion of false-negative outcomes/disease prevalence expressed as a proportion). Results of renal (n = 24), thyroid (n = 163), and breast (n = 456) FNA biopsies performed from January 1992 through December 1998 were reviewed and correlated with results of tissue biopsies. For each body site, the FNA biopsies were placed into 1 of 2 diagnostic categories: unqualified diagnoses (UQDs) or QDs. Comparison of test performance characteristics for UQDs only and UQDs combined with QDs demonstrated that inclusion of UQDs increased FNA sensitivity and reduced FNA false-negative diagnoses. More important, the probability that a QD was negative could be predicted from test performance characteristics derived from UQDs.


Some unusual features of fine structure observed in HeLa cells.
HeLa cells from conventional culture media have been studied in thin sections with the electron microscope; in many cases cells were examined in sets of sections cut in series. The fine structure of the cells is described including three unusual features not hitherto reported. It has been found that numerous cells contained rows of parallel smooth surfaced cisternae spaced about 150 mmicro apart and communicating with rough surfaced elements of the endoplasmic reticulum. These cisternae resembled "annulate lamellae" but did not contain regular arrays of pores. In many cells an area of juxtanuclear cytoplasm was occupied by a membranous structure composed of closely applied pairs of narrow cisternae either arranged in concentric rings or else extending in several directions in a haphazard manner. Sparse particles were present on the outer membranes of each pair of cisternae. Communications between the double cisternae and other membrane-bounded structures were not observed. A small number of cells contained areas of cytoplasm devoid of organelles and filled with amorphous fuzzy material. The observations recorded are discussed.


Development of a Novel Vaccine Containing Binary Toxin for the Prevention of Clostridium difficile Disease with Enhanced Efficacy against NAP1 Strains.
Clostridium difficile infections (CDI) are a leading cause of nosocomial diarrhea in the developed world. The main virulence factors of the bacterium are the large clostridial toxins (LCTs), TcdA and TcdB, which are largely responsible for the symptoms of the disease. Recent outbreaks of CDI have been associated with the emergence of hypervirulent strains, such as NAP1/BI/027, many strains of which also produce a third toxin, binary toxin (CDTa and CDTb). These hypervirulent strains have been associated with increased morbidity and higher mortality. Here we present pre-clinical data describing a novel tetravalent vaccine composed of attenuated forms of TcdA, TcdB and binary toxin components CDTa and CDTb. We demonstrate, using the Syrian golden hamster model of CDI, that the inclusion of binary toxin components CDTa and CDTb significantly improves the efficacy of the vaccine against challenge with NAP1 strains in comparison to vaccines containing only TcdA and TcdB antigens, while providing comparable efficacy against challenge with the prototypic, non-epidemic strain VPI10463. This combination vaccine elicits high neutralizing antibody titers against TcdA, TcdB and binary toxin in both hamsters and rhesus macaques. Finally we present data that binary toxin alone can act as a virulence factor in animal models. Taken together, these data strongly support the inclusion of binary toxin in a vaccine against CDI to provide enhanced protection from epidemic strains of C. difficile.


Use of adult dog serum as a substitute for colostrum in the neonatal dog.
Failure to obtain passive transfer of immunity via colostrum can be detrimental to the health and survival of a young pup. It has been stated that pups that do not receive colostrum in the first 2 days after birth, be given adult dog serum as a source of protective immunoglobulins. Twenty-five Beagle pups were obtained by cesarean section from 6 Beagle bitches. The pups were allotted to 3 groups at birth. Group 1 was a control group and was allowed to suckle colostrum. Group-2 pups received 22 ml of pooled adult dog serum/kg of body weight (10 ml/lb) SC at birth. Group-3 pups were given 22 ml of pooled adult dog serum/kg by stomach tube at birth. Pups from groups 2 and 3 were separated from the bitch for 48 hours to prevent colostral antibody absorption and were fed a commercially available milk replacer by stomach tube. After 48 hours, all pups were returned to the bitch until they were weaned at 6 weeks of age. Blood samples were collected from all of the pups at birth and on days 1, 2, 7, 14, 21, 28, and 35. The concentration of IgA, IgG, and IgM in serum was determined by radial immunodiffusion and compared by use of a one-way analysis of variance. The control pups had significantly higher serum concentrations of IgA and IgG, than the pups in groups 2 and 3 on days 1 and 2 and 2 and 7, respectively. Group-2 pups had significantly higher serum IgM concentrations on day 1 than either group 1- or group-3 pups.


A Multi-Serotype Approach Clarifies the Catabolite Control Protein A Regulon in the Major Human Pathogen Group A Streptococcus.
Catabolite control protein A (CcpA) is a highly conserved, master regulator of carbon source utilization in gram-positive bacteria, but the CcpA regulon remains ill-defined. In this study we aimed to clarify the CcpA regulon by determining the impact of CcpA-inactivation on the virulence and transcriptome of three distinct serotypes of the major human pathogen Group A Streptococcus (GAS). CcpA-inactivation significantly decreased GAS virulence in a broad array of animal challenge models consistent with the idea that CcpA is critical to gram-positive bacterial pathogenesis. Via comparative transcriptomics, we established that the GAS CcpA core regulon is enriched for highly conserved CcpA binding motifs (i.e. cre sites). Conversely, strain-specific differences in the CcpA transcriptome seems to consist primarily of affected secondary networks. Refinement of cre site composition via analysis of the core regulon facilitated development of a modified cre consensus that shows promise for improved prediction of CcpA targets in other medically relevant gram-positive pathogens.


Endoscopic exploration and repair of brachial plexus with telerobotic manipulation: a cadaver trial.
The aim of this paper was to develop an effective minimally invasive approach to brachial plexus surgery and to determine the feasibility of using telerobotic manipulation to perform a diagnostic dissection and microsurgical repair of the brachial plexus utilizing an entirely endoscopic approach. The authors performed an endoscopic approach using 3 supraclavicular portals in 2 fresh human cadaver brachial plexuses with the aid of the da Vinci telemanipulation system. Dissection was facilitated inflating the area with CO(2) at 4 mm Hg pressure. The normal supraclavicular plexus was dissected in its entirety to confirm the feasibility of a complete supraclavicular brachial plexus diagnostic exploration. Subsequently, an artificial lesion to the upper trunk was created, and nerve graft reconstruction was performed. Images and video of the entire procedure were obtained and edited to illustrate the technique. All supraclavicular structures of the brachial plexus could be safely dissected and identified, similar to the experience in open surgery. The reconstruction of the upper trunk with nerve graft was successfully completed using an epineural microsurgical suture technique performed exclusively with the aid of the robot. There were no instances of inadvertent macroscopic damage to the vascular and nervous structures involved. An endoscopic approach to the brachial plexus is feasible. The use of the robot makes it possible to perform microsurgical procedures in a very small space with telemanipulation and minimally invasive techniques. The ability to perform a minimally invasive procedure to explore and repair a brachial plexus injury may provide a new option in the acute management of these injuries.


Arthroscopy of the elbow for synovial chondromatosis.
Two cases of arthroscopic removal of multiple loose bodies are presented. Successful results were achieved, and patients had 4-year follow-up. Both cases involved classic manifestations of synovial chondromatosis. Associated degenerative changes were present in one case; histologic examination could not confirm synovial origin of the disease. Arthroscopy for removal of symptomatic loose bodies is an excellent choice as exemplified by these two cases. Care should be taken to review histologic findings, which may help in understanding the natural history of this type of process.


Current trends in autoimmunity and the nervous system.
In the broad field of autoimmunity and clinical immunology, experimental evidence over the past few years have demonstrated several connections between the immune system and the nervous system, both central and peripheral, leading to the definition of neuroimmunology and of an immune-brain axis. Indeed, the central nervous system as an immune-privileged site, thanks to the blood-brain barrier, is no longer a dogma as the barrier may be altered during chronic inflammation with disruptive changes of endothelial cells and tight junctions, largely mediated by adenosine receptors and the expression of CD39/CD73. The diseases that encompass the neuroimmunology field vary from primary nervous diseases such as multiple sclerosis to systemic conditions with neuropsychiatric complications, such as systemic lupus erythematosus or vasculitidies. Despite potentially similar clinical manifestations, the pathogenesis of each condition is different, but the interaction between the ultra-specialized structure that is the nervous system and inflammation mediators are crucial. Two examples come from anti-dsDNA cross-reacting with anti-N-Methyl-d-Aspartate receptor (NMDAR) antibodies in neuropsychiatric lupus or the new family of antibody-associated neuronal autoimmune diseases including classic paraneoplastic syndromes with antibodies directed to intracellular antigens (Hu, Yo, Ri) and autoimmune encephalitis. In the case of multiple sclerosis, the T cell paradigm is now complicated by the growing evidence of a B cell involvement, particularly via aquaporin antibodies, and their influence on Th1 and Th17 lineages. Inspired by a productive AARDA-sponsored colloquium among experts we provide a critical review of the literature on the pathogenesis of different immune-mediated diseases with neurologic manifestations and we discuss the basic immunology of the central nervous system and the interaction between immune cells and the peripheral nervous system.


Characteristics and Health Status of Informal Unpaid Caregivers - 44 States, District of Columbia, and Puerto Rico, 2015-2017.
In 2015, an estimated 17.7 million U.S. persons were informal caregivers who provided substantial services through in-home, unpaid assistance to their family members and friends (1). Caregiving can have many benefits, such as enhancing the bond between caregiver and recipient, but it can also place an emotional and physical strain on caregivers, leading to higher rates of depression, lower quality of life, and poorer overall health (2). As the U.S. population continues to age (3), the need for informal caregivers will likely increase. However, little nationally representative information on prevalence of caregivers is available. This study examined demographic characteristics and health status of informal caregivers from 44 states,* the District of Columbia (DC), and Puerto Rico, based on data from the Behavioral Risk Factor Surveillance System (BRFSS) collected during 2015-2017. Overall, approximately one in five adults reported that they had provided care to a family member or friend in the preceding 30 days. Fifty-eight percent of caregivers were women, and a majority were non-Hispanic white, with at least some college education, and married or living with a partner. Across all states, 19.2% of caregivers reported being in fair or poor health, although significant state-to-state variation occurred. Caregivers provide important support to family members, friends, and the health care system and might compromise their own health to provide this support (1,2). Better understanding of caregivers and the challenges they face could inform implementation of improvements in support systems that could enhance not only the health of the caregiver, but that of the care recipient as well. For example, additional data regarding demographics at the state level might aid in more effective planning and support of caregivers with evidence-based programs and assistance (https://www.cdc.gov/aging/publications/features/caring-for-yourself.html).


Seminal plasma metabolomics analysis of differences in liquid preservation ability of boar sperm.
The preservation of semen is pivotal in animal reproduction to ensure successful fertilization and genetic improvement of livestock and poultry. However, investigating the underlying causes of differences in sperm liquid preservation ability and identifying relevant biomarkers remains a challenge. This study utilized liquid chromatography-mass spectrometry (LC-MS) to analyze the metabolite composition of seminal plasma (SP) from two groups with extreme differences in sperm liquid preservation ability. The two groups namely the good liquid preservation ability (GPA) and the poor preservation ability (PPA). The aim was to explore the relationship between metabolite composition in SP and sperm liquid preservation ability, and to identify candidate biomarkers associated with this ability of sperm. The results revealed the identification of 756 metabolites and 70 differentially expressed metabolites (DEM) in the SP from two groups of boar semen with differing liquid preservation abilities at 17 °C. The majority of identified metabolites in the SP belonged to organic acids and derivatives as well as lipids and lipid-like molecules. The DEM in the SP primarily consisted of amino acids, peptides, and analogs. The Kyoto Encyclopedia of Genes and Genomes analysis also demonstrated that the DEM are mainly concentrated in amino acid synthesis and metabolism-related pathways (P < 0.05). Furthermore, eleven key metabolites were identified and six target amino acids were verified, and the results were consistent with the non-targeted metabolic analysis. These findings indicated that amino acids and their associated pathways play a potential role in determining boar sperm quality and liquid preservation ability. D-proline, arginine, L-citrulline, phenylalanine, leucine, DL-proline, DL-serine, and indole may serve as potential biomarkers for early assessment of boar sperm liquid preservation ability. The findings of this study are helpful in understanding the causes and mechanisms of differences in the liquid preservation ability of boar sperm, and provide valuable insights for improving semen quality assessment methods and developing novel extenders or protocols.


Bacterial community structure in a sympagic habitat expanding with global warming: brackish ice brine at 85-90 °N.
Larger volumes of sea ice have been thawing in the Central Arctic Ocean (CAO) during the last decades than during the past 800,000 years. Brackish brine (fed by meltwater inside the ice) is an expanding sympagic habitat in summer all over the CAO. We report for the first time the structure of bacterial communities in this brine. They are composed of psychrophilic extremophiles, many of them related to phylotypes known from Arctic and Antarctic regions. Community structure displayed strong habitat segregation between brackish ice brine (IB; salinity 2.4-9.6) and immediate sub-ice seawater (SW; salinity 33.3-34.9), expressed at all taxonomic levels (class to genus), by dominant phylotypes as well as by the rare biosphere, and with specialists dominating IB and generalists SW. The dominant phylotypes in IB were related to Candidatus Aquiluna and Flavobacterium, those in SW to Balneatrix and ZD0405, and those shared between the habitats to Halomonas, Polaribacter and Shewanella. A meta-analysis for the oligotrophic CAO showed a pattern with Flavobacteriia dominating in melt ponds, Flavobacteriia and Gammaproteobacteria in solid ice cores, Flavobacteriia, Gamma- and Betaproteobacteria, and Actinobacteria in brine, and Alphaproteobacteria in SW. Based on our results, we expect that the roles of Actinobacteria and Betaproteobacteria in the CAO will increase with global warming owing to the increased production of meltwater in summer. IB contained three times more phylotypes than SW and may act as an insurance reservoir for bacterial diversity that can act as a recruitment base when environmental conditions change.


Characterization of the 5'-terminal cap structures of early simian virus 40 mRNA.
Early simian virus 40-specific mRNA was isolated from lytically infected and stably transformed cells and analyzed with respect to the 5'-terminal cap content. An analogous diversity of capped structures was found in both RNA preparations, indicating that 5'-terminal heterogeneity is not limited to late simian virus 40 RNA transcription but concerns a more general feature. Correlation of our data with previously published results of characterization of early mRNA's by reverse transcription allowed a tentative localization of the major 5' termini on the viral genome.


Radio noise from towns: measured from an airplane.
Measurements of broadband radio noise in the range 73 to 440 megahertz were made over several small Illinois cities during August, September, and December 1972. Results for cities with a population larger than 25,000 are presented as brightness temperatures between 2400 and 9600 degrees Kelvin. Even the smallest villages produce significant noise pollution. There is considerable diurnal variation and some evidence for seasonal variation.


Kidney Function Alters the Relationship between Postoperative Troponin T Level and Death.
Cardiac troponin T (cTnT), even at low concentrations, is a risk factor for 30-day mortality in patients undergoing noncardiac surgery, but it is uncertain whether that risk is generalizable to patients with poor kidney function. We, therefore, evaluated the relationship between cTnT concentration and kidney function on the outcome of 30-day mortality in a post hoc analysis of a prospective cohort study of patients undergoing noncardiac surgery. cTnT was measured for 3 days after surgery and considered abnormal if the peak was ≥0.02 ng/ml. Of the included 14,037 patients, 267 (1.9%) patients died within 30 days of surgery. The adjusted hazard ratios for death with an abnormal cTnT concentration were 4.37 (95% confidence intervals [95% CI], 3.21 to 6.22), 6.15 (95% CI, 2.95 to 140.9), 6.30 (95% CI, 3.12 to 21.23), 1.33 (95% CI, 0.56 to 4.85), and 1.46 (95% CI, 0.46 to 9.21) for eGFR≥60, 45 to <60, 30 to <45, 15 to <30, and <15 ml/min per 1.73 m(2) or on dialysis, respectively. Compared with patients with eGFR≥60 ml/min per 1.73 m(2), the adjusted hazard ratio was significantly lower for patients with eGFR=15 to <30 ml/min per 1.73 m(2) (interaction P value=0.02). Redefining abnormal cTnT concentration as ≥0.03 ng/ml or a change of ≥0.02 ng/ml did not alter results. Because the risk associated with postoperative cTnT levels may be different for patients with eGFR<30 ml/min per 1.73 m(2), additional research is required to determine how to interpret perioperative cTnT values for patients with low kidney function.


The role of the turn in beta-hairpin formation during WW domain folding.
The folding of WW domains is rate limited by formation of a beta-hairpin comprising residues from strands 1 and 2. Residues in the turn of this hairpin have reported Phi-values for folding close to 1 and have been proposed to nucleate folding. High Phi-values do not necessarily imply that the energetics of formation are a driving force for initiating folding. We demonstrate by NMR studies and molecular dynamics simulations that the first turn of the hYAP, FBP28, and PIN1 WW domains is structurally dynamic and solvent exposed in the native and folding transition states. It is, therefore, unlikely that the formation of the beta-turn per se provides the energetic driving force for hairpin folding. It is more likely that the turn acts as an easily formed hinge that facilitates the formation of the hairpin; it is a nucleus as defined by the nucleation-condensation mechanism whereby a diffuse nucleus is stabilized by associated interactions.


The Emerging Role of NRAS Mutations in Colorectal Cancer Patients Selected for Anti-EGFR Therapies.
Colorectal cancer (CRC) is one of the most common cancers worldwide. Despite the improvement in overall survival (OS) due to new treatments and targeted therapies alone or in combination with chemotherapy up-to-date, little is known about cellular mechanisms, both of primary and acquired resistance of CRC to anti-Epidermal Growth Factor Receptor (EGFR) antibodies. EGFR is characterized by tyrosine kinase activity and occupies a key-role in the control of cellular transduction pathways. Its activation triggers both the RAS-RAF and PIK3CA pathways and is required to promote cell growth, differentiation, proliferation, and invasion. Cetuximab and panitumumab are both monoclonal antibodies (MoAbs) directed against the extracellular domain of EGFR, thus leading to inhibition of the downstream signaling pathways. Mutations in oncogene Kirsten-RAS (KRAS) are frequently associated with resistance to anti-EGFR therapy. However, a significant number of KRAS wild-type (WT) tumors fail to obtain disease control with anti-EGFR agents. Therefore, additional biomarkers of response/resistance to these drugs such as BRAF, NRAS, PIK3CA and PTEN have been investigated. This review will point attention on Neuroblastoma-RAS (NRAS) status in metastatic CRC (mCRC) patients (pts) selected for anti-EGFR therapy.


A single myocardial stretch or decreased systolic fiber shortening stimulates the expression of heat shock protein 70 in the isolated, erythrocyte-perfused rabbit heart.
The regulation of heat shock protein 70 (HSP 70) expression was examined in the isolated, red blood cell-perfused rabbit heart by Northern and Western blot analysis. In the isovolumic (balloon in left ventricle), isolated perfused heart, HSP 70 mRNA was increased threefold after 30 min and sevenfold at 2 and 4 h compared to normal, nonperfused hearts. To further elucidate the etiology of the increase in HSP 70 mRNA, the effects of decreased systolic shortening (isovolumic heart) and of a single ventricular stretch were examined. Perfusion without the application of a stretch or the presence of a balloon resulted in no increase in HSP 70 mRNA; while a single stretch resulted in a threefold increase in HSP 70 mRNA. These changes were accompanied by an increase in HSP 70 protein by Western blot analysis. To elucidate the signalling mechanism mediating the increase in HSP 70, hearts were perfused with H7, a protein kinase C inhibitor. H7 did not prevent the induction of HSP 70. These results indicate that initiation of expression of myocardial HSP 70 can be stimulated by a single myocardial stretch or by prevention of systolic shortening. These mechanisms may contribute to the rapid expression of HSP 70 after coronary occlusion when dyskinesis, reduced systolic shortening, and increased diastolic segment length all occur.


Severe anemia in a 25-day-old infant due to gastric teratoma with focal neuroblastoma.
Gastric teratoma is an extremely rare embryonic neoplasm containing tissue from all three germ layers (ectoderm, endoderm, and mesoderm). A 25-day-old infant presented with anemia and a palpable abdominal mass. Computed tomography (CT) scanning showed a solid and cystic multiloculated tumor of mixed echogenicity and calcifications. An encapsulated bleeding tumor localized to the posterior wall of the stomach with extension to a bowel segment was promptly excised. Histology revealed a grade III immature teratoma with small foci of neuroblastoma. To the best of our knowledge, this is the first infant with gastric teratoma containing foci of neuroblastoma causing bleeding and anemia as presentation symptoms at neonatal age.


Practice Patterns for Women With Overactive Bladder Syndrome: Time Between Medications and Third-Line Treatments.
The aims of this study are to determine how long it takes female patients with overactive bladder (OAB) to receive third-line treatment after starting OAB medications and identify factors associated with increased time. This was a retrospective observational cohort study of adult female patients with OAB who received third-line treatment between 2013 and 2015 using insurance claims databases. Primary outcome was time between first OAB medication and first third-line treatment. Additional variables were patient demographics, diagnostic tests, and medical comorbidities. Of 3232 patients included in this study, 48.8% underwent sacral neuromodulation, 31.6% percutaneous tibial nerve stimulation, and 23% intradetrusor onabotulinumtoxin A injections. Twenty-one percent of patients filled medication prescriptions for 3 or more antimuscarinic medications, 30.4% took mirabegron, and 32.3% had advanced diagnostic tests suggestive of a specialist evaluation prior to starting medications. Median time to third-line treatment was 37.7 (interquartile range, 14.9, 16.3) months. Adjusted linear regression model revealed 2 predominant predictors of time to third-line treatments: each antimuscarinic medication trial was associated with 5.3 (95% confidence interval, 4.4-6.3) more months before third-line treatment (P < 0.001), and advanced diagnostic evaluations prior to starting medications were associated with 28.2 (95% confidence interval, 21-35) fewer months before third-line treatment (P < 0.001). Women with OAB who undergo third-line therapy do so on average more than 3 years after starting medications. Time to third-line treatment is largely driven by the number of antimuscarinic medications tried and timing of diagnostic evaluation by a specialist. Based on these results, we suggest providers consider limiting antimuscarinic trials to 2 medications prior to moving on to other treatment options.


In vitro synergy of eugenol and methyleugenol with fluconazole against clinical Candida isolates.
The species Candida is a group of opportunistic pathogenic commensals in immune-compromised patients. Treatment of Candida infections is becoming increasingly difficult due to antifungal drug resistance, especially with fluconazole (FLC), which is a commonly used azole. In the present study the in vitro antifungal activity of eugenol (EUG) and methyleugenol (MEUG) alone and in combination against 64 FLC-sensitive and 34 FLC-resistant clinical Candida isolates is highlighted. All the strains were susceptible to both the naturally occurring phenyl propanoids. The nature of the interaction was studied from fractional inhibitory concentration indices (FICIs) for both EUG plus FLC, and MEUG plus FLC combinations calculated from chequerboard microdilution assays. FICI values depicted a high synergism of FLC with both compounds, which was greatest with MEUG. FLC-resistant Candida isolates showed high sensitivity to both compounds. No antagonistic activity was seen in the strains tested in the present study. From these results we suggest that EUG and MEUG have great potential as antifungals, and that FLC can be supplemented with EUG and MEUG to treat FLC-resistant Candida infections.


Preventive use of exercise rehabilitation after myocardial infarction.
Randomized controlled clinical trials of exercise after myocardial infarction, although difficult to compare, have not shown a reduction in mortality or morbidity. However, physiological and psychological improvements occur that enable patients to improve their quality of life. The effectiveness of exercise programmes is impaired by poor patient compliance. Some characteristics of poor compliers may be identified, but it is safer to assume all participants are potential non-compliers, and to apply compliance-improving strategies within exercise programmes. The authors' experience has indicated that a number of strategies may be followed at little cost. These include a spouse support programme, a written agreement to participate, self-control techniques including self-monitored exercise testing, and group discussion periods.


Differential DNA methylation correlates with response to methotrexate in rheumatoid arthritis.
Identifying blood-based biomarkers that predict treatment response in RA is a clinical priority. We investigated differential DNA methylation as a candidate biomarker of response for the first-line drug used in RA, MTX. DNA methylation was measured in DNA samples from individuals recruited to the Rheumatoid Arthritis Medication Study. Differentially methylated positions were compared between whole blood samples collected at baseline and at 4 weeks from patients who, by 6 months, had a good (n = 34) or poor response (n = 34) to MTX using linear modelling, adjusting for gender, age, cell composition, baseline 28-joint disease activity score (DAS28) and smoking status. Analyses also compared methylation with changes in DAS28 and changes in swollen joint count and tender joint count, and changes in CRP over the initial 6 months after MTX commencement. Differentially methylated positions showing significant differences with any response parameter were tested using pyrosequencing in an independent group of 100 patients from the Rheumatoid Arthritis Medication Study. In the discovery group, two CpG sites showed methylation changes at 4 weeks associated with clinical EULAR response by 6 months. Significant changes in methylation for three differentially methylated positions associated with change in tender joint counts, three with change in swollen joint count and a further four with change in CRP. Of the 12 CpGs, four showed replicated association in an independent dataset of samples from the Rheumatoid Arthritis Medication Study. These data represent an advance on current practice by contributing to a personalized medicine strategy allowing an escalation or change in therapy as early as 4 weeks.


Multimodal assessment shows misalignment of structural and functional thalamocortical connectivity in children and adolescents born very preterm.
Thalamocortical connections are altered following very preterm birth but it is unknown whether structural and functional alterations are linked and how they contribute to neurodevelopmental deficits. We used a multimodal approach in 27 very preterm and 35 term-born children and adolescents aged 10-16 years: Structural thalamocortical connectivity was quantified with two measures derived from probabilistic tractography of diffusion tensor data, namely the volume of thalamic segments with cortical connections and mean fractional anisotropy (FA) within the respective segments. High-density sleep EEG was recorded and sleep spindles were identified at each electrode. Sleep spindle density and integrated spindle activity (ISA) were calculated to quantify functional thalamocortical connectivity. In term-born participants, the volume of the global thalamic segment with cortical connections was strongly related to sleep spindles across the entire head (mean r = .53 ± .10; range = 0.35 to 0.78). Regionally, the volume of the thalamic segment connecting to frontal brain regions correlated with sleep spindle density in two clusters of electrodes over fronto-temporal brain regions (.42 ± .06; 0.35 to 0.51 and 0.43 ± .08; 0.35 to 0.62) and the volume of the thalamic segment connecting to parietal brain regions correlated with sleep spindle density over parietal brain regions (mean r = .43 ± .07; 0.35 to 0.61). In very preterm participants, the volume of the thalamic segments was not associated with sleep spindles. In the very preterm group, mean FA within the global thalamic segment was negatively correlated with ISA over a cluster of frontal and temporo-occipital brain regions (mean r = -.53 ± .07; -.41 to -.72). No association between mean FA and ISA was found in the term-born group. With this multimodal study protocol, we identified a potential misalignment between structural and functional thalamocortical connectivity in children and adolescents born very preterm. Eventually, this may shed further light on the neuronal mechanisms underlying neurodevelopmental sequelae of preterm birth.


Ganciclovir-resistant cytomegalovirus clinical isolates: mode of resistance to ganciclovir.
Cytomegalovirus strains with reduced in vitro susceptibilities to ganciclovir have been recovered from patients who failed long-term ganciclovir therapy. The ganciclovir-resistant clinical isolates in this study were unable to induce ganciclovir phosphorylation in virus-infected cells. The viral DNA polymerase function appeared unaltered in one genetically pure ganciclovir-resistant strain, compared with that of its wild-type ganciclovir-sensitive counterpart. All nine of the ganciclovir-resistant strains were susceptible to foscarnet. Moreover, these strains were sensitive to inhibition both by vidarabine and 1-(2'-deoxy-2'-fluoro-beta-D-arabinofuranosyl)-5-iodocytosine (FIAC), antiviral agents that are activated by cellular enzymes, and by (S)-1(3-hydroxy-2-phosphonylmethoxypropyl)cytosine (HPMPC), which is a monophosphate nucleoside analog. The in vitro resistance to ganciclovir of the ganciclovir-resistant clinical isolates studied was attributed to the inability of the cells infected with these isolates to phosphorylate ganciclovir; the virally encoded DNA polymerase did not appear to play a role in this ganciclovir resistance.


miR-277 regulates the phase of circadian activity-rest rhythm in Drosophila melanogaster.
Circadian clocks temporally organize behaviour and physiology of organisms with a rhythmicity of about 24 h. In Drosophila, the circadian clock is composed of mainly four clock genes: period (per), timeless (tim), Clock (Clk) and cycle (cyc) which constitutes the transcription-translation feedback loop. The circadian clock is further regulated via post-transcriptional and post-translational mechanisms among which microRNAs (miRNAs) are well known post-transcriptional regulatory molecules. Here, we identified and characterized the role of miRNA-277 (miR-277) expressed in the clock neurons in regulating the circadian rhythm. Downregulation of miR-277 in the pacemaker neurons expressing circadian neuropeptide, pigment dispersing factor (PDF) advanced the phase of the morning activity peak under 12 h light: 12 h dark cycles (LD) at lower light intensities and these flies exhibited less robust rhythms compared to the controls under constant darkness. In addition, downregulation of miR-277 in the PDF expressing neurons abolished the Clk gene transcript oscillation under LD. Our study points to the potential role of miR-277 in fine tuning the Clk expression and in maintaining the phase of the circadian rhythm in Drosophila.


Formalin (0.25%) as topical anti-microbial agent in burns.
In a prospective controlled trial, 0.25% formalin spray was compared with 2% silver sulfadiazine cream as the local treatment of burns. Formation and separation of eschar, infection and death rates were recorded. In the group receiving formalin, rates of formation and separation of eschar were significantly more (P less than 0.001 and P less than 0.05 resp.) compared to other group. Infection rate and fatality due to infection were also reduced. Other advantages of formalin are ease of application and the low east.


Hippocampus-dependent memory formation: do memory type-specific mechanisms exist?
Long-term memory (LTM) formation requires gene transcription and de novo protein synthesis. The transcription factor CREB is required for hippocampus-dependent LTM formation, and it is activated by several signaling pathways, including protein kinase A (PKA), the mitogen activated protein/extracellular signal-regulated kinases (MAPK or ERKs), and Ca(2+)/calmodulin kinases (CaMKs). However, it is unknown whether all types of hippocampus-dependent LTM use the same signaling to activate transcription, and whether the transcriptional output is the same. Here we present molecular genetic and behavioral studies to demonstrate that two types of hippocampus-dependent LTM formation, spatial and contextual, require different signaling molecules. This can be illustrated by the CaMK kinases, CaMKKalpha, and CaMKKbeta, which have converse roles. CaMKKalpha is required for contextual and CaMKKbeta is required for spatial LTM formation. This leads to the surprising conclusion that there are distinct types of hippocampus-dependent LTM, which differ in their underlying molecular mechanisms.


A comprehensive e-education engine for a virtual diabetes centre.
It seems likely that the development of effective diabetes education for patients, carers and staff would prove highly cost-effective. Diabetes-e is an electronic diabetes encyclopaedia designed to provide comprehensive education to patients, carers (e.g. family, schools, care homes) and health professionals (specialist and non-specialist). In addition, educational media such as information leaflets (that can be printed during a consultation), streaming educational video and slide resource packs are available. Self-assessment questionnaires with feedback guide further education and facilitate targeted continuing professional development (CPD) for health professionals. The prototype has been developed with a particular emphasis on patient input. It is anticipated that Diabetes-e will be implemented across Central Nottinghamshire, including training of key personnel, by the end of 2005. The project has already gone live for insulin commencement.


Genome-wide functional annotation of dual-specificity protein- and lipid-binding modules that regulate protein interactions.
Emerging evidence indicates that membrane lipids regulate protein networking by directly interacting with protein-interaction domains (PIDs). As a pilot study to identify and functionally annodate lipid-binding PIDs on a genomic scale, we performed experimental and computational studies of PDZ domains. Characterization of 70 PDZ domains showed that ~40% had submicromolar membrane affinity. Using a computational model built from these data, we predicted the membrane-binding properties of 2,000 PDZ domains from 20 species. The accuracy of the prediction was experimentally validated for 26 PDZ domains. We also subdivided lipid-binding PDZ domains into three classes based on the interplay between membrane- and protein-binding sites. For different classes of PDZ domains, lipid binding regulates their protein interactions by different mechanisms. Functional studies of a PDZ domain protein, rhophilin 2, suggest that all classes of lipid-binding PDZ domains serve as genuine dual-specificity modules regulating protein interactions at the membrane under physiological conditions.


Effect of intermittent pneumatic soft-tissue compression on fracture-healing in an animal model.
The fracture-healing process is closely related to blood supply. Intermittent pneumatic compression of the surrounding soft tissue may alter blood flow and, therefore, modify the healing process. The object of the present study was to evaluate the effect of intermittent pneumatic compression on fracture-healing in an animal model. Unilateral, transverse, mid-tibial osteotomies with a 3-mm gap were performed in thirty rabbits. The osteotomy site was stabilized with a double-bar external fixator. The femoral vein was ligated to induce venous stasis. Beginning on the fourth postoperative day, fifteen rabbits were treated with intermittent pneumatic compression with use of four rubber balloons, two around the distal part of the calf and two around the midpart of the calf, for one hour daily for four weeks (the study group) and fifteen rabbits were not treated with intermittent pneumatic compression (the control group). Peripheral computerized tomographic examination was performed biweekly to measure callus area and mineral content at the fracture gap. At eight weeks, the rabbits were killed, and the biomechanical properties of the healing fractures were evaluated with a torsional test. An increase in callus area and mineral content at the osteotomy gap was observed in the study group, compared with the values in the control group, starting four weeks after the index procedure. At six weeks, the rabbits treated with intermittent pneumatic compression exhibited, on the average, a 32.2% larger callus area (p = 0.035) and a 49.7% higher mineral content (p = 0.01) at the osteotomy site compared with the values in the control group. The torsional stiffness, maximum torque, angular displacement at maximum torque, and energy required to failure of specimens in the study group were an average of 27.0% (p = 0.05), 61.5% (p = 0.0001), 35.4% (p = 0.0003), and 110.8% (p = 0.0001) higher, respectively, than those in the control group at eight weeks. Intermittent pneumatic compression enhanced callus mineralization and development and it improved the biomechanical properties of a healing osteotomy site in the rabbit tibia.


Bovine tuberculosis in livestock and wild boar on the Mediterranean island, Corsica.
The zoonotic agent of bovine tuberculosis (bTB), Mycobacterium bovis, can be transmitted between domestic and wild animals, threatening wildlife populations and control programs for bTB in cattle. In Corsica, a French Mediterranean island where domestic and wild species have close interactions, bTB cases have been reported in cattle, pigs, and wild boar. Moreover, genotypes of M. bovis found in wild and domestic animals from the same area were identical. These data strongly suggest that wild and domestic animals are associated in an epidemiologic bTB-transmission cycle. More investigations are needed, not only to understand the role played by each species in order to implement appropriate control measures, but also to assess the risk of transmission to humans.


Coral reefs in the northeastern Saudi Arabian Red Sea are resilient to mass coral mortality events.
We conducted an integrated survey combining visual census and baited remote underwater video survey on the coral reefs in the northeastern Red Sea and examined their health by comparing the baseline information from two decades ago. The mean coverage of the corals of all stations was 36 %, including 32 % stony corals and 4.0 % soft corals, significantly higher and lower to previous baseline. Observed high proportion of dead corals indicated the occurrence of the events of mass mortality, and the heating events were the most likely cause. Similar levels of coral coverage compared to two decades ago indicated their resilience to past events with mass coral mortality. Small proportions of macroalgae and sea urchins indicated that they might be controlled by their predators frequently observed in both visual census and underwater video survey. Regular monitoring and careful development plans are needed to safeguard these invaluable reefs.


Intradermal Testing With COVID-19 mRNA Vaccines Predicts Tolerance.
The newly developed mRNA-based COVID-19 vaccines can provoke anaphylaxis, possibly induced by polyethylene glycol (PEG) contained in the vaccine. The management of persons with a history of PEG allergy or with a suspected allergic reaction after the first dose remains to be defined. In this real-life study, we defined two cohorts of individuals: one pre-vaccination including 187 individuals with high-risk profiles for developing anaphylaxis and a second post-vaccination including 87 individuals with suspected allergic reactions after the COVID-19 mRNA vaccine. Upon negative skin test with an mRNA vaccine, a two-step (10-90%) vaccination protocol was performed. Positive skin tests were confirmed with the basophil activation test (BAT). Among 604,267 doses of vaccine, 87 suspected allergic reactions (5 after the booster) were reported to our division for further investigations: 18/87 (21%) were consistent with anaphylaxis, 78/87 (90%) were female, and 47/87 (54%) received the BNT162b2 mRNA vaccine. Vaccine skin tests were negative in 96% and 76% of the pre- and post-vaccination cohorts, respectively. A two-step vaccination was tolerated in 232/236 (98%) of individuals with negative tests. Four individuals experienced isolated asthmatic reactions during the two-step challenge. Vaccine-positive skin tests were consistently confirmed by BAT; CD63 and CD203c expression was selectively inhibited with ibrutinib, suggesting an IgE-dependent mechanism. Sensitization to SARS-CoV-2 mRNA vaccines can be detected with intradermal testing. Significantly more individuals were sensitized to mRNA vaccines in the post-vaccination cohort. A two-step 10-90%-vaccination protocol can be safely administered upon negative skin testing.


[Violence in the school--analysis of the problem and possible interventions].
This article deals with a topic being controversially discussed in public for several years now: violence in school. Following the outlining of the current state of research and the naming of causes is a representation of the research-project "Violence in School' sponsored by the German Research Community (Deutsche Forschungsgemeinschaft, DFG). This four-stage program which was designed to analyze and prevent violence in school has set itself the aim to get a comprehensive idea of extent and appearance of violent behavior as well as to find condition-constellations in the school environment and also externally. Finally, some ideas for prevention and intervention of violence in school are given. Those recommendations represent a set of proposals that can be found in the bibliography.


Sunitinib for patients with metastatic non-clear cell renal cell carcinoma: a Multicenter Retrospective Turkish Oncology Group trial.
This study aimed to assess the clinical efficacy and toxicity of sunitinib, a targeted-agent, for non-clear cell renal cell carcinoma. Sixty-three patients with complete clinical data from 13 oncology Centers were retrospectively evaluated. Outcomes analyzed were objective response rate (ORR), progression-free survival (PFS), overall survival (OS) and adverse events. The median age of all patients, 38 men (60.3%) and 25 women (39.7%), was 63 years (range=25-82 years). Histological subtypes included 46 (88%) cases of papillary RCC, 10 of chromophobe, and 7 unclassified cases. Median treatment duration was seven months (range=2-86 months). At the time of this analysis, 52 patients had discontinued treatment, 33 of whom had died. Treatment discontinuation was due to disease progression in 43 patients, and toxicity in nine. Dose interruption was necessary in 22 (34.9%) patients, and dose reduction in 27 (42.9%). The objective response rate and disease control rate were 11.1% and 63.5%, respectively. The median PFS and OS were 7.6 months (95% confidence interval (CI)=5.5-9.7 months) and 22.0 months (95% CI=13.4-30.6 months), respectively, with 1-year rates of 64.7% and 33.7%, respectively. Clinical outcome of the metastatic non-clear cell RCC patients with sunitinib treatment seemed to be worse than the historical data of clear cell RCC patients, in terms of PFS, OS and objective response. New and more effective targeted-therapies and better understanding of the underlying molecular processes are necessary to improve survival outcome for these patients.


Nucleolin Improves Heart Function During Recovery From Myocardial Infarction by Modulating Macrophage Polarization.
Nucleolin has multiple functions within cell survival and proliferation pathways. Our previous studies have revealed that nucleolin can significantly reduce myocardial ischemia-reperfusion injury by promoting myocardial angiogenesis and reducing myocardial apoptosis. In this study, we attempted to determine the role of nucleolin in myocardial infarction (MI) injury recovery and the underlying mechanism. Male BALB/c mice aged 6-8 weeks were used to set up MI models by ligating the left anterior descending coronary artery. Nucleolin expression in the heart was downregulated by intramyocardial injection of a lentiviral vector expressing nucleolin-specific small interfering RNA. Macrophage infiltration and polarization were measured by real-time polymerase chain reaction, flow cytometry, and immunofluorescence. Cytokines were detected by enzyme-linked immunosorbent assay. Nucleolin expression in myocardium after MI induction decreased a lot at early phase and elevated at late phase. Nucleolin knockdown impaired heart systolic and diastolic functions and decreased the survival rate after MI. Macrophage infiltration increased in the myocardium after MI. Most macrophages belonged to the M1 phenotype at early phase (2 days) and the M2 phenotype increased greatly at late phase after MI. Nucleolin knockdown in the myocardium led to a decrease in M2 macrophage polarization with no effect on macrophage infiltration after MI. Furthermore, Notch3 and STAT6, key regulators of M2 macrophage polarization, were upregulated by nucleolin in RAW 264.7 macrophages. Lack of nucleolin impaired heart function during recovery after MI by reducing M2 macrophage polarization. This finding probably points to a new therapeutic option for ischemic heart disease.


[Nursing care of propedeutic and therapeutic nature and its interface with other professional actions].
This paper is based on a qualitative research, with an approach based on phenomenological hermeneutics. Its aim is to understand the singularities of nursing therapeutic and propedeutic care actions and their interfaces with the actions of other professionals. The participants are five nurses from the Trauma Intensive Care Unit of an university hospital. The data has been collected through semi-structured interviews and has been analyzed according to Ricoeur's hermeneutics. The understanding of what has been shown by the participants, concerning the meaning of care actions, presented five distinct categories: organization of the caring environment; expressiveness of being; development of educative actions; systematization of care and interfaces of care.


Meeting the needs of primary care physicians: a guide to content for programs on depression.
The purpose of this article is to identify literature-based content for the design of educational programs on depression for practicing primary care physicians. A MEDLINE search was conducted of English-language medical literature published from 1982 through July 1997 for studies describing primary care physicians' knowledge, skills, practice patterns, and perceived barriers related to care of depressed patients. Studies focusing exclusively on residency training and those describing physician practices outside North America were excluded. Of 377 articles identified, forty met inclusion and exclusion criteria. Recommendations for educational content were identified from the literature review. For recognition, educators should prioritize communication skills and strategies for the use of depression questionnaires. For diagnosis, practice interpreting symptoms in the medically ill, strategies for efficient diagnosis, and systematic approaches to assessing suicide risk should be emphasized. For treatment, greater attention to the therapeutic alliance, staged therapy, and strategies for improving medication adherence are indicated. There is a moderately well developed literature describing self-perceived and observed gaps in the current care for depression in primary care. Addressing the entire list of needs would take more time than practicing physicians are likely to have. An important challenge for educators is to design flexible programs based on individualized needs assessment or, when not possible, to prioritize the most generalizable needs.


Drinking moderately and pregnancy. Effects on child development.
Children exposed to moderate levels of alcohol during pregnancy show growth deficits and intellectual and behavioral problems similar to, although less severe than, those found in children with fetal alcohol syndrome. Research has begun to examine the extent to which these problems affect the child's ability to function on a day-to-day basis at school and with peers. Findings indicate that "moderate" drinking has much more impact on child development when the mother consumes several drinks in a single day than when she drinks the same quantity in doses of one to two drinks per day over several days.


Identifying psychosocial characteristics that predict outcome to the UPLIFT programme for people with persistent back pain: protocol for a prospective cohort study.
Prognostic screening of people with low back pain (LBP) improves utilisation of primary healthcare resources. Whether this also applies to secondary healthcare remains unclear. Therefore, this study aims to develop prognostic models to determine at baseline which patients with persistent LBP are likely to have a good and poor outcome to a 5-week programme of combined education and exercise ('UPLIFT') delivered in a secondary healthcare setting. A prospective cohort study of 246 people with persistent LBP will be conducted in a secondary healthcare outpatient setting. Patients will be recruited from a physiotherapy-led neurosurgical screening clinic. Demographic data, medical history and psychosocial characteristics will be recorded at baseline. Fear avoidance beliefs, pain self-efficacy, LBP treatment beliefs, pain catastrophising, perceived injustice, depression, anxiety and stress, disability level, pain intensity and interference, health status and social connectedness will be considered as potential prognostic variables, which will be assessed using self-reported questionnaires. Participants will attend the UPLIFT programme, consisting of weekly 90 min group sessions that combine interactive education sessions and a graded exercise programme. The outcome measure to identify good and poor outcome is the Global Rating of Change scale, assessed at completion of the UPLIFT programme and at 6 months follow-up. Multiple imputation analyses will be performed for missing values. Prognostic models will be developed using multivariable logistic regression analyses, with bootstrapping techniques for internal validation. We will calculate the explained variance of the models and the area under the receiver operating characteristic curve. Furthermore, we will determine whether participation in the UPLIFT programme is associated with changes in psychosocial characteristics. Gold Coast Health Service Human Research Ethics Committee (HREC/18/QGC/41) and the Griffith University Human Research Ethics Committee (GU Ref No: 2018/408) approved the study. Dissemination of findings will occur via peer-reviewed publications and conference presentations. ACTRN12618001525279.


Design and formulation of functional pluripotent stem cell-derived cardiac microtissues.
Access to robust and information-rich human cardiac tissue models would accelerate drug-based strategies for treating heart disease. Despite significant effort, the generation of high-fidelity adult-like human cardiac tissue analogs remains challenging. We used computational modeling of tissue contraction and assembly mechanics in conjunction with microfabricated constraints to guide the design of aligned and functional 3D human pluripotent stem cell (hPSC)-derived cardiac microtissues that we term cardiac microwires (CMWs). Miniaturization of the platform circumvented the need for tissue vascularization and enabled higher-throughput image-based analysis of CMW drug responsiveness. CMW tissue properties could be tuned using electromechanical stimuli and cell composition. Specifically, controlling self-assembly of 3D tissues in aligned collagen, and pacing with point stimulation electrodes, were found to promote cardiac maturation-associated gene expression and in vivo-like electrical signal propagation. Furthermore, screening a range of hPSC-derived cardiac cell ratios identified that 75% NKX2 Homeobox 5 (NKX2-5)+ cardiomyocytes and 25% Cluster of Differentiation 90 OR (CD90)+ nonmyocytes optimized tissue remodeling dynamics and yielded enhanced structural and functional properties. Finally, we demonstrate the utility of the optimized platform in a tachycardic model of arrhythmogenesis, an aspect of cardiac electrophysiology not previously recapitulated in 3D in vitro hPSC-derived cardiac microtissue models. The design criteria identified with our CMW platform should accelerate the development of predictive in vitro assays of human heart tissue function.


A Type IA DNA/RNA Topoisomerase with RNA Hydrolysis Activity Participates in Ribosomal RNA Processing.
Topoisomerases maintain topological homeostasis of bacterial chromosomes by catalysing changes in DNA linking number. The resolution of RNA entanglements occurring in the cell would also require catalytic action of topoisomerases. We describe RNA topoisomerase and hydrolysis activities in DNA topoisomerase I (topo I) from mycobacteria. The interaction of topo I with mRNA, tRNA and rRNA suggested its role in some aspect of RNA metabolism; the enzyme participates in rRNA maturation via its RNA hydrolysis activity. Accumulation of rRNA precursors in a topo I knockdown strain and the rescue of rRNA processing deficiency in RNaseE knockdown cells by topo I expression indicated the enzyme's back-up support to RNases involved in rRNA processing. We demonstrate that the active-site tyrosine of the enzyme mediates catalytic reactions with both DNA/RNA substrates, and RNA topoisomerase activity can follow two reaction paths in contrast to its DNA topoisomerase activity. Mutation in the canonical proton relay pathway impacts DNA topoisomerase activity whilst retaining activity on RNA substrates. The mycobacterial topo I thus exemplifies the resourcefulness and parsimony of biological catalysis in harnessing the limited chemical repertoire at its disposal to find common solutions to mechanistically related challenges of phosphodiester breakage/exchange reactions in DNA and RNA that are essential for cell survival.


Euglossine bees as potential bio-indicators of coffee farms: does forest access, on a seasonal basis, affect abundance?
In order to understand the implications of agriculture on the environment, ecosystem health must be measured. Observing the presence of a biological indicator within an ecosystem is one such method. In this study, male euglossine bees were observed using as attractant cineole 1:8, at adjacent organic (La Paz) and conventional (La Carena) coffee farms near the Northern Barranca River, San Ramón, Alajuela, Costa Rica. Simultaneous data collections were conducted on both farms in April 2004 (late-dry season) and June 2004 (early-rainy season) and combined with the findings of August 2004 (mid-rainy season). These observations show that orchid bees are a viable bio-indicator of organic farm health on a seasonal basis. In the dry season there was no significant difference in orchid bee abundance between the two farms. There is a strong tendency for more bees during the rainy season, suggesting that orchid bee abundance is linked to seasonality and forest access.


In vitro activity of 19 antimicrobial agents against enterococci from healthy subjects and hospitalized patients and use of an ace gene probe from Enterococcus faecalis for species identification.
We tested 165 enterococcal isolates, biased toward vancomycin resistant (VR) isolates, collected during recent years from fecal samples of healthy subjects and clinical specimens of hospitalized patients (mostly from United States and some from Europe) for susceptibility to 19 antimicrobials. Nosocomial isolates, whether VR or not, were more often highly resistant to aminoglycosides and clindamycin than fecal isolates from healthy community volunteers and more often resistant to erythromycin, chloramphenicol, trimethoprim, levofloxacin and, for E. faecium, ampicillin (93 vs. 0%). Resistance rates were similar between nosocomial and community-fecal isolates for minocycline, rifampin and quinupristin-dalfopristin (Q-D). None of the 165 enterococci tested hybridized with aph(2'')-Ic and aph(2'')-Id probes for recently described gentamicin resistance genes and 37 of the 39 isolates with high level resistance (HLR) to gentamicin hybridized with an intragenic aac(6')-aph(2'') probe. Of the two newer drugs tested, daptomycin MIC90s were 0.25 microg/mL for E. faecalis and 1 microg/mL for E. faecium, regardless of their vancomycin resistance level or source. For Q-D, none of 28 E. faecium from community based healthy subjects in the USA and 7 of 66 E. faecium from hospitalized patients in the United States were resistant. Among these 7 Q-Dr United States isolates and 7 Q-Dr isolates from Europe (MICs of Q-D of 4-8 microg/mL), none hybridized with vat(D) (formerly satA) and vat(E) (formerly satG) DNA probes, indicating the involvement of other mechanism/s of resistance in these isolates. We also demonstrated that an intragenic probe of the gene ace from E. faecalis showed specific hybridizations to all E. faecalis isolates, suggesting the usefulness of this gene for identification of this species.


The effects of sodium bicarbonate on thioridazine-induced cardiac dysfunction in the isolated perfused rat heart.
To determine the site of thioridazine-induced cardiotoxicity and investigate the effectiveness of sodium bicarbonate (NaHCO3) therapy, isolated rat hearts were perfused with Krebs-Henseleit-Bicarbonate buffer (KHB) at a constant coronary flow of 10 mL/min and electrically paced at 300 bpm. Experimental protocol included 15 min intervals of KHB, thioridazine (TDZ), TDZ + NaHCO3, KHB. Left ventricular (LV) pressure was measured with a balloon-tipped catheter placed in the LV via the mitral valve. Coronary perfusion pressure was monitored continuously as an index of coronary vascular resistance (CVR). LV generated pressure (LVGP) was used as our index of cardiac function and was calculated by subtracting LV end diastolic pressure (LVEDP) from LV peak systolic pressure (LVPSP). TDZ at 7,500 ng/mL was chosen as the toxic dose. NaHCO3 treatment was at an approximate sodium = 155 mM and pH = 7.60. Hearts perfused with TDZ resulted in a progressive decrease in LVGP. After 15 min of TDZ perfusion, LVGP decreased by 50%, and 75% at 30 min (n = 5). TDZ increased LVEDP and decreased LVPSP. TDZ perfusion increased CVR by 83%. In another experiment, hearts were perfused with TDZ for 15 min and then for an additional 15 min with TDZ + NaHCO3. NaHCO3 treatment transiently (approximately 5 min) increased LVGP by 23% (n=5). During NaHCO3 treatment, LVPSP increased and LVEDP and CVR decreased during the first 5 min. During the remainder of the NaHCO3 protocol, the hearts failed, similar to TDZ alone. TDZ diminished left ventricular function and promoted coronary artery vasoconstriction. NaHCO3 temporariy reversed these toxic effects.


Importance of faith on medical decisions regarding cancer care.
Decisions regarding cancer treatment choices can be difficult. Several factors may influence the decision to undergo treatment. One poorly understood factor is the influence of a patient's faith on how they make medical decisions. We compared the importance of faith on treatment decisions among doctors, patients, and patient caregivers. One hundred patients with advanced lung cancer, their caregivers, and 257 medical oncologists were interviewed. Participants were asked to rank the importance of the following factors that might influence treatment decisions: cancer doctor's recommendation, faith in God, ability of treatment to cure disease, side effects, family doctor's recommendation, spouse's recommendation, and children's recommendation. All three groups ranked the oncologist's recommendation as most important. Patients and caregivers ranked faith in God second, whereas physicians placed it last (P <.0001). Patients who placed a high priority on faith in God had less formal education (P <.0001). Patients and caregivers agree on the factors that are important in deciding treatment for advanced lung cancer but differ substantially from doctors. All agree that the oncologist's recommendation is most important. This is the first study to demonstrate that, for some, faith is an important factor in medical decision making, more so than even the efficacy of treatment. If faith plays an important role in how some patients decide treatment, and physicians do not account for it, the decision-making process may be unsatisfactory to all involved. Future studies should clarify how faith influences individual decisions regarding treatment.


Multistep Signaling in Nature: A Close-Up of Geobacter Chemotaxis Sensing.
Environmental changes trigger the continuous adaptation of bacteria to ensure their survival. This is possible through a variety of signal transduction pathways involving chemoreceptors known as methyl-accepting chemotaxis proteins (MCP) that allow the microorganisms to redirect their mobility towards favorable environments. MCP are two-component regulatory (or signal transduction) systems (TCS) formed by a sensor and a response regulator domain. These domains synchronize transient protein phosphorylation and dephosphorylation events to convert the stimuli into an appropriate cellular response. In this review, the variability of TCS domains and the most common signaling mechanisms are highlighted. This is followed by the description of the overall cellular topology, classification and mechanisms of MCP. Finally, the structural and functional properties of a new family of MCP found in Geobacter sulfurreducens are revisited. This bacterium has a diverse repertoire of chemosensory systems, which represents a striking example of a survival mechanism in challenging environments. Two G. sulfurreducens MCP-GSU0582 and GSU0935-are members of a new family of chemotaxis sensor proteins containing a periplasmic PAS-like sensor domain with a c-type heme. Interestingly, the cellular location of this domain opens new routes to the understanding of the redox potential sensing signaling transduction pathways.


Lichenoid drug reactions to chlorpropamide and tolazamide.
Many medications, including gold, antimalarials, quinidine, and thiazide diuretics have been implicated in lichenoid drug reactions. Chlorpropamide and tolazamide are sulfonylurea oral hypoglycemic agents, neither of which has previously been implicated in cutaneous lichenoid reactions. We report a case of lichenoid drug reaction related to both chlorpropamide and tolazamide.


Mechanical injury of peripheral nerves. Fine structure and dysfunction.
In summary we have examined the morphology of the normal peripheral nerve, presented the types of mechanical nerve injury and associated histopathology, and discussed possible mechanisms responsible for symptoms of pain, paresthesiae, and weakness associated with these lesions. Neurapraxia consists of intussusception of axon and myelin through the nodes of Ranvier resulting in prolonged nerve conduction block. Axonotmesis and neurotmesis describe more severe disruptions of nerve fiber architecture, are difficult to distinguish electrophysiologically, and have poorer prognoses for functional regenerative repair. Chronic entrapment lesions consist of telescoping myelin internodes and tapering of the sheaths with bulbous polarization of internodes away from the site of injury. Both acute and chronic lesions chiefly involve large myelinated fibers and both may create neuralgia, although the mechanism by which this occurs is poorly understood. Presently, increasing evidence suggests ectopic impulse generators and ephaptic transmission may be responsible for sensorimotor phenomena in these lesions.


Efferent vagal innervation of the canine atria and sinus and atrioventricular nodes. The third fat pad.
The purpose of this study was to investigate the functional pathways of efferent vagal innervation to the atrial myocardium and sinus and atrioventricular (AV) nodes. Using vagally induced atrial effective refractory period shortening, slowing of spontaneous sinus rate, and prolongation of AV nodal conduction time as end points of vagal effects, we determined the actions of phenol and epicardial radiofrequency catheter ablation (RFCA) applied to different sites at or near the atrial myocardium to inhibit these responses. We found that efferent vagal fibers to the atria are located both subepicardially and intramurally or subendocardially. Most efferent vagal fibers to the atria appear to travel through a newly described fat pad located between the medial superior vena cava and aortic root (SVC-Ao fat pad), superior to the right pulmonary artery, and then project onto two previously noted fat pads at the inferior vena cava-left atrial junction (IVC-LA fat pad) and the right pulmonary vein-atrial junction (RPV fat pad) and to both atria. A few vagal fibers may bypass the SVC-Ao fat pad and go directly to the IVC-LA or RPV fat pad and then innervate the atrial myocardium. Vagal fibers to the sinus and AV nodes also converge at the SVC-Ao fat pad (a few fibers to the sinus node go directly to the RPV fat pad) before projecting to the RPV and IVC-LA fat pads. Long-term vagal denervation of the atria and sinus and AV nodes can be produced by RFCA of these fat pads and results in vagal denervation supersensitivity. Vagal denervation prevents induction of atrial fibrillation in this model. The newly described SVC-Ao fat pad receives most of the vagal fibers to the atria and sinus and AV nodes. Elimination of the fat pads with RFCA selectively vagally denervated the atria and sinus and AV nodes.


Near misdiagnosis of glioblastoma as primary central nervous system lymphoma.
Primary central nervous system (CNS) lymphoma, most frequently a diffuse large B-cell lymphoma, is a rare aggressive lymphoma confined to the CNS, thus requiring differentiation from other brain malignancies such as glioblastoma. Although stereotactic biopsy can confirm the diagnosis, this is invasive, not always feasible and can be inconclusive after steroid use. Hence, cranial magnetic resonance imaging (MRI) with contrast and cerebrospinal fluid analysis are frequently used to make a prompt diagnosis. We report a case of a woman with two brain masses who presented unique diagnostic challenge.