Isolation of cDNAs encoding secreted and transmembrane proteins from Schistosoma mansoni by a signal sequence trap method.
Surface and secreted proteins of schistosomes orchestrate the basic physiologic requirements of a parasitic existence. These proteins are often exposed to host tissues during penetration, migration, feeding, and immune evasion, and they are obvious targets for control strategies. Signal sequence trap (SST) represents a novel approach that selects for cDNAs encoding secreted and surface proteins with N-terminal signal peptides, so we constructed a randomly primed adult Schistosoma mansoni cDNA library fused to a signalless reporter gene encoding placental alkaline phosphatase. The library was used to transfect COS-7 cells, which were then assayed for the presence of reporter at the cell surface. Eighteen S. mansoni cDNA fragments were isolated and sequenced. Expression profiles of the novel clones were determined for different developmental stages; some transcripts were restricted to single-sex adult worms, while others were ubiquitously distributed. Most clones contained signal peptides or signal anchors as determined by the SignalP algorithm. Open reading frames (ORFs) were categorized as follows: (i) previously identified S. mansoni cDNAs encoding proteins of known function; (ii) cDNAs encoding proteins of known function in other organisms but novel for Schistosoma; (iii) S. mansoni expressed sequence tags (ESTs) of unknown function; and (iv) completely novel ORFs without homologues (including ESTs) from any phylum. Clones of particular interest included tetraspanins similar to human cell surface antigens, a protein kinase, and ORFs transcribed in the antisense orientation to previously characterized S. mansoni cDNAs. This is the first report describing the use of SST as a tool for identifying secreted proteins from any pathogenic organism.


Electron Redistribution within the Nitrogenase Active Site FeMo-Cofactor During Reductive Elimination of H2 to Achieve N≡N Triple-Bond Activation.
Nitrogen fixation by nitrogenase begins with the accumulation of four reducing equivalents at the active-site FeMo-cofactor (FeMo-co), generating a state (denoted E4(4H)) with two [Fe-H-Fe] bridging hydrides. Recently, photolytic reductive elimination (re) of the E4(4H) hydrides showed that enzymatic re of E4(4H) hydride yields an H2-bound complex (E4(H2,2H)), in a process corresponding to a formal 2-electron reduction of the metal-ion core of FeMo-co. The resulting electron-density redistribution from Fe-H bonds to the metal ions themselves enables N2 to bind with concomitant H2 release, a process illuminated here by QM/MM molecular dynamics simulations. What is the nature of this redistribution? Although E4(H2,2H) has not been trapped, cryogenic photolysis of E4(4H) provides a means to address this question. Photolysis of E4(4H) causes hydride-re with release of H2, generating doubly reduced FeMo-co (denoted E4(2H)*), the extreme limit of the electron-density redistribution upon formation of E4(H2,2H). Here we examine the doubly reduced FeMo-co core of the E4(2H)* limiting-state by 1H, 57Fe, and 95Mo ENDOR to illuminate the partial electron-density redistribution upon E4(H2,2H) formation during catalysis, complementing these results with corresponding DFT computations. Inferences from the E4(2H)* ENDOR results as extended by DFT computations include (i) the Mo-site participates negligibly, and overall it is unlikely that Mo changes valency throughout the catalytic cycle; and (ii) two distinctive E4(4H) 57Fe signals are suggested as associated with structurally identified "anchors" of one bridging hydride, two others with identified anchors of the second, with NBO-analysis further identifying one anchor of each hydride as a major recipient of electrons released upon breaking Fe-H bonds.


Valence Change Bipolar Resistive Switching Accompanied With Magnetization Switching in CoFe2O4 Thin Film.
Resistive Switching in oxides has offered new opportunities for developing resistive random access memory (ReRAM) devices. Here we demonstrated bipolar Resistive Switching along with magnetization switching of cobalt ferrite (CFO) thin film using Al/CFO/FTO sandwich structure, which makes it a potential candidate for developing future multifunctional memory devices. The device shows good retention characteristic time (>104 seconds) and endurance performance, a good resistance ratio of high resistance state (HRS) and low resistance state (LRS) ~103. Nearly constant resistance values in LRS and HRS confirm the stability and non-volatile nature of the device. The device shows different conduction mechanisms in the HRS and LRS i.e. Schottky, Poole Frenkel and Ohmic. Magnetization of the device is also modulated by applied electric field which has been attributed to the oxygen vacancies formed/annihilated during the voltage sweep and indicates the presence of valence change mechanism (VCM) in our device. It is suggested that push/pull of oxygen ions from oxygen diffusion layer during voltage sweep is responsible for forming/rupture of oxygen vacancies conducting channels, leading to switching between LRS and HRS and for switching in magnetization in CFO thin film. Presence of VCM in our device was confirmed by X-ray Photoelectron Spectroscopy at Al/CFO interface.


Two novel HLA-A*0201 T-cell epitopes in avian H5N1 viral nucleoprotein induced specific immune responses in HHD mice.
The influenza A nucleoprotein (NP) is an attractive target for avian flu vaccine development because of its high conversancy in the evolutionary chain of the virus. Here we identified two novel HLA-A*0201 restricted NP epitopes, named H5N1 NP373-381 AMDSNTLEL (NP373) and NP458-466 FQGRGVFEL (NP458), using computational bioinformatic analysis. The NP peptides showed a high binding affinity to HLA-A*0201 on T2 cells, and were able to induce the activation of the cytotoxic T cells in the human peripheral blood mononuclear cells. We examined the potential of using NP373 and NP458 peptide sequences supplemented with a single-chain trimer as potential DNA vaccine candidates in an HHD transgenic mouse model. A gene gun delivery system was used for administrating the vaccine candidates into the animals. The results from cytotoxicity and ELISPOT assays indicated that a significant amount of IFN-gamma was secreted by the T cells of the vaccinated mice, and the T cells were able to eliminate the corresponding peptide-loaded T2 cells. The discovery of these novel immunogenic NP peptides provides valuable information for avian flu vaccine design and construction.


[Nuclei with protrusions--"tailed" nuclei--and radiation cytogenetic markers in a lymphocyte culture after x-ray irradiation].
Frequency of the appearance of binuclear cells with nuclei having outgrowth into the cytoplasmic space and arise after first mitosis in human lymphocyte culture is linear-square dependent on the X-irradiation at doses from 0.0 to 4.0 Gy. Positive correlation between frequency of cells with "tailed" nuclei and frequency of metaphases of first mitosis having dicentrics and rings was established. Apparently, formation such "tailed" nuclei is connected with dicentrics and rings.


Discrimination of odors in olfactory bulb, pyriform-amygdaloid areas, and orbitofrontal cortex of the monkey.
In the orbitofrontal olfactory area (LPOF) which was delineated in a previous paper, the capacity for odor discrimination was studied and compared with that in the anterior pyriform cortex (AP), the medial portion of the amygdala (MA), and the olfactory bulb (OB). Unanesthetized monkeys were used and eight odors were applied. 1. In the OB, 12.5% of the cells responded to only one odor, and the cells which responded to five odors were most numerous (25%). The total of the cells which responded to two, three, and four odors was 52%, which was less than the total of the cells responding to three, four, and five odors (67.5%). A small number oc cells responded to all eight odors (2.5%). The responses were classified as an increase (+type), a decrease (-type), or no change (no-type) in the rate of spike discharge. 2. In the AP and MA, no difference in the response patterns was found. The cells which responded to only one odor were 12.3% of the total, and the cells which responded to three different kinds of odors were most numerous (34.3%). The total of the cells responding to two, three, and four odors was 80%, much more than that in the OB. In addition, no cell responded to all eight odors. Concerning the response types, an increase followed by a decrease, or vice versa, in the rate of spike discharges (mixed-type) was observed which did not appear in the OB. Thus, an advance was found in the processing of olfactory information when compared with the OB. 3. A most striking finding in the LPOF was that 50% of the cells responded to only one odor. The cells which responded to two, three, and four odors decreased in this order, and no cell responded to more than five odors. These cells never responded to light or sound. 4. Using three very similar odors and five very different odors, it was apparent that the ability to discriminate odors of the same category is far more advanced in the LPOF than in the lower olfactory areas; and, in contrast, the lower olfactory areas also play a significant role in the discrimination of odors which belong to different categories. 5. It was concluded that the capacity for odor discrimination definitely improves along the olfactory nervous system from the lower to the higher areas. It is highly probable that a fine and sepcific discrimination of odors is performed in the LPOF.


Photobiomodulation effect on local hemoglobin concentration assessed by near-infrared spectroscopy in humans.
Exposure of biological tissue to photobiomodulation therapy (PBMT) seems to increase the oxygen availability and mitochondrial electrochemical activity. With the advancement of new technologies, such as near-infrared spectroscopy (NIRS), information can be obtained about the balance between oxygen utilization and delivery by assessing local oxy- ([O2Hb]) and deoxy-myohemoglobin ([HHb]) concentrations, both measured in micromolars (μM). Consequently, NIRS can be used to study ("in vivo") PBMT effects on the oxidative system, including oxygen availability. Thus, the main objective of the present study was to use NIRS to investigate the acute effects of PBMT by light-emitting diode (LED) on the oxygen delivery and utilization in humans. Twelve healthy young participants were treated with a LED device (850 nm, 50 mW, 2 J) and placebo applied over the proximal third of the flexor carpi ulnaris muscle of the left or right forearm selected in a random order. The LED was applied in direct contact with skin and the device was switched on for 40 s in 4 different interventions (I1, I2, I3 and I4) with a 3-min interval between interventions. The placebo condition was considered as the period before the first PBMT. The NIRS device was used to evaluate the relative changes in [O2Hb] and [HHb] before and after placebo and interventions. We found that PBMT statistically increased the [O2Hb] in 0.39 μM. These results demonstrate the potential of PBMT to increase oxygen availability.


The Effect of Hypoxia on Cardiovascular Disease: Friend or Foe?
Savla, Jainy J., Benjamin D. Levine, and Hesham A. Sadek. The effect of hypoxia on cardiovascular disease: Friend or foe? High Alt Med Biol. 19:124-130, 2018.-Over 140 million people reside at altitudes exceeding 2500 m across the world, resulting in exposure to atmospheric (hypobaric) hypoxia. Whether this chronic exposure is beneficial or detrimental to the cardiovascular system, however, is uncertain. On one hand, multiple studies have suggested a protective effect of living at moderate and high altitudes for cardiovascular risk factors and cardiovascular disease (CVD) events. Conversely, residence at high altitude comes at the tradeoff of developing diseases such as chronic mountain sickness and high-altitude pulmonary hypertension and worsens outcomes for diseases such as chronic obstructive pulmonary disease. Interestingly, recently published data show a potential role for severe hypoxia as a unique and unexpected therapy after myocardial infarction. In this review, we will discuss the current literature evaluating the effects of altitude exposure and the accompanying hypoxia on health and the potential therapeutic applications of hypoxia on CVD.


Respiration-induced B0 fluctuations and their spatial distribution in the human brain at 7 Tesla.
In functional magnetic resonance imaging (fMRI), it is known that physiological influences such as cardiac pulsation, respiration, and brain motion can induce fluctuations in signal intensity and phase. Some of the mechanisms potentially involved in those phenomena are expected to be amplified at higher magnetic fields. This study addresses the issue of B(0) fluctuations induced by susceptibility changes during respiration attributed to movements of chest and diaphragm, and variations in the oxygen concentration. It is demonstrated that respiration-induced resonance offsets (RIROs) are significant at 7T. Data were acquired with an RF pulse (no gradients), multislice echo-planar imaging (EPI), and dynamic 3D fast low-angle shot (3D- FLASH) imaging. Three main observations summarize the experimental findings. First, in FIDs measured after a single RF pulse, a RIRO with a large amplitude was consistently detected, although the average amplitude varied between subjects from 1.45 Hz to 4 Hz. Second, in transverse EPI images obtained in the occipital lobe, the RIRO amplitude showed a monotonic increase along the z axis toward the lungs. Third, a more detailed spatial analysis with 3D-FLASH phase maps revealed that a previously published analytical model can accurately describe the spatial distribution of RIRO. Consequential apparent motions in the EPI series, as well as the implications of slice orientation for correction strategies are discussed.


Current antiviral drugs and their analysis in biological materials-Part I: Antivirals against respiratory and herpes viruses.
This review article is the first in the series providing an overview of currently used antiviral drugs and presenting contemporary approaches to their analysis. Large number of available antivirals and their structural variability makes this task very challenging. Trying to cover this topic comprehensively while maintaining reasonable size of the article, the review is presented in two parts. For the purpose of the overall review, antivirals were divided into four groups: (i) antivirals against herpes viruses, (ii) antivirals against respiratory viruses, (iii) antivirals against hepatitis viruses, and (iv) antivirals against HIV. Part one is devoted to the groups (i) and (ii) and also concerns the key features of the bioanalytical method. The mechanisms of action of antivirals against respiratory and herpes viruses and their use in clinical practice are briefly outlined, and the analytical methods for selected representatives of each class are described in more detail. The methods developed for the determination of drugs from these classes mostly include conventional procedures. In contrast, current trends such as UHPLC are used rarely and proper method validation based on requirements of bioanalytical guidelines can be often considered insufficient.


Comparative Genomic Analysis of Three Salmonid Species Identifies Functional Candidate Genes Involved in Resistance to the Intracellular Bacterium Piscirickettsia salmonis.
Piscirickettsia salmonis is the etiologic agent of salmon rickettsial syndrome (SRS) and is responsible for considerable economic losses in salmon aquaculture. The bacterium affects coho salmon (CS; Oncorhynchus kisutch), Atlantic salmon (AS; Salmo salar), and rainbow trout (RT; Oncorhynchus mykiss) in several countries, including Norway, Canada, Scotland, Ireland, and Chile. We used Bayesian genome-wide association study analyses to investigate the genetic architecture of resistance to P. salmonis in farmed populations of these species. Resistance to SRS was defined as the number of days to death and as binary survival (BS). A total of 828 CS, 2130 RT, and 2601 AS individuals were phenotyped and then genotyped using double-digest restriction site-associated DNA sequencing and 57K and 50K Affymetrix® Axiom® single nucleotide polymorphism (SNP) panels, respectively. Both traits of SRS resistance in CS and RT appeared to be under oligogenic control. In AS, there was evidence of polygenic control of SRS resistance. To identify candidate genes associated with resistance, we applied a comparative genomics approach in which we systematically explored the complete set of genes adjacent to SNPs, which explained more than 1% of the genetic variance of resistance in each salmonid species (533 genes in total). Thus, genes were classified based on the following criteria: i) shared function of their protein domains among species, ii) shared orthology among species, iii) proximity to the SNP explaining the highest proportion of the genetic variance, and iv) presence in more than one genomic region explaining more than 1% of the genetic variance within species. Our results allowed us to identify 120 candidate genes belonging to at least one of the four criteria described above. Of these, 21 of them were part of at least two of the criteria defined above and are suggested to be strong functional candidates influencing P. salmonis resistance. These genes are related to diverse biological processes, such as kinase activity, GTP hydrolysis, helicase activity, lipid metabolism, cytoskeletal dynamics, inflammation, and innate immune response, which seem essential in the host response against P. salmonis infection. These results provide fundamental knowledge on the potential functional genes underpinning resistance against P. salmonis in three salmonid species.


Key mechanistic features of Ni-catalyzed C-H/C-O biaryl coupling of azoles and naphthalen-2-yl pivalates.
The mechanism of the Ni-dcype-catalyzed C-H/C-O coupling of benzoxazole and naphthalen-2-yl pivalate was studied. Special attention was devoted to the base effect in the C-O oxidative addition and C-H activation steps as well as the C-H substrate effect in the C-H activation step. No base effect in the C(aryl)-O oxidative addition to Ni-dcype was found, but the nature of the base and C-H substrate plays a crucial role in the following C-H activation. In the absence of base, the azole C-H activation initiated by the C-O oxidative addition product Ni(dcype)(Naph)(PivO), 1B, proceeds via ΔG = 34.7 kcal/mol barrier. Addition of Cs2CO3 base to the reaction mixture forms the Ni(dcype)(Naph)[PivOCs·CsCO3], 3_Cs_clus, cluster complex rather than undergoing PivO(-) → CsCO3(-) ligand exchange. Coordination of azole to the resulting 3_Cs_clus complex forms intermediate with a weak Cs-heteroatom(azole) bond, the existence of which increases acidity of the activated C-H bond and reduces C-H activation barrier. This conclusion from computation is consistent with experiments showing that the addition of Cs2CO3 to the reaction mixture of 1B and benzoxazole increases yield of C-H/C-O coupling from 32% to 67% and makes the reaction faster by 3-fold. This emerging mechanistic knowledge was validated by further exploring base and C-H substrate effects via replacing Cs2CO3 with K2CO3 and benzoxazole (1a) with 1H-benzo[d]imidazole (1b) or quinazoline (1c). We proposed the modified catalytic cycle for the Ni(cod)(dcype)-catalyzed C-H/C-O coupling of benzoxazole and naphthalen-2-yl pivalate.


Use of early biomarkers in neonatal brain damage and sepsis: state of the art and future perspectives.
The identification of early noninvasive biochemical markers of disease is a crucial issue of the current scientific research, particularly during the first period of life, since it could provide useful and precocious diagnostic information when clinical and radiological signs are still silent. The ideal biomarker should be practical and sensitive in the precocious identification of at risk patients. An earlier diagnosis may lead to a larger therapeutic window and improve neonatal outcome. Brain damage and sepsis are common causes of severe morbidity with poor outcome and mortality during the perinatal period. A large number of potential biomarkers, including neuroproteins, calcium binding proteins, enzymes, oxidative stress markers, vasoactive agents, and inflammatory mediators, have been so far investigated. The aim of the present review was to provide a brief overview of some of the more commonly investigated biomarkers used in case of neonatal brain damage and sepsis.


Aroclor-1254 affects mRNA polyadenylation, translational activation, cell morphology, and DNA integrity of rat primary prostate cells.
Environmental xenobiotics have been shown to act as endocrine disruptors and to be implicated in increased cancer susceptibility. In particular, there is a significant concern regarding the impact of these contaminants on prostate cancer development and progression. However, the mechanisms with which these contaminants exert their detrimental effects are yet unclear and need to be further elucidated. In the present study, we investigated the effects of Aroclor-1254, a mixture of more than 60 environmental pollutants belonging to the polychlorinated biphenyl family, on rat prostate primary cultures. The results obtained after 24-h exposure indicated the ability of this contaminant mixture to influence mRNA stability and length of the 3'-end poly(A)tail of Connexin-32, Connexin-43, and heat shock protein-70. Consistent with this observation, immunostaining experiments demonstrated the altered availability of the encoded proteins. We also focused our attention on possible effects of Aroclor-1254 on cell morphology and could detect ultrastructural changes with gap junction disruption, fusion of single cells into clusters, and different aspects of apoptosis that became evident when exposure to Aroclor-1254 was extended to 72 h. The effects on the nuclear compartment were confirmed by the results obtained with Comet assay that showed DNA decompression and double-strand breaks already after 24-h exposure. Taken together, these findings show a detrimental effect of Aroclor 1254 on rat prostate cells and indicate a possible association between exposure to polychlorinated biphenyl mixture and induction of transformation process in prostate cells.


[Current status and future progress of reproductive/developmental toxicity test].
Currently, the European Centre for the Validation of Alternative Methods in the EU appears to be at the forefront of the development of alternative methods for developmental toxicity test (reproductive/developmental toxicity test). Why is it difficult to develop alternative methods for developmental toxicity test in comparison with other toxicity tests? In developmental toxicity test, chemical substances first enter the bloodstream and then reach the placenta via metabolism in the liver and other organs. After further metabolism in the placenta, chemical substances finally reach the fetus, where they affect fetal development. The difference in the in vivo route of chemical substances is an important reason for the difficulty in the establishment of new methods for developmental toxicologic test in comparison with general toxicity tests. According to the EU, the use of "in silico" techniques for developmental toxicity test may be difficult, and I agree with this. The in silico technique is basically a method for prediction of toxicologic effects from existing data, and cannot predict new effects, because data obtained by developmental toxicologic test are too complex. Three techniques are now being examined to overcome the difficulty in changing the method of developmental toxicologic test: the technique utilizing embryonic stem cells; micromass culture technique; and the whole embryonic culture technique. In this symposium, the current status of developmental toxicity tests and the three techniques being examined in the EU are introduced, and opinions on future progress are presented.


Concept of a new Medical Data-Driven Health Care Model based on Remote Patient Monitoring.
This paper introduces a health care model for a physician supervised remote monitoring process of patient's vital signs. The model is discussed from a process view, a medical view and a technical view. Subsequently, different scenarios for patients at home with and without outpatient care, and in a nursing home were compared. Parts of this model have been implemented and evaluated as a proof of concept.Clinical Relevance- Remote patient monitoring has the potential to relieve general practitioners in their work and help them to improve prevention and treatment of their patients. The prevention aspect in particular can contribute to a general reduction in the burden on the entire health care system.


[Luminescence, induced by UV-irradiation, of intact human skin].
UV-C induced chemiluminescence of human skin was investigated in vivo by means of an image-producing system using photon-counting camera and computer PERICOLOR-1000. Luminescence after UV-C application is shown to decline nonexponentially, the parameters of the decline depending on irradiation dose, skin specimen and previous irradiations. If the same skin specimen is irradiated second time 3-36 hours after the first irradiation, the luminescence decline time increases from one-two minutes to more than half an hour. During the time when the decline is slow the images produced by irradiation through the diaphragm do not sustain distinct contours due to the luminescence of nonirradiated skin. The luminescence is shown to be under the organisms' control and to diminish significantly after the application of acetylsalicylic acid.


Seduction without cause: uncovering explanatory neurophilia.
Credibility is a cherished currency in science, but its cues can be counterfeit. A novel series of experiments by Weisberg and her colleagues show that non-expert consumers of behavioral explanations assign greater standing to explanations that contain neuroscientific details, even if these details provide no additional explanatory value. Here, we discuss the part that this 'placebic' information might play in producing a potentially misleading sense of intellectual fluency and, consequently, an unreliable sense of understanding.


Extra-Virgin Olive Oil Enhances the Blood-Brain Barrier Function in Mild Cognitive Impairment: A Randomized Controlled Trial.
Mild cognitive impairment (MCI) and early Alzheimer's disease (AD) are characterized by blood-brain barrier (BBB) breakdown leading to abnormal BBB permeability ahead of brain atrophy or dementia. Previous findings in AD mouse models have reported the beneficial effect of extra-virgin olive oil (EVOO) against AD, which improved BBB and memory functions and reduced brain amyloid-β (Aβ) and related pathology. This work aimed to translate these preclinical findings to humans in individuals with MCI. We examined the effect of daily consumption of refined olive oil (ROO) and EVOO for 6 months in MCI subjects on BBB permeability (assessed by contrast-enhanced MRI), and brain function (assessed using functional-MRI) as the primary outcomes. Cognitive function and AD blood biomarkers were also assessed as the secondary outcomes. Twenty-six participants with MCI were randomized with 25 participants completed the study. EVOO significantly improved clinical dementia rating (CDR) and behavioral scores. EVOO also reduced BBB permeability and enhanced functional connectivity. While ROO consumption did not alter BBB permeability or brain connectivity, it improved CDR scores and increased functional brain activation to a memory task in cortical regions involved in perception and cognition. Moreover, EVOO and ROO significantly reduced blood Aβ42/Aβ40 and p-tau/t-tau ratios, suggesting that both altered the processing and clearance of Aβ. In conclusion, EVOO and ROO improved CDR and behavioral scores; only EVOO enhanced brain connectivity and reduced BBB permeability, suggesting EVOO biophenols contributed to such an effect. This proof-of-concept study justifies further clinical trials to assess olive oil's protective effects against AD and its potential role in preventing MCI conversion to AD and related dementias.


Increased neutrophil-to-lymphocyte ratio is associated with higher incidence of acute kidney injury and worse survival after transcatheter aortic valve implantation.
Although considered a minimally invasive procedure, transcatheter aortic valve implantation (TAVI) generates an inflammatory response which is related to post-procedural complications including acute kidney injury (AKI). The aim of the present study was to analyse the association between simple, easily available post-operative morphological parameters of inflammatory status such as neutrophil-to-lymphocyte ratio (NLR) and AKI as well as post-discharge survival. The study group was comprised of 203 consecutive patients (102 females and 101 males, mean age 78 ± 6.9 years) who underwent TAVI between January 2013 and March 2017. Demographic and clinical data were collected. Baseline and subsequent post-procedural blood samples (8, 24, 48, 72 at discharge) were taken. Blood morphology (including NLR) and creatinine concentration were assessed. Long-term survival was also analyzed. Seventy-four (36.5%) patients developed AKI. Baseline morphological parameters did not differ between subject with and without AKI. Those reflecting post-procedural inflammatory response, including leucocytes, neutrophils and NLR increased significantly following TAVI in both subgroups and the rise was more pronounced in AKI patients (p < 0.001). A comparison of Kaplan-Meier curves for patients with the lowest (NLR 1; below 25th percentile) and highest NLR (NLR 3; above 75th) revealed a significant difference in the log-rank test (p = 0.049). Estimated probability of 1-, 2- and 5-year survival were 100% vs. 79%, 94% vs. 77% and 75% vs. 46%, respectively in subgroup NLR 1 and NLR 3. Inflammatory response after TAVI, estimated by means of NLR, is more pronounced in patients with AKI. A higher value of NLR is associated with a lower probability of long-term survival after TAVI.


Prospective evaluation of cancer clinical trial accrual patterns: identifying potential barriers to enrollment.
Well-conducted cancer clinical trials are essential for improving patient outcomes. Unfortunately, only 3% of new cancer patients participate in clinical trials. Barriers to patient accrual in cancer clinical trials must be identified and overcome to increase patient participation. We prospectively tracked factors that potentially affected patient accrual into cancer clinical trials at the University of California Davis Cancer Center. Oncologists seeing new outpatients were asked to complete questionnaires regarding patient characteristics and the physician's decision-making on patient eligibility, protocol availability, and patient opinions on participation. Statistical analysis was performed to correlate these parameters with subsequent protocol accrual. There were 276 assessable patients. At the initial visits, physicians did not consider clinical trials in 38% (105/276) of patients principally because of a perception of protocol unavailability and poor performance status. Physicians considered 62% (171/276) of patients for participation in clinical trials. Of these, only 53% (91/171) had an appropriate protocol available for site and stage of disease. Seventy-six of 90 patients (84%) with available protocols met eligibility criteria for a particular study. Only 39 of 76 patients (51%) agreed to participate in cancer clinical trials, for an overall accrual rate of 14% (39/276). The remainder (37/76, 49%) declined trial participation despite meeting eligibility criteria. The most common reasons were a desire for other treatment (34%), distance from the cancer center (13%), patient refusal to disclose reason (11%), and insurance denial (8%). Patients with private insurance were less likely to enroll in clinical trials compared to those with government-funded insurance (OR, 0.34; P =.03; 95% CI, 0.13 to 0.9). Barriers to cancer clinical trial accrual can be prospectively identified and addressed in the development and conduct of future studies, which may potentially lead to more robust clinical trials enrollment. Investigation of patient perceptions regarding the clinical trials process and the role of third party-payers is warranted.


Experimental reproduction of malabsorption syndrome with different combinations of reovirus, Escherichia coli, and treated homogenates obtained from broilers.
Attempts to reproduce malabsorption syndrome (MAS) by oral inoculation with several different combinations including intestinal homogenate, reovirus, and hemolytic Escherichia coli obtained from MAS-affected chickens and intestinal homogenate from healthy chickens (healthy homogenate) were performed in 1-day-old specific-pathogen-free (SPF) broilers. The MAS homogenate, serving as a positive control, induced weight gain depression and intestinal lesions such as cystic crypts of Lieberkuhn, villus atrophy, and lymphoid and/or granulocytic infiltration. The healthy homogenate, the formalin-treated MAS homogenate, the formalin-treated healthy homogenate, and phosphate-buffered saline caused neither weight gain depression nor intestinal lesions. We were able to reproduce both weight gain depression and intestinal lesions by inoculation of reovirus either combined with the formalin-treated MAS homogenate or combined with healthy homogenate. Surprisingly, when hemolytic E. coli was added to the combination of reovirus with formalin-treated MAS homogenate, this did not cause weight gain depression although this combination caused the described intestinal lesions. Identical results were obtained with the combination of formalin-treated MAS homogenate with hemolytic E coli or the combination of reovirus with hemolytic E. coli. The intestinal lesions were more severe and developed faster by combinations including reovirus and formalin-treated MAS homogenate. This study indicates that a combination of enteropathogenic reovirus with other agents or substances that are present in an intestinal homogenate from MAS-affected and healthy chickens can induce MAS in SPF broilers. Escherichia coli is not essential for induction of weight gain depression but can play a role in development of intestinal lesions. Furthermore, intestinal lesions alone will not always result in weight gain depression.


Exhaled nitric oxide: a test for diagnosis and control of asthma?
The fractional concentration of nitric oxide (FE(NO)) in exhaled breath is a noninvasive marker of airway inflammation in asthma. The precise role of FE(NO) in the asthma management algorithm has not been defined. However, there are compelling data for use of FE(NO) for diagnosing asthma, assessing control and severity, titrating inhaled corticosteroids, and detecting ongoing airway inflammation. This article reviews the biology of nitric oxide in airway pathology and its role in asthma.


Sodium-potassium pump in low-renin hypertension.
Recent studies suggest that sodium-dependent low-renin hypertension in animals results at least in part from sodium-potassium pump inhibition in blood vessels and heart by a humoral agent released from or influenced by the anteroventral third ventricular area of the brain. For example, a high salt intake in a rat with reduced renal mass results in the appearance of a heat-stable sodium pump inhibitor in the plasma, decreased cardiac Na+, K+-ATPase activity, decreased arterial sodium-potassium pump activity, and hypertension. These changes are reversed by reducing the salt intake or by producing a lesion in the anteroventral third ventricular area of the brain. The course of the development of pump inhibition is similar to the course of the development of hypertension. Sodium-potassium pump inhibition by a humoral agent may also occur in humans with low-renin hypertension. A high potassium intake may stimulate pump activity.


Preexisting cognitive impairment is associated with postoperative cognitive dysfunction after hip joint replacement surgery.
This study investigated the prevalence of cognitive impairment in elderly noncardiac surgery patients and any association between preoperative cognitive impairment and postoperative cognitive dysfunction (POCD). Additionally, the incidence of cognitive decline at 12 months after surgery was identified. Three hundred patients for hip joint replacement and 51 nonsurgical controls aged 60 yr or older were studied in a prospective observational clinical trial. All study participants and controls completed a battery of eight neuropsychological tests before surgery and at 7 days, 3 months, and 12 months afterwards. Preoperative cognitive status was assessed using preexisting cognitive impairment (PreCI) defined as a decline of at least 2 SD on two or more of seven neuropsychological tests compared to population norms. POCD and cognitive decline were assessed using the reliable change index utilizing the results of the control group. PreCI was classified in 96 of 300 (32%) patients (95% CI, 23 to 43%). After surgery, 49 of 286 (17%) patients (95% CI, 13 to 22%) and 27 of 284 (10%) patients (95% CI, 6 to 13%) demonstrated POCD at 7 days and 3 months, respectively, while 7 of 271 (3%) patients (95% CI, 1 to 4%) demonstrated cognitive decline at 12 months. Patients with PreCI had a significantly increased incidence of POCD at 7 days and 3 months and cognitive decline at 12 months. Patients with PreCI have an increased incidence of POCD and cognitive decline. PreCI is a good predictor of subsequent POCD and cognitive decline. The incidence of cognitive decline after 12 months in this group of patients is low.


[Mode of serotype inheritance in exoconjugant progeny of the ciliate Dileptus anser].
Two clones of Dileptus anser, originally isolated from natural reservoirs and referred to below as B and D clones, were found to display different serotypes, when cultured under identical laboratory conditions. On being tested with two different polyclonal rabbit immune sera against each particular clone (the classic immobilization test) these clones showed no cross-reaction. At a standard dilution (1:50) and at a standard exposure time (4 h), either of the two immune sera immobilized 100% or commonly 0% of homologous and heterologous clone cells, respectively. In addition, the difference in serotypes was confirmed by the immunofluorescence analysis. By crossing (conjugation) between B (mating type I) and D (mating type III) cells, exconjugant F1 clones were obtained. Their serotypes were then tested (the same immobilization test) with antisera against both the "parental" clones: some clones were tested before their sexual maturation in ca. one month after conjugation, while others were examined in approximately 4 months after conjugation, i.e. after reaching maturity. Each of the F1 clones could react with both immune sera, which means that they possessed the intermediate, "hybrid" phenotype. Five different F1 clones were selected, and each of them was back-crossed to both "parental" clones, B and D. We succeeded in raising 25 exconjugant F2 (B1, to be more exact) clones from F1 x B crosses and 26 clones from F1 x D crosses. The conventional testing of these clones in 5-10 weeks after conjugation provided quite unexpected results, since among them no segregation for "parental" serotypes was observed. Each of the 51 tested clones demonstrated the "hybrid" serotype--seemingly the same as that of F1 clones. Such a non-Mendelian inheritance of the character is hardly to explain from the standard, canonical assumptions on the genetic control of serotype difference between original "parental" clones (different alleles in one locus? different loci?). Also it does not seem likely that the absence of segregation could result from differential survival of various phenotypes in F2 (although the total viability of exconjugant clones appeared rather low). The above data obviously need further confirmations and experimental analyses. We attempt to discuss the obtained results in terms of the epigene hypothesis (Tchuraev, 1975) and in relation to the epigenetic control of serotype expression in species of the Paramecium aurelia complex and in Tetrahymena thermophila, which are "the chosen few" subjects in ciliate genetics.


Safety and effectiveness of continuous aerosolized albuterol in the non-intensive care setting.
To describe the design features, utilization, and outcomes of a protocol treating children with status asthmaticus with continuous albuterol in the inpatient setting. We performed a retrospective cohort analysis of children ages 2 to 18 treated in the non-intensive care, inpatient setting on a standardized treatment protocol for status asthmaticus from July 2011 to June 2013. We assessed characteristics associated with continuous albuterol therapy and, for those treated, duration of therapy and the proportion who clinically deteriorated (ICU transfer or progression to enhanced respiratory support) or who were identified as having hypokalemia or an arrhythmia. Using multivariable logistic regression, we determined which factors were associated with clinical deterioration or prolonged (>24 hours) continuous albuterol. Of 3003 children meeting study criteria, 1298 (43%) received continuous albuterol. Older age, black race, lower initial oxygen saturation, and higher initial age-standardized heart rate and respiratory rate were associated with initiation of continuous albuterol therapy (P < .001 for all). Median duration of therapy was 14.4 hours (interquartile range, 7.7, 24.6); 340 children (26%) experienced prolonged therapy. Seventy children (5%) experienced clinical deterioration, and 33 children (3%) had identified hypokalemia or arrhythmia. Comorbid pneumonia and emergency department administration of intravenous magnesium or subcutaneous terbutaline were associated with prolonged therapy and clinical deterioration. With appropriate support structures and care processes, continuous albuterol can be delivered effectively in the non-ICU, inpatient setting with low rates of adverse outcomes. Certain initial clinical characteristics may help identify patients needing more intensive therapy.


The externalizing and internalizing pathways to marijuana use initiation: Examining the synergistic effects of impulsiveness and sensation seeking.
Adolescent marijuana use has become increasingly more problematic compared with the past; thus, understanding developmental processes that increase the liability of marijuana use is essential. Two developmental pathways to adolescent substance use have been proposed: an externalizing pathway that emphasizes the expression of aggressive and delinquent behavior, and an internalizing pathway that emphasizes the role of depressive symptoms and negative affect. In this study, we aimed to examine the synergistic role of impulsiveness and sensation seeking in the two risk pathways to determine whether both high and low levels of the traits are risk factors for marijuana use. Our study included 343 adolescents (52% were girls, 78% identified as Hispanic) that oversampled high-risk youth (78% had a family history of substance use disorder), assessed biannually between the ages of 13-16 years old. Moderated mediation analyses revealed that high levels of sensation seeking indirectly predicted marijuana use through higher mean levels of externalizing behavior. The positive relationship between sensation seeking and externalizing behavior was only significant at high levels of impulsiveness. Conversely, low levels of sensation seeking indirectly predicted marijuana use through higher mean levels of internalizing behavior. The negative relationship between sensation seeking and internalizing behavior was only significant at low levels of impulsiveness. Collectively, these results demonstrate that high and low levels of both impulsiveness and sensation seeking confer increased risk of marijuana use, albeit through different mechanisms. (PsycInfo Database Record (c) 2021 APA, all rights reserved).


[Heterotopic pregnancy: report of a case and review of the literature].
A case of spontaneous tubal heterotopic pregnancy in primigest patient with survival of intrauterine conception is presented. She was treated in H.G.Z.M.F. No. 8 IMSS in Ciudad Sahagún Hgo. The frequency antecedents, clinical picture, auxiliary methods of diagnosis and therapy are discussed. It is concluded that the heterotopic pregnancy is a rare illness, but it can occur, and is potentially dangerous to the mother and intrauterine conception. The instant detection improves the prognosis.


Translation and Validation of a State-Measure of Body Image Satisfaction: The Body Image State Scale.
The aim of the present study is to test the validity and reliability of the French Body Image State Scale (F-BISS). The scale was translated using a back-translation technique, with discrepancies being settled through consensus. Three hundred and twelve female participants were recruited. Convergent validity was assessed using eating disorder evaluation and social comparison. Exploratory and confirmatory factor analyses were also conducted. The translated Body Image State Scale (BISS) demonstrated good psychometric properties, with good internal consistency (α = 0.83), and adequate goodness-of-fit. The translated BISS presented a unifactorial structure, with one factor explaining 56% of the variance. The exploratory factor analysis led to the removal of a single item due to insufficient factor loading (<0.45). Its convergent validity seems consistent with previous literature. Discriminant analyses showed a significant difference in F-BISS score between participants relative to eating disorder symptomatology (t = 11.65; p < 0.001). This translation could prove useful in both research and clinical settings to assess state body satisfaction in French populations.


Proteins in mesoporous silicates.
Mesoporous silicates (MPS) have an ordered pore structure with dimensions comparable to many biological molecules. They have been extensively explored as supports for proteins and enzymes in biocatalytic applications. Since their initial discovery, novel syntheses methods have led to precise control over pore size and structure, particle size, chemical composition, and stability, thus allowing the adsorption of a wide variety of biological macromolecules, such as heme proteins, lipases, antibody fragments, and proteases, into their structures. This Review discusses the application of ordered, large-pore, functionalized mesoporous silicates to immobilize proteins for biocatalysis.


Neurohumoral regulation of spontaneous constrictions in suburothelial venules of the rat urinary bladder.
Venules of the bladder suburothelium develop spontaneous phasic constrictions that may play a critical role in maintaining venular drainage of tissue metabolites. We aimed to investigate neurohumoral regulation of the spontaneous venular constrictions (SVCs). Changes in venular diameter of the rat bladder suburothelium were monitored using a video tracking system, whilst the effects of electrical field stimulation (EFS) and bath-applied bioactive substances were investigated. The innervation of the suburothelial microvasculature was examined by immunohistochemistry. EFS (10Hz for 30s) induced an increase in the frequency of SVCs that was prevented by phentolamine (1μM). In phentolamine-pretreated venules, EFS suppressed SVCs with a venular dilatation in a manner attenuated by propranolol (1μM) or l-nitro arginine (LNA, 10μM). BRL37344 (1μM), a β3 adrenoceptor agonist, dilated venules and reduced the frequency of SVCs in an LNA-sensitive manner. ACh (1-10μM) increased the frequency of SVCs. ATP (1μM) transiently constricted venules and then caused LNA-sensitive cessation of SVCs associated with a dilatation. Substance P (100nM) caused a venular constriction, whilst calcitonin gene related peptide (CGRP, 100nM) caused a dilatation of venules and suppression of SVCs that were not inhibited by LNA. Immunohistochemical staining demonstrated sympathetic as well as substance P- and CGRP-containing nerves running along the venules. Spontaneous constrictions of suburothelial venules are accelerated by sympathetic α-adrenergic stimulation, but suppressed upon β-adrenergic stimulation. In addition, suburothelial venular constrictions appear to be modulated by several bioactive substances that could be released from urothelium or suburothelial sensory nerves.


Adaptation and psychometric evaluation of the Swedish version of the Good Nursing Care Scale for Patients.
The aim of this study was to adapt the instrument 'Good Nursing Care Scale for Patients' to Swedish conditions as a measure of patients' satisfaction, as well as estimating its reliability and validity. Following a pilot test, discussions in the author group, testing for readability among patients and judgement of content validity by a panel of experts, the final version was reduced to 72 items focusing on good caring. The refined instrument was assessed for internal consistency in 447 surgical in-patients, for 2 week test-retest reliability in 100 patients and subjected to orthogonal principal components factor analysis with varimax rotation, followed by second-order factor analysis. The internal consistency item-item correlation coefficient ranged from 0.15 to 0.91, correlation between each item and the total scale was >or=0.30 for 70 items, Cronbach's alpha coefficient for the final scale was 0.79 and test-retest reliability was 0.75. An orthogonal principal components factor analysis with varimax rotation was conducted on the final 71 items and the 15 first-order factors with eigenvalues >or=1 explained 66% of the total variance. A second-order factor analysis of these 15 factors as items resulted in a seven-factor solution. The total variance explained by the seven factors was 79%. Cronbach's alpha coefficient for the seven factors ranged between 0.32 and 0.95. The instrument seems reliable and valid to assess the patients' satisfaction with what happened during their hospital stay. To confirm the factor structure and improve factor consistency additional development and testing is suggested.


Highly diastereoselective and stereodivergent dihydroxylations of acyclic allylic amines: application to the asymmetric synthesis of 3,6-dideoxy-3-amino-L-talose.
Aminohydroxylation of tert-butyl sorbate [tert-butyl (E,E)-hexa-2,4-dienoate] using enantiopure lithium (R)-N-benzyl-N-(α-methylbenzyl)amide and (-)-camphorsulfonyloxaziridine gives tert-butyl (R,R,R,E)-2-hydroxy-3-[N-benzyl-N-(α-methylbenzyl)amino]hex-4-enoate in >99:1 dr. Subsequent dihydroxylation under Upjohn conditions (OsO(4)/NMO) gives tert-butyl (2R,3R,4S,5S,αR)-2,4,5-trihydroxy-3-[N-benzyl-N-(α-methylbenzyl)amino]hexanoate (in 95:5 dr) while dihydroxylation under Donohoe conditions (OsO(4)/TMEDA) proceeds with antipodal diastereofacial selectivity to give the (R,R,R,R,R)-diastereoisomer (in 95:5 dr). The amino triols resulting from these dihydroxylation reactions are useful for further elaboration, as demonstrated by the asymmetric synthesis of 3,6-dideoxy-3-amino-L-talose.


Longitudinal trajectory of vitamin D status from birth to early childhood in the development of food sensitization.
Increasing evidence supports the immunomodulatory effect of vitamin D on allergic diseases. The combined role of prenatal and postnatal vitamin D status in the development of food sensitization (FS) and food allergy remains understudied. Plasma 25-hydroxyvitamin D (25(OH)D) levels of 460 children in the Boston Birth Cohort (BBC) were measured at birth and early childhood, and the subjects were genotyped for rs2243250 (C-590T) in the IL4 gene. We defined FS as specific IgE levels of ≥0.35 kUA/l to any of eight common food allergens; we defined persistently low vitamin D status as cord blood 25(OH)D <11 ng/ml and postnatal 25(OH)D <30 ng/ml. We observed a moderate correlation between cord blood 25(OH)D at birth and venous blood 25(OH)D measured at 2-3 y (r = 0.63), but a weak correlation at <1 y (r = 0.28). There was no association between low vitamin D status and FS at any single time point alone. However, in combination, persistence of low vitamin D status at birth and in early childhood increased the risk of FS (odds ratio (OR) = 2.03, 95% confidence interval (CI): 1.02-4.04), particularly among children carrying the C allele of rs2243250 (OR = 3.23, 95% CI: 1.37-7.60). Prenatal and early postnatal vitamin D levels, along with individual genetic susceptibility, should be considered in assessing the role of vitamin D in the development of FS and food allergy.


Cyatta abscondita: taxonomy, evolution, and natural history of a new fungus-farming ant genus from Brazil.
Cyatta abscondita, a new genus and species of fungus-farming ant from Brazil, is described based on morphological study of more than 20 workers, two dealate gynes, one male, and two larvae. Ecological field data are summarized, including natural history, nest architecture, and foraging behavior. Phylogenetic analyses of DNA sequence data from four nuclear genes indicate that Cyatta abscondita is the distant sister taxon of the genus Kalathomyrmex, and that together they comprise the sister group of the remaining neoattine ants, an informal clade that includes the conspicuous and well-known leaf-cutter ants. Morphologically, Cyatta abscondita shares very few obvious character states with Kalathomyrmex. It does, however, possess a number of striking morphological features unique within the fungus-farming tribe Attini. It also shares morphological character states with taxa that span the ancestral node of the Attini. The morphology, behavior, and other biological characters of Cyatta abscondita are potentially informative about plesiomorphic character states within the fungus-farming ants and about the early evolution of ant agriculture.


Tau deposition in young adults with drug-resistant focal epilepsy.
To evaluate the presence of tau deposition and pathologic features of chronic traumatic encephalopathy (CTE) in young adult patients treated with focal cortical resections for drug-resistant epilepsy. Sixty consecutive patients who had undergone surgical treatment for drug-resistant focal epilepsy between 18 and 45 years of age were identified (2010-2017). Medical records were reviewed to determine clinical factors, including history of head trauma, age at seizure onset, age at surgical resection, seizure type(s) and frequency, imaging findings, and surgical outcome. All formalin-fixed, paraffin-embedded blocks from the surgical specimens from each subject were sectioned and stained with hematoxylin and eosin and antibodies to tau (Thermo Fisher Scientific Clone AT8), and examined blindly for tau pathology, including lesions characteristic of CTE. The median age at resection was 29.5 years (range = 19-45). A history of head trauma was reported in 19 patients. Although none of the patients had pathological findings characteristic of CTE, 23 patients (38%) demonstrated tau-immunoreactive lesions, including neurites, neurofibrillary pretangles, neurofibrillary tangles, subpial tau, and/or glial tau. In 4 of the 23 patients (7% of the cohort; 17% of those with tau pathology), substantial tau burden was identified. Three of these 4 patients had no significant history of head trauma; 1 patient had multiple sports-related concussions. No specific clinical factors correlated with the presence of tau pathology. Tau-immunoreactive lesions were found in 38% of 60 patients who underwent a focal cortical resection for drug-resistant focal epilepsy. Diagnostic features of CTE were not detected in any patient; however, the pathological evaluation for CTE was limited to a surgical specimen. The prominent and excessive tau deposition in 23 patients (38%) is abnormal in this age group and warrants further investigation.


Fighting with the enemy's weapons? the role of costimulatory molecules in HIV.
HIV infection is characterized by a number of abnormalities in several components of the immune system. For example, during HIV infection, a massive decrease of CD4(+) T cells is observed, as well as a progressive depletion of naïve CD8(+) T cells. Furthermore, elevated numbers of apoptotic B and T cells are present in HIV-infected patients, and a systemic immune activation results in T-cell exhaustion. Finally, HIV infection is characterized by the presence of functionally impaired dendritic cells, with decreased expression of maturation markers, decreased secretion of cytokines and defects in antigen processing and presentation. All these characteristics result in the occurrence of non-functional cytotoxic T lymphocytes, that fail to control HIV-replication in most individuals during progressive disease. Costimulatory and co-inhibitory molecules are involved in the activation, differentiation and survival of several cell-types of the immune system. Each costimulatory receptor (generally expressed on effector cells) can conjugate with one or more specific ligands (expressed on antigen-presenting cells), which leads to an activation of intracellular signaling pathways inside the cells on which they are expressed. HIV infection is characterized by an aberrant expression of these molecules on cells of the immune system. Many of the immune deficiencies mentioned in the previous paragraph can be explained by abnormal expression of costimulatory molecules, and could consequently be overcome by interfering with their interactions. In this review, we give an overview of the functions and expression patterns of the receptor/ligand pairs of the tumor necrosis factor and the B7 super-families of costimulatory and co-inhibitory molecules in HIV-infected patients. We will also discuss possibilities for manipulating their signaling as a therapeutic anti-HIV tool.


Complexity in the diagnosis and management of 45,X Turner Syndrome mosaicism.
Diagnosis, decision making, and counseling for patients with disorders of sexual development pose challenges for physicians and families. Accurate antenatal evaluation combined with effective communication between the family and multidisciplinary team is important to provide the best patient outcome. We reviewed 2 cases from our institution that illustrate the complexity of antenatal and postnatal management in Turner Syndrome patients who have 45,X mosaicism. We concluded that because of the complexity involved in providing appropriate care to these individuals, it is critical that accurate and universally accessible counseling materials are available to providers and families at the time of diagnosis and management decision making.


The effect of the new ADA and WHO guidelines on the number of diagnosed cases of diabetes mellitus.
In the new lowered diagnostic discriminator for diabetes mellitus (DM) from the American Diabetes Association (ADA), fasting peripheral venous plasma glucose (f-vPG) of 7.0 mmol/l is identical to the 99.9 centile of f-vPG (7.05 mmol/l, 95%CI: 6.91-7.20 mmol/l) in a low-risk reference population. We investigated its diagnostic concordance with other diagnostic discriminators. As no index test is available for DM we used the ADA discriminator as gold standard. We isolated a low-risk reference population (n = 424) from a randomised general population (n = 726) by ruling out of all cases with clinical and biochemical risk indicators for DM. We based our analysis on measurements traceable to primary standard concentration, a bias of < 1.5% and CV% < 2.5. The distribution of the fasting capillary whole blood glucose (f-CBG; mmol/l) in the reference population was in Gaussian with the 99.9 centile of 6.62 mmol/l (95% CI 6.47-6.77 mmol/l) and the 97.5 centile of 5.92 mmol/l (5.82-6.02 mmol/l). The 6.1 mmol/l f-CBG WHO limit corresponds approximately to the 97.6 centile, and this limit is thus not traceable to the ADA discriminator, which corresponds to f-CBG of 6.4 mmol/l. This is the case in groups only, as recalculation will introduce unpredictable errors. Thus, in our general population a varying number of subjects will be at risk of DM as a mere consequence of different limits. The f-CBG limit of 6.1 mmol/l will thus lead to 2.4% false-positive diagnoses or, in EU, to around 44 x 10(6) adults being diagnosed. The number of cases at risk of DM vary from 5.4 x 10(6) to 44 x 10(6) in EU. We conclude that application of different diagnostic limits results in highly variable number of diagnosed DM cases, and therefore one diagnostic discriminator is needed to provide reproducible diagnoses.


Comparison of young male mice of two different strains (C57BL/6J and the hybrid B6129SF1/J) in selected behavior tests: a small scale study.
All mouse strains are different, before choosing a strain for a large study, a small scale study should be done. In this study, we compared young males of two mouse strains, C57BL/6J and the hybrid B6129SF1/J, and gained knowledge on their performance in three different behavioral tests; open field (OF) test, Barnes maze (BM) test and a restraint stress test. We found that the young males of the C57BL/6J strain spent more time moving in the OF. In the BM, the hybrid covered less ground before reaching the goal box during the first three sessions, than the C57BL/6J. The hybrid left more fecal pellets than C57BL/6J both in OF and BM. During the stress test, the C57BL/6J had a lower corticosterone response than the hybrid. Our findings indicate that the C57BL/6J has a presumably higher locomotor activity and/or explorative behavior than the hybrid, while the hybrid appeared more sensitive to stress.


Heart Disease Dataset Clusterization.
Clusterization is a promising group of methods in the context of patient similarity. However, results of clustering are not often clear for physicians as well as different clustering methods can produce different results. We have examined a well-known dataset and implemented 3 clustering methods (k-means, Agglomerative and Spectral). We have compared and evaluated clusters and their correlation with data attributes. In contrast to original dataset's target value, the clusters correlated with only a few attributes. Finally, we train 2 predictive models based on k-nearest neighbors (KNN) algorithm and Artificial Neural Network (ANN). Models evaluation demonstrates that using the results of clustering algorithms as predictive attribute give a higher F-score than the original target attribute.


Congenital epulis of the newborn: 10 new cases of a rare oral tumor.
Congenital epulis of the newborn (CEN) is a rare benign lesion that exclusively occurs in the oral and maxillofacial regions of newborns. The clinicopathologic features of CEN were examined and reviewed from the files of the Armed Forces Institute of Pathology from 1970 to 2000. Ten cases were included. Patient lesions were all present at birth but were surgically excised between 2 days and 6 weeks (median, 5.5 days). Nine lesions were in females; 1 case did not designate patient sex. Locations included 6 on the maxilla, 2 on the mandible, 1 on the designated maxillary lip, and 1 unknown. The cases included a patient with 2 lesions: 1 on mandibular and 1 on maxillary alveolar ridges, respectively. All other lesions were solitary and polypoid. Microscopically, these were pedunculated and nodular, composed of sheets to grouped clusters of medium-sized, ovoid-to-polygonal cells with abundant granular cytoplasm, distinct cell membranes, vascular-rich stroma, and attenuated overlying mucosa. Two cases also demonstrated spindled cells. The nuclei were vesicular and focally stippled, with distinct and slightly convoluted nuclear membranes; nucleoli were visible but not prominent. Mitotic activity was not observed. The vascular channels ranged from capillary-sized to venous, some staghorn-like with rare perivascular long-term inflammation. The venules exhibited a perivascular pericytic proliferation. Odontogenic epithelial rests were present in 2 cases. No cases demonstrated cytoplasmic hyaline globules. The lesional cells in all cases were negative for S-100 protein, CD68, CD34, CD31, keratins, desmin, calponin, and smooth muscle actin. Perivenular pericytes were positive for smooth muscle actin. Congenital epulis of the newborn is a rare oral entity with characteristic clinicopathologic features. It predominately affects girls, mainly on the maxillary alveolar ridge. It may be separated from "granular cell tumor" by location, patient age, absence of cytoplasmic hyaline globules, solid growth pattern, pericytic proliferation, attenuated overlying epithelium, and negativity for S-100 protein.


Nestling recognition via direct cues by parental male bluegill sunfish ( Lepomis macrochirus).
Parental care can be costly to a parent in terms of both time and energy invested in the young. In species with cuckoldry or brood parasitism not all of the young under a parent's care are necessarily offspring. In such cases, distinguishing between kin and non-kin, and investing only in the former (nepotism), can be advantageous. Bluegill sunfish ( Lepomis macrochirus) are characterized by paternal care and cuckoldry, and care-providing males appear to show nepotistic behaviours. Here, we investigated nestling recognition in bluegill, determining whether parental males can differentiate between young from their own nest (familiar and related) and young from non-neighbouring nests (unfamiliar and unrelated) using (1) visual and chemical cues, and (2) chemical cues only. In the first experiment, wild-caught parental males were presented with samples of eggs or fry (newly hatched eggs) collected from their own nest or a foreign nest and placed on opposite sides of an aquarium. The time these parental males spent associating with each sample, and their "pecking" behaviours (indicating cannibalism), were recorded. Parental males showed no preference between eggs from their own nest and eggs from a non-neighbouring nest, but they preferred to associate with fry from their own nest over foreign fry. There also was a positive relationship between male body size and the time spent associated with fry from their own nest. Parental males pecked at foreign fry more than 5 times as often as fry from their own nest, though this difference was not statistically significant. In the second experiment, fry that were collected from the nest of a wild-caught parental male or a non-neighbouring nest were placed in different containers and the water from each was dripped into opposite ends of an aquarium. The time the male spent on each side was recorded. In this case, parental males spent more time near the source of water conditioned by unrelated fry, but there was a positive relationship between male condition (fat reserves) and the time he spent near the source of water conditioned by fry from his own nest. Results confirm that chemicals cue nestling recognition by parental male bluegill.


Evaluation of drug permeation under fed state conditions using mucus-covered Caco-2 cell epithelium.
The absence of a surface-lining mucus layer is a major pitfall for the Caco-2 epithelial model. However, this limitation can be alleviated by applying biosimilar mucus (BM) to the apical surface of the cell monolayer, thereby constructing a mucosa mimicking in vivo conditions. This study aims to elucidate the influence of BM as a barrier towards exogenic compounds such as permeation enhancers, and components of fed state simulated intestinal fluid (FeSSIF). Caco-2 cell monolayers surface-lined with BM were exposed to several compounds with distinct physicochemical properties, and the cell viability and permeability of the cell monolayer was compared to that of cell monolayers without BM and well-established mucus-secreting epithelial models (HT29-MTX-E12 cell monolayers and HT29-MTX-E12/Caco-2 cell co-culture monolayers). Exposure of BM-covered cells to constituents from FeSSIF revealed that it comprised a strong, hydrophilic barrier effect as 90% of BM-covered cells remained viable for >4 h, and the permeation rate of hydrophobic drugs was reduced. In contrast, the permeation rate of hydrophilic drugs was largely unaffected. Control monolayers displayed a loss of barrier function and <10% viable cells. The efficacy of fatty acid permeation enhancers were altered when investigated in BM-covered cells as compared to all the other studied epithelial models. Thus, Caco-2 cell monolayers surface-lined with BM constitute a valuable in vitro model that makes it possible to mimic intestinal fed state conditions when studying drug permeation.


Unintended consequences of human research ethics committees: au revoir workplace studies?
To protect the welfare and rights of participants in research and to facilitate research that will be of benefit, as well as protect them against litigation, universities and research-funding agencies in Australia adopted the National Statement on Ethical Conduct in Research Involving Humans (NHMRC 1999). In many other countries there are similar statements. However, the ways in which such statements are often implemented by Human Research Ethics Committees (HRECs) are in conflict with an important stream of industrial sociological research. This stream seeks to deconstruct workplaces and de-layer management rhetoric to understand the realities and complexities of the social relations of production. There is a pluralist basis for much industrial sociology that challenges the unitarist view of the workplace as essentially harmonious. While views of workplaces as being conflictual and exploitative have to be tempered with an understanding of the accommodative and cooperative nature of workplace relations, there is nevertheless a general recognition of acts of resistance, as well as those of cooperation. The way in which the National Statement is typically implemented in Australia means that many HRECs require written, informed consent, which in the first instance will usually be that of management. An unintended consequence is a research focus on consensus, which is at best one-sided and at worst seriously misleading. It is unlikely that managerial consent will be granted unless there is a 'good news story' guaranteed. This article explores the ways in which HRECs may influence workplace research. The publication of the revised National Statement provides a valuable opportunity not to be missed by HRECs to implement more effective and efficient practices which would not have the unintended consequences of the earlier version. This would deserve the support of researchers in industrial sociology and other branches of the social sciences.


Primary cutaneous mucinous carcinoma: a systematic review and meta-analysis of outcomes after surgery.
Evidence-based treatment guidelines are not available for primary cutaneous mucinous carcinoma (PCMC). To assess outcomes associated with surgical treatment of PCMC. MEDLINE, Cumulative Index to Nursing and Allied Health, and Embase from 1952 to 2010. Search terms were "primary cutaneous mucinous carcinoma," "primary mucinous adenocarcinoma of the skin," "primary mucinous sweat-gland carcinoma," and "endocrine mucin-producing sweat gland carcinoma." Articles describing primary data on treatment (ie, case reports, case series, and cohort studies) of any patients with PCMC. A total of 116 articles were identified, with 90 of these assessed for eligibility and 87 used for final analysis. Each case was verified to be of primary cutaneous origin by 2 observers. Histopathologic descriptions were confirmed to be consistent with PCMC. Extracted fields included age, sex, race, lesion duration, tumor diameter, method of treatment, follow-up, and whether the lesion recurred or metastasized. Outcomes were dichotomized into good and bad depending on the presence of recurrence or metastasis during follow-up. Multivariate logistic regression analysis was performed to determine significant factors for predicting bad outcomes. RESULTS One hundred fifty-nine cases of PCMC, of whom 54.7% were male and 77.2% were white, with mean (SD) age 63.5 (13.2) years, were analyzed. Most had been treated with traditional surgical excision (85.5%), with only 9.4% of cases treated with Mohs surgery. Older (odds ratio [OR], 0.93; P = .04) and Asian (OR, 0.02; P = .01) patients had relatively better postsurgical outcomes. Larger tumors (OR, 6.71; P = .14), those persistent for longer prior to surgery (OR, 1.02; P = .11), and those located on the trunk (OR, 103.24; P = .005) also were associated with poorer outcomes. Limitations included reliance on case report data. Patient demographic characteristics and tumor-specific features may provide predictive information regarding the risk of postsurgical recurrence and metastasis after treatment of PCMC.


Novel extraction of high quality genomic DNA from frozen bovine blood samples by using detergent method.
DNA is the prerequisite for life's inception that transfers hereditary information, past several years; various types of commercial kits are made available which vary depending on the type of the biological sample being used. The present study is focused on developing an improvised methodology for the isolation of genomic DNA from stored bovine blood samples. DNA was isolated by using the conventional Phenol: Chloroform: Isoamyl alcohol (PCI) method and Detergent method. The aim of the study was to make a comparative analysis and evaluation of these two methods to identify the one that gives a superior quality and quantity of genomic DNA. Total (n=48) each duplicate blood samples from three different buffalo(Bubalus bubalis) breeds Banni, Surti, Murrah, three zebu cattle (Bos indicus) breeds Kankerj, Gir, Sahiwal were collected from the jugular vein. The quantity, purity of the genomic DNA was assessed based on the total DNA yield, purity ratios, spectral profile, agarose gel electrophoresis analysis and polymerase chain reaction amplification of MC1R gene product without any inhibitors. The results of our study suggest that detergent method is also suitable for extraction of genomic DNA from the bovine blood and results were significant (*P>0.05). The total mean yield was found to be 329.05±11 μg/5ml for all six breeds while the PCI method was employed. The total mean yield of the gDNA for all six breeds was 406.6±43 μg/5ml of blood when the detergent method was used. One way ANOVA test showed that the total DNA yield varied depending on the isolation method used. The DNA yield obtained from the DG method was (***P< 0.001) significant as compared to the PCI method (**P<0.01).


The Dynamic Effects of Changes in Prices and Affordability on Alcohol Consumption: An Impulse Response Analysis.
To investigate how changes in alcohol price and affordability are related to aggregate level alcohol consumption in Australia to help to inform effective price and tax policy to influence consumption. Annual time series data between 1974 and 2012 on price and per-capita consumption for beer, wine and spirits and average weekly income were collected from the Australian Bureau of Statistics. Using a Vector Autoregressive model and impulse response analysis, the dynamic responses of alcohol consumption to changes in alcohol prices and affordability were estimated. Alcohol consumption in Australia was negatively associated with alcohol price and positively associated with the affordability of alcohol. The results of the impulse response analysis suggest that a 10% increase in the alcohol price was associated with a 2% decrease in the population-level alcohol consumption in the following year, with further, diminishing, effects up to year 8, leading to an overall 6% reduction in total consumption. In contrast, when alcohol affordability increased, per-capita alcohol consumption increased over the following 6 years. Our findings suggest that increasing alcohol prices or taxes can help to reduce alcohol consumption at the population level in Australia. However, the impact of affordability in our findings highlights that pricing policies need to consider increases in income to ensure effectiveness. Alcohol price policy should only cautiously focus on individual beverage types, because increasing the price of one beverage generally leads to an increase in consumption of substitutes.


Pain experiences of men and women after coronary artery bypass graft surgery.
Individuals with coronary artery disease undergo coronary artery bypass graft (CABG) surgery to relieve symptoms, improve quality of life, and reduce early death. Pain is the most prevalent symptom identified by persons after CABG surgery. The objective of the study was to compare the prevalence and severity of pain and pain-related interference with activities in men and women 9 weeks after CABG surgery. Participants included men (n = 78) and women (n = 17) who were having first-time nonemergency CABG surgery. Pain outcome data were collected via telephone using the McGill Pain Questionnaire and the Brief Pain Inventory-Interference Subscale. Forty-seven percent of the women (n = 8) had moderate to severe pain described as the "worst pain in previous 24 hours with movement" 9 weeks following discharge from CABG surgery. More women were divorced, widowed, or single (P = .0002). There was a statistically significant between-groups difference, with more women reporting moderate to severe pain with movement (P = .03), as well as greater interference with walking (P = .01) and sleeping (P = .01) due to pain. Further research with larger sample sizes should investigate what conditions lead to the sex differences in the pain experience after CABG surgery, what mechanisms and support structures underlie these differences, and how these differences can inform the clinical management of pain.


Cooperation and conflict in human pregnancy.
For many humans living today, obstetric care begins early in pregnancy, and most babies are born in hospitals. These are precautionary measures. Medical complications during the brief nine months of pregnancy are such a common part of human experience that we rarely ask ourselves why gestation does not always proceed as smoothly and reliably as the lifelong beating of our heart or filtration of blood by our kidneys. The birth of a healthy child is central to reproductive fitness and must have been subject to strong natural selection. Why then should placentas be less reliable organs than hearts or kidneys? Why should maternal hearts and kidneys be more subject to catastrophic failures during pregnancy than at other times? A crucial contrast distinguishes obstetrics from cardiology and nephrology. The coordinated activities of heart and kidneys take place within an individual comprised of genetically largely identical cells, whereas pregnancy involves an interaction between genetically-distinct individuals whose cooperation is obviated by evolutionary conflicts of interest.


Preoperative Neutrophil-to-Lymphocyte Ratio Has a Better Predictive Capacity in Diagnosing Tubo-Ovarian Abscess.
The aim of this study is to identify the inflammatory markers which predict a tubo-ovarian abscess (TOA) in the most accurate way. This study involves 312 women. Preoperative inflammatory markers in the study group were compared with those in the healthy control group to identify the most efficient predictor of TOA with a high sensitivity and specificity. The recommended cutoff values of the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), white blood cell count, and red cell distribution width were determined using receiver operating characteristic curve (ROC) analyses. The area under the curve (AUC = 0.99) in the ROC analysis was found to be statistically significant for NLR (p < 0.001) with a cutoff value of ≥4.15 (95% CI 0.97-1.00, sensitivity 95.2%, specificity 99.4%). The positive predictive value of NLR was 99.2%, and the negative predictive value was 96.7% (p < 0.001). The recommended threshold for PLR was found to be 164.37 (AUC = 0.95, 95% CI 0.93-0.98, sensitivity 86.7%, specificity 92%), and the cutoff point of the white blood cell count in the ROC analysis was 9.55 × 103/μl (AUC = 0.90, 95% CI 0.87-0.95, sensitivity 78.68%, specificity 96.68%). Preoperative NLR and PLR improve the predictive value of serum markers for the presence of TOA.


Specific activation of estrogen receptor alpha and beta enhances male sexual behavior and neuroplasticity in male Japanese quail.
Two subtypes of estrogen receptors (ER), ERα and ERβ, have been identified in humans and numerous vertebrates, including the Japanese quail. We investigated in this species the specific role(s) of each receptor in the activation of male sexual behavior and the underlying estrogen-dependent neural plasticity. Castrated male Japanese quail received empty (CX) or testosterone-filled (T) implants or were daily injected with the ER general agonist diethylstilbestrol (DES), the ERα-specific agonist PPT, the ERβ-specific agonist DPN or the vehicle, propylene glycol. Three days after receiving the first treatment, subjects were alternatively tested for appetitive (rhythmic cloacal sphincter movements, RCSM) and consummatory aspects (copulatory behavior) of male sexual behavior. 24 hours after the last behavioral testing, brains were collected and analyzed for aromatase expression and vasotocinergic innervation in the medial preoptic nucleus. The expression of RCSM was activated by T and to a lesser extent by DES and PPT but not by the ERβagonist DPN. In parallel, T fully restored the complete sequence of copulation, DES was partially active and the specific activation of ERα or ERβ only resulted in a very low frequency of mount attempts in few subjects. T increased the volume of the medial preoptic nucleus as measured by the dense cluster of aromatase-immunoreactive cells and the density of the vasotocinergic innervation within this nucleus. DES had only a weak action on vasotocinergic fibers and the two specific ER agonists did not affect these neural responses. Simultaneous activation of both receptors or treatments with higher doses may be required to fully activate sexual behavior and the associated neurochemical events.


Repair of a large primary subtemporal encephalocele in a 3-year-old child: case report.
Primary encephaloceles (PEs) present only rarely in the temporal region; in the rare instance that they project through the floor of the middle fossa they are secondary. In this case report the authors report on the management of a giant PE extending through the floor of the middle fossa.An 8-month-old boy presented to the authors' service with a large PE projecting into his neck through a missing left middle fossa floor; the lesion was causing significant meta-, dys-, and hypoplasia of the structures of the anterolateral neck on that side. Surgical goals for this patient included the following: 1) removal of potentially epileptogenic and dysfunctional tissue; 2) preservation of cranial nerves; 3) prevention of cognitive decline or iatrogenic deficit; 4) prevention of CSF leak; 5) reconstruction of skull base; 6) prevention of airway and swallowing compromise; and 7) cosmesis. After a multidisciplinary evaluation with ENT, plastic surgery, and neurology, an operation was performed using a preauricular infratemporal approach when the patient was 3 years old. Gliotic tissue was resected and amygdala, hippocampus, and middle cerebral artery were preserved.The immediate results of the operation showed good immediate outcome. Seizure freedom and neurodevelopment outcomes remain to be seen at follow-up.


The "Land of Fires" Toxic Waste Scandal and Its Effect on Consumer Food Choices.
The present study focused on an environmental scandal that occurred in Italy, the Land of Fires toxic waste scandal, which caused consumer concerns related to the safety of food produced in the affected region, as well as massive market reduction in products associated with the polluted area. Based on a representative sample of Italian households (N = 1134), this study applied an extended Theory of Planned Behavior (TPB) model to analyze consumer purchases of regional food products after this environmental hazard. In addition to attitudes, subjective norms and perceived behavioral control, the model included risk perception, trust, and actual purchases. Using a structural equation model, our results provided support to the hypothesis that consumer perceptions of risk negatively impacted their purchase behaviors and suggested that increasing Italians' trust in government information could reduce their perceived risk and, consequently, increase their intention to purchase regional food.


Causes of death after fluid bolus resuscitation: new insights from FEAST.
The Fluid Expansion as Supportive Therapy (FEAST study) was an extremely well conducted study that gave unexpected results. The investigators had reported that febrile children with impaired perfusion treated in low-income countries without access to intensive care are more likely to die if they receive bolus resuscitation with albumin or saline compared with no bolus resuscitation at all. In a secondary analysis of the trial, published in BMC Medicine, the authors found that increased mortality was evident in patients who presented with clinical features of severe shock in isolation or in conjunction with features of respiratory or neurological failure. The cause of excess deaths was primarily refractory shock and not fluid overload. These features are consistent with a potential cardiotoxic or ischemia-reperfusion injury following resuscitation with boluses of intravenous fluid. Although these effects may have been amplified by the absence of invasive monitoring, mechanical ventilation or vasopressors, the results provide compelling insights into the effects of intravenous fluid resuscitation and potential adverse effects that extend beyond the initial resuscitation period. These data add to the increasing body of literature about the safety and efficacy of intravenous resuscitation fluids, which may be applicable to management of other populations of critically ill patients.


MR Thermometry in Cerebrovascular Disease: Physiologic Basis, Hemodynamic Dependence, and a New Frontier in Stroke Imaging.
The remarkable temperature sensitivity of the brain is widely recognized and has been studied for its role in the potentiation of ischemic and other neurologic injuries. Pyrexia frequently complicates large-vessel acute ischemic stroke and develops commonly in critically ill neurologic patients; the profound sensitivity of the brain even to minor intraischemic temperature changes, together with the discovery of brain-to-systemic as well as intracerebral temperature gradients, has thus compelled the exploration of cerebral thermoregulation and uncovered its immutable dependence on cerebral blood flow. A lack of pragmatic and noninvasive tools for spatially and temporally resolved brain thermometry has historically restricted empiric study of cerebral temperature homeostasis; however, MR thermometry (MRT) leveraging temperature-sensitive nuclear magnetic resonance phenomena is well-suited to bridging this long-standing gap. This review aims to introduce the reader to the following: 1) fundamental aspects of cerebral thermoregulation, 2) the physical basis of noninvasive MRT, and 3) the physiologic interdependence of cerebral temperature, perfusion, metabolism, and viability.


Identification and preliminary characterization of Vibrio cholerae outer membrane proteins.
Outer membrane proteins of Vibrio cholerae were purified by sucrose density centrifugation and Triton X-100 extraction at 10 mM Mg2+. The proteins were separated by polyacrylamide gel electrophoresis in the presence of sodium dodecyl sulfate. V. cholerae outer membrane proteins presented a unique pattern when compared with the patterns of other gram-negative rods. There were 8 to 10 major bands (Mr 94,000 to 27,000), with most of the protein located in band 5 (Mr approximately 45,000), which thus appears to be the major structural protein of the outer membrane. Lipid and carbohydrate were associated with band 6.


Identification of fibronectin 1 as a candidate genetic modifier in a Col4a1 mutant mouse model of Gould syndrome.
Collagen type IV alpha 1 and alpha 2 (COL4A1 and COL4A2) are major components of almost all basement membranes. COL4A1 and COL4A2 mutations cause a multisystem disorder that can affect any organ but typically involves the cerebral vasculature, eyes, kidneys and skeletal muscles. In recent years, patient advocacy and family support groups have united under the name of Gould syndrome. The manifestations of Gould syndrome are highly variable, and animal studies suggest that allelic heterogeneity and genetic context contribute to the clinical variability. We previously characterized a mouse model of Gould syndrome caused by a Col4a1 mutation in which the severities of ocular anterior segment dysgenesis (ASD), myopathy and intracerebral hemorrhage (ICH) were dependent on genetic background. Here, we performed a genetic modifier screen to provide insight into the mechanisms contributing to Gould syndrome pathogenesis and identified a single locus [modifier of Gould syndrome 1 (MoGS1)] on Chromosome 1 that suppressed ASD. A separate screen showed that the same locus ameliorated myopathy. Interestingly, MoGS1 had no effect on ICH, suggesting that this phenotype could be mechanistically distinct. We refined the MoGS1 locus to a 4.3 Mb interval containing 18 protein-coding genes, including Fn1, which encodes the extracellular matrix component fibronectin 1. Molecular analysis showed that the MoGS1 locus increased Fn1 expression, raising the possibility that suppression is achieved through a compensatory extracellular mechanism. Furthermore, we found evidence of increased integrin-linked kinase levels and focal adhesion kinase phosphorylation in Col4a1 mutant mice that is partially restored by the MoGS1 locus, implicating the involvement of integrin signaling. Taken together, our results suggest that tissue-specific mechanistic heterogeneity contributes to the variable expressivity of Gould syndrome and that perturbations in integrin signaling may play a role in ocular and muscular manifestations.


Production of recycled manure solids for use as bedding in Canadian dairy farms: II. Composting methods.
Recent technological advances in the dairy industry have enabled Canadian farms with liquid manure systems to use mechanical solid-liquid separation paired with composting of the separated solids for on-farm production of low-cost bedding material. However, because several approaches are available, it is difficult for farmers to select the appropriate one to achieve high quality recycled manure solids (RMS). Whereas 3 solid-liquid manure separators were compared in part I of the series (companion paper in this issue), the present study (part II) aims to assess the performance of 4 composting methods (static or turned windrow and drum composter for 24 or 72 h) under laboratory conditions. Parameters evaluated included temperature, physico-chemical characteristics, and bacterial composition of RMS, as well as airborne microorganisms, dust, and gases associated with composting RMS. Because each treatment attained the desired composting temperature range of 40 to 65°C (either in heaps or in the drum composter), reductions in bacteria were a better indicator of the sanitation efficiency. The treatment of fresh RMS in a drum composter for 24 h showed decreased bacterial counts, especially for Escherichia coli (from 1.0 × 105 to 2.0 × 101 cfu/g of dry matter) and Klebsiella spp. (from 3.2 × 104 to 4.0 × 102 cfu/g of dry matter). Increasing the time spent in the rotating vessel to 72 h did not result in further decreases of these pathogens. Composting in a static or turned windrow achieved similar E. coli and Klebsiella spp. reductions as the 24-h drum composting but in 5 or 10 d, and generally showed the lowest occupational exposure risk for dairy farmers regarding concentrations of airborne mesophilic bacteria, mesophilic and thermotolerant fungi, and total dust. Drum-composted RMS stored in piles exhibited intermediate to high risk. Composting approaches did not have a major influence on the physico-chemical characteristics of RMS and gas emissions. Drum composting for 24 h was the best compromise in terms of product quality, temperature reached, decreased bacterial numbers, and emitted airborne contaminants. However, because levels of pathogenic agents rapidly increase once composted RMS are spread in stalls, bacteriological characteristics of RMS along with milk quality and animal health and welfare features should be monitored in Canadian dairy barns applying recommended separation (part I) and composting (part II) systems to evaluate health risk and optimize management practices.


Physiological changes induced by sodium chloride stress in Aphanizomenon gracile, Cylindrospermopsis raciborskii and Dolichospermum sp.
Due to anthropogenic activities, associated with climate change, many freshwater ecosystems are expected to experience an increase in salinity. This phenomenon is predicted to favor the development and expansion of freshwater cyanobacteria towards brackish waters due to their transfer along the estuarine freshwater-marine continuum. Since freshwater cyanobacteria are known to produce toxins, this represents a serious threat for animal and human health. Saxitoxins (STXs) are classified among the most powerful cyanotoxins. It becomes thus critical to evaluate the capacity of cyanobacteria producing STXs to face variations in salinity and to better understand the physiological consequences of sodium chloride (NaCl) exposure, in particular on their toxicity. Laboratory experiments were conducted on three filamentous cyanobacteria species isolated from brackish (Dolichospermum sp.) and fresh waters (Aphanizomenon gracile and Cylindrospermopsis raciborskii) to determine how salinity variations affect their growth, photosynthetic activity, pigment composition, production of reactive oxygen species (ROS), synthesis of compatible solutes and STXs intracellular quotas. Salinity tolerance was found to be species-specific. Dolichospermum sp. was more resistant to salinity variations than A. gracile and C. raciborskii. NaCl variations reduced growth in all species. In A. gracile, carotenoids content was dose-dependently reduced by NaCl. By contrast, in C. raciborskii and Dolichospermum sp., variations in carotenoids content did not show obvious relationships with NaCl concentration. While in Dolichospermum sp. phycocyanin and phycoerythrin increased within the first 24 h exposure to NaCl, in both A. gracile and C. raciborskii, these pigments decreased proportionally to NaCl concentration. Low changes in salinity did not impact STXs production in A. gracile and C. raciborskii while higher increase in salinity could modify the toxin profile and content of C. raciborskii (intracellular STX decreased while dc-GTX2 increased). In estuaries, A. gracile and C. raciborskii would not be able to survive beyond the oligohaline area (i.e. salinity > 5). Conversely, in part due to its ability to accumulate compatible solutes, Dolichospermum sp. has the potential to face consequent salinity variations and to survive in the polyhaline area (at least up to salinity = 24).


Renal cell carcinoma presenting with cutaneous metastasis: a case report.
Renal cell carcinoma is the most common kidney tumor in adults. Cutaneous metastasis is a rare first symptom of the disease. This paper describes the diagnosis of a renal cell carcinoma that was indicated by cutaneous metastasis in the head and neck region, and considers the etiopathogenesis of such cases. A careful skin examination is important to detect cutaneous metastasis associated with renal cell carcinomas. Metastatic skin lesions in the head and neck region must be taken into consideration during a differential diagnosis.


Deviation in the Age Structure of Mortality as an Indicator of COVID-19 Pandemic Severity.
Objectives. To test whether distortions in the age distribution of deaths can track pandemic activity. Methods. We compared weekly distributions of all-cause deaths by age during the COVID-19 pandemic in the United States from March to December 2020 with corresponding prepandemic weekly baseline distributions derived from data for 2015 to 2019. We measured distortions via Kolmogorov-Smirnov (K-S) and χ2 goodness-of-fit statistics as well as deaths among individuals aged 65 years or older as a percentage of total deaths (PERC65+). We computed bivariate correlations between these measures and the number of recorded COVID-19 deaths for the corresponding weeks. Results. Elevated COVID-19-associated fatalities were accompanied by greater distortions in the age structure of mortality. Distortions in the age distribution of weekly US COVID-19 deaths in 2020 relative to earlier years were highly correlated with COVID fatalities (K-S: r = 0.71, P < .001; χ2: r = 0.90, P < .001; PERC65+: r = 0.85, P < .001). Conclusions. A population-representative sample of age-at-death data can serve as a useful means of pandemic activity surveillance when precise cause-of-death data are incomplete, inaccurate, or unavailable, as is often the case in low-resource environments. (Am J Public Health. 2022;112(1):165-168. https://doi.org/10.2105/AJPH.2021.306567).