Cutaneous and soft-tissue manifestations of sepsis due to gram-negative enteric bacilli.
Four patterns of tissue involvement can be distinguished in sepsis due to gram-negative enteric bacilli. When intense local inflammation predominates, cellulitis or thrombophlebitis results, often with venous or arterial obstruction. Bacteria are present in the affected tissues, but not in sufficient numbers to be seen microscopically. When bacterial proliferation is unchecked by an appropriate leukocyte response, ecthyma gangrenosum, erythema multiforme, or diffuse bullous lesions may occur with minimal clinical or histologic signs of inflammation. In symmetric peripheral gangrene associated with disseminated intravascular coagulation, bland fibrinous deposits are seen in small vessels but neither inflammatory cells nor bacteria are present. The fourth kind of lesion is that seen in bacterial endocarditis. In all four patterns a vascular component is prominent clinically and histologically. The pathogenesis of these lesions is multifactorial; in each individual case the interaction between bacterial and host factors probably determines which clinical picture will result. The appearance of symmetric soft tissue lesions of the extremities in the absence of predisposing local conditions suggests the possibility of sepsis due to gram-negative bacilli, especially if other clinical features indicate that sepsis might be present.


Relative Biological Effectiveness of Energetic Heavy Ions for Intestinal Tumorigenesis Shows Male Preponderance and Radiation Type and Energy Dependence in APC(1638N/+) Mice.
There are uncertainties associated with the prediction of colorectal cancer (CRC) risk from highly energetic heavy ion (HZE) radiation. We undertook a comprehensive assessment of intestinal and colonic tumorigenesis induced after exposure to high linear energy transfer (high-LET) HZE radiation spanning a range of doses and LET in a CRC mouse model and compared the results with the effects of low-LET γ radiation. Male and female APC(1638N/+) mice (n=20 mice per group) were whole-body exposed to sham-radiation, γ rays, (12)C, (28)Si, or (56)Fe radiation. For the >1 Gy HZE dose, we used γ-ray equitoxic doses calculated using relative biological effectiveness (RBE) determined previously. The mice were euthanized 150 days after irradiation, and intestinal and colon tumor frequency was scored. The highest number of tumors was observed after (28)Si, followed by (56)Fe and (12)C radiation, and tumorigenesis showed a male preponderance, especially after (28)Si. Analysis showed greater tumorigenesis per unit of radiation (per cGy) at lower doses, suggesting either radiation-induced elimination of target cells or tumorigenesis reaching a saturation point at higher doses. Calculation of RBE for intestinal and colon tumorigenesis showed the highest value with (28)Si, and lower doses showed greater RBE relative to higher doses. We have demonstrated that the RBE of heavy ion radiation-induced intestinal and colon tumorigenesis is related to ion energy, LET, gender, and peak RBE is observed at an LET of 69 keV/μm. Our study has implications for understanding risk to astronauts undertaking long duration space missions.


Selected β-glucans act as immune-training agents by improving anti-mycobacterial activity in human macrophages - a pilot study.
Epigenetic reprogramming of innate immune cells by β-glucan in a process called trained immunity, leads to an enhanced host response to a secondary infection. β-glucans are structural components of plants, algae, fungi and bacteria and thus recognized as non-self by human macrophages. We selected the β-glucans curdlan from Alcaligenes faecalis, WGP dispersible from Saccharomyces cerevisiae, and β-glucan-rich culture supernatant of Alternaria and investigated whether they could produce trained immunity effects leading to an increased control of virulent Mycobacterium tuberculosis. We observed a significant M. tuberculosis growth-reduction in macrophages trained with curdlan and Alternaria, which also correlated with increased IL-6 and IL-1β release. WGP dispersible-trained macrophages were stratified into 'non responders' and 'responders', according to their ability to control M. tuberculosis, with 'responders' producing higher IL-6 levels. The addition of neutrophils to infected macrophage cultures further enhanced macrophage control of virulent M. tuberculosis, but not in a stimuli-dependent manner. Pathway enrichment analysis of DNA methylome data also highlighted hypomethylation of genes in pathways associated with signaling and cellular reorganization and motility, and 'responders' to WGP-training were enriched in the interferon-gamma signaling pathway. This study adds evidence that certain β-glucans show promise as immune training agents.


Surveillance of febrile patients in a district and evaluation of their spatiotemporal associations: a pilot study.
Fever is an undifferentiated clinical feature that may enhance the sensitivity of syndromic surveillance systems. By studying the spatiotemporal associations of febrile patients, it may allow early detection of case clustering that indicates imminent threat of infectious disease outbreaks in the community. We captured consecutive emergency department visits that led to hospitalization in a district hospital in Hong Kong during the period of 12 Sep 2005 to 14 Oct 2005. We recorded demographic data, provisional diagnoses, temperature on presentation and residential location for each patient-episode, and geocoded the residential addresses. We applied Geographical Information System technology to study the geographical distribution these cases, and their associations within a 50-m buffer zone spatially. A case cluster was defined by three or more spatially associated febrile patients within each three consecutive days. One thousand and sixty six patient-episodes were eligible for analysis; 42% of them had fever (>37 degrees C; oral temperature) on presentation. Two hundred and four patient-episodes (19.1%) came from residential care homes for elderly (RCHE). We detected a total of 40 case clusters during the study period. Clustered cases were of older age; 57 (33.3%) were residents of RCHE. We found a median of 3 patients (range: 3 - 8) and time span of 3 days (range: 2 - 8 days) in each cluster. Twenty five clusters had 2 or more patients living in the same building block; 18 of them were from RCHE. It is technically feasible to perform surveillance on febrile patients and studying their spatiotemporal associations. The information is potentially useful for early detection of impending infectious disease threats.


Diagnostic value of a bedside test for cardiac troponin T in the patient with chest pain presenting to the emergency room.
Identification of patients with acute chest pain due to acute coronary syndrome is a common and difficult challenge for emergency physicians. A prospective study was conducted to assess the diagnostic value of a bedside test of cardiac troponin T in the emergency room setting. Forty-nine consecutive patients, who visited the emergency room within 6 hours of the onset of acute chest pain, were enrolled. Of the 26 patients who were ultimately diagnosed as having acute coronary syndrome, seven patients (27%) had positive cardiac troponin T assay results, whereas none of the patients without acute coronary syndrome had positive results (0%). For patients with acute coronary syndrome who presented later than 3 hours after the onset (n = 4), the test was positive in all cases (positive predictive value: 100%, negative predictive value: 100%, p < 0.01). However, the positive rate was only 14% for those who presented earlier than 3 hours after the onset (n = 22) (positive predictive value: 100%, negative predictive value: 47%, p = 0.84). In conclusion, bedside troponin T test results should be evaluated considering the time interval from the onset of chest symptoms.


Effects of di-(2-ethylhexyl) phthalate on growth, metabolism, and virulence of the plant pathogenic bacterium Acidovorax citrulli.
Acidovorax citrulli is a seed-borne bacterial pathogen that causes bacterial fruit blotch in cucurbits and severely affects the production of cucumbers and watermelons globally. In this study, we investigated the effects of di-(2-ethylhexyl) phthalate (DEHP) on the growth, metabolism, and virulence of A. citrulli. Bacterial population was not affected by DEHP exposure; moreover, significant changes were not observed in lipid peroxidation, membrane permeability, and nucleic acid leakage. However, palmitoleic acid content was increased in the cell membrane of DEHP-exposed A. citrulli. Further, DEHP exposure increased the activity of TCA cycle-related enzymes, including α-ketoglutarate dehydrogenase and succinyl-CoA synthetase, along with increase in the content of glutamate, succinate, fumarate, and malate in TCA cycle. Additionally, total 270 genes were differentially expressed by the treatment, of which 28 genes were upregulated and 242 genes, including those related to translation, flagellum-dependent cell motility, and flagellum assembly, were downregulated. Regarding virulence traits, swimming activity was decreased in DEHP-exposed A. citrulli; however, biofilm formation was not affected in in vitro assay. Moreover, relative expression of pathogenicity genes, including hrpX and hrpG, were decreased in DEHP-exposed A. citrulli compared to that of unexposed A. citrulli. Therefore, these results suggest that DEHP accumulation in soil could potentially influence the metabolism and virulence traits of A. citrulli.


Reactivity of metal-oxo clusters towards biomolecules: from discrete polyoxometalates to metal-organic frameworks.
Metal-oxo clusters hold great potential in several fields such as catalysis, materials science, energy storage, medicine, and biotechnology. These nanoclusters of transition metals with oxygen-based ligands have also shown promising reactivity towards several classes of biomolecules, including proteins, nucleic acids, nucleotides, sugars, and lipids. This reactivity can be leveraged to address some of the most pressing challenges we face today, from fighting various diseases, such as cancer and viral infections, to the development of sustainable and environmentally friendly energy sources. For instance, metal-oxo clusters and related materials have been shown to be effective catalysts for biomass conversion into renewable fuels and platform chemicals. Furthermore, their reactivity towards biomolecules has also attracted interest in the development of inorganic drugs and bioanalytical tools. Additionally, the structural versatility of metal-oxo clusters allows for the efficiency and selectivity of the biomolecular reactions they promote to be readily tuned, thereby providing a pathway towards reaction optimization. The properties of the catalyst can also be improved through incorporation into solid supports or by linking metal-oxo clusters together to form Metal-Organic Frameworks (MOFs), which have been demonstrated to be powerful heterogeneous catalysts. Therefore, this review aims to provide a comprehensive and critical analysis of the state of the art on biomolecular transformations promoted by metal-oxo clusters and their applications, with a particular focus on structure-activity relationships.


Do preschool special education services make a difference in kindergarten reading and mathematics skills?: A propensity score weighting analysis.
The purpose of this study was to examine the average treatment effect of preschool special education services on children's kindergarten academic skills. Using data from a nationally representative sample of United States children who participated in the Early Childhood Longitudinal Study-Birth Cohort, we examined the effectiveness of preschool special education services by comparing reading and math outcomes for children who received special education services at preschool-age to a propensity-score-weighted sample of children who did not receive these services. Results indicated that the receipt of these special education services had a statistically significant moderate negative effect on children's kindergarten skills in both reading (d=-0.21) and mathematics (d=-0.29). These findings have implications for the implementation and evaluation of services for young children experiencing developmental delays or disabilities.


Spt6 Is Essential for rRNA Synthesis by RNA Polymerase I.
Spt6 (suppressor of Ty6) has many roles in transcription initiation and elongation by RNA polymerase (Pol) II. These effects are mediated through interactions with histones, transcription factors, and the RNA polymerase. Two lines of evidence suggest that Spt6 also plays a role in rRNA synthesis. First, Spt6 physically associates with a Pol I subunit (Rpa43). Second, Spt6 interacts physically and genetically with Spt4/5, which directly affects Pol I transcription. Utilizing a temperature-sensitive allele, spt6-1004, we show that Spt6 is essential for Pol I occupancy of the ribosomal DNA (rDNA) and rRNA synthesis. Our data demonstrate that protein levels of an essential Pol I initiation factor, Rrn3, are reduced when Spt6 is inactivated, leading to low levels of Pol I-Rrn3 complex. Overexpression of RRN3 rescues Pol I-Rrn3 complex formation; however, rRNA synthesis is not restored. These data suggest that Spt6 is involved in either recruiting the Pol I-Rrn3 complex to the rDNA or stabilizing the preinitiation complex. The findings presented here identify an unexpected, essential role for Spt6 in synthesis of rRNA.


Assessing the value and pest management window provided by neonicotinoid seed treatments for management of soybean aphid (Aphis glycines Matsumura) in the Upper Midwestern United States.
A 2-year, multi-state study was conducted to assess the benefits of using soybean seed treated with the neonicotinoid thiamethoxam to manage soybean aphid in the upper Midwestern USA and compare this approach with an integrated pest management (IPM) approach that included monitoring soybean aphids and treating with foliar-applied insecticide only when the economic threshold was reached. Concentrations of thiamethoxam in soybean foliage were also quantified throughout the growing season to estimate the pest management window afforded by insecticidal seed treatments. Both the IPM treatment and thiamethoxam-treated seed resulted in significant reductions in cumulative aphid days when soybean aphid populations reached threshold levels. However, only the IPM treatment resulted in significant yield increases. Analysis of soybean foliage from thiamethoxam-treated seeds indicated that tissue concentrations of thiamethoxam were statistically similar to plants grown from untreated seeds beginning at the V2 growth stage, indicating that the period of pest suppression for soybean aphid is likely to be relatively short. These data demonstrate that an IPM approach, combining scouting and foliar-applied insecticide where necessary, remains the best option for treatment of soybean aphids, both in terms of protecting the yield potential of the crop and of break-even probability for producers. Furthermore, we found that thiamethoxam concentrations in foliage are unlikely to effectively manage soybean aphids for most of the pests' activity period across the region. © 2017 Society of Chemical Industry.


The perception of moving subjective contours by 4-month-old infants.
We investigated whether 4-month-old infants are capable of perceiving illusory contours produced by the Kanizsa-square display, first introduced by Prazdny (1983, Perception & Psychophysics 34 403-404), which tests whether a viewer perceives the illusory contour in the absence of brightness contrast (illusory brightness). Because the illusory square appears to move across the computer screen and infants are attracted to motion, this display holds their interest. In experiment 1, 4-month-old infants were tested for their ability to distinguish between a continuously moving illusory square and a continuously moving control display in which the pacman elements were rotated so that the perception of subjective contours did not occur. Data analysis revealed a significant preference for the subjective contour display. In experiment 2, habituation-dishabituation was used with 4-month-old infants. They were tested for their ability to discriminate between the illusory Kanizsa square that continuously moved back and forth and an illusory square which changed positions randomly. Although the infants did not show differences in dishabituation as a function of the habituation display, they looked significantly longer at the continuously moving display.


Cooperative reinforcement of opioid pharmacophores.
In recent years several opioid receptors have been characterized (mu, kappa, delta, et cetera); furthermore, it has been suggested that different receptor types mediate different neurophysiological responses. It has also been found that there exist endogenous opioid peptides which reveal some selectivity for a particular receptor type. These observations created a need for selective agonists and antagonists of a particular receptor type, and indicated a possibility of developing selective opioid drugs with reduced side effects. All endogenous peptides have an identical N-terminal part, which suggests that opioid receptor pockets in the message part are similar or identical. The main elements which differentiate the selectivity of endogenous peptides are surroundings of receptor pockets, different organization of opioid receptors and their interactions with other receptors and enzymatic systems. This opens a possibility of successful modifications of biochemical and/or physiological properties of opioid pharmacophores through modification of the elements which could be connected with the opioid message. Depending on the character of the connecting element, the pharmacophores may be divided into three main types: (i) opioid pharmacophores coordinated with the address; (ii) bivalent opioids; (iii) bifunctional pharmacophores.


Oblique facial clefts: pathology, etiology, and reconstruction.
Modern views on embryology have increased our understanding of the nature of oblique facial clefts. The anomalies that have their origin at the junction of facial processes, such as the nasomaxillary dysplasias, may be named primary clefts or transformation. The maxillary clefts that are due to a developmental arrest of the skeleton are in fact secondary defects of differentiation defects. The teratology of these malformations is discussed, and attention is drawn to the amniotic rupture syndrome as a possible cause. All these clefts are rare, their incidence ranging from 0.75 to 5.4 per 1000 common clefts. This author has been involved in the treatment of nine of these patients. Four had their malformation reconstructed with one of the conventional procedures described in the literature, but the results, although initially acceptable, soon deteriorated. A more aggressive approach was therefore chosen. Rotation and advancement of the cheek proved to be extremely effective and is now advocated as the procedure of choice. The transposition of a median forehead flap is considered an excellent alternative. Use of these procedures in five patients is reported. There were no complications.


The effect of peritoneal re-approximation on lymphocele formation in transperitoneal robot-assisted radical prostatectomy and extended pelvic lymphadenectomy.
The objective of the study was to evaluate the effect of peritoneal re-approximation at the end of the procedure in transperitoneal robot-assisted radical prostatectomy (tRARP) and extended pelvic lymphadenectomy (ePLND) on operative, oncologic, and symptomatic lymphocele rates. A total of 79 patients were included in the study who underwent tRARP and bilateral ePLND performed by two different experienced surgeons. One of the surgeons performed the peritoneal re-approximation (Group 1, n=41) and the other did not re-approximate the peritoneum (Group 2, n=38) at the end of the procedure in tRARP and ePLND. Operative parameters and symptomatic lymphocele rates were compared between the groups. There were no significant differences between the preoperative parameters age, body mass index, and preoperative prostate-specific antigen values (p>0.05). The perioperative parameters were as follows: the operation time and estimated blood loss (EBL) was less, and the number of removed lymph nodes was higher in Group 2. However, only the difference in the EBL was statistically significant (p=0.03). Hospitalization time, symptomatic lymphocele, intervention requiring lymphocele, and complication rates were found to be less in Group 2, but only hospitalization time was statistically significant (p=0.04). Pathological parameters were similar for both groups. There was a significant correlation between lymph node positivity and the presence of symptomatic lymphocele in the correlation analysis (p=0.05). It has been shown in this study that the re-approximation of the peritoneum does not provide any additional benefit in terms of complications. Considering that this process also increases the operation time and lymphocele formation, we think there is no need for re-approximation after robot-assisted radical prostatectomy and pelvic lymphadenectomy.


Astrocyte elevated gene-1 and c-Myc cooperate to promote hepatocarcinogenesis in mice.
Astrocyte elevated gene-1 (AEG-1) and c-Myc are overexpressed in human hepatocellular carcinoma (HCC) functioning as oncogenes. AEG-1 is transcriptionally regulated by c-Myc, and AEG-1 itself induces c-Myc by activating the Wnt/β-catenin-signaling pathway. We now document the cooperation of AEG-1 and c-Myc in promoting hepatocarcinogenesis by analyzing hepatocyte-specific transgenic mice expressing either AEG-1 (albumin [Alb]/AEG-1), c-Myc (Alb/c-Myc), or both (Alb/AEG-1/c-Myc). Wild-type and Alb/AEG-1 mice did not develop spontaneous HCC. Alb/c-Myc mice developed spontaneous HCC without distant metastasis, whereas Alb/AEG-1/c-Myc mice developed highly aggressive HCC with frank metastasis to the lungs. Induction of carcinogenesis by N-nitrosodiethylamine significantly accelerated the kinetics of tumor formation in all groups. However, in Alb/AEG-1/c-Myc, the effect was markedly pronounced with lung metastasis. In vitro analysis showed that Alb/AEG-1/c-Myc hepatocytes acquired increased proliferation and transformative potential with sustained activation of prosurvival and epithelial-mesenchymal transition-signaling pathways. RNA-sequencing analysis identified a unique gene signature in livers of Alb/AEG-1/c-Myc mice that was not observed when either AEG-1 or c-Myc was overexpressed. Specifically, Alb/AEG-1/c-Myc mice overexpressed maternally imprinted noncoding RNAs (ncRNAs), such as Rian, Meg-3, and Mirg, which are implicated in hepatocarcinogenesis. Knocking down these ncRNAs significantly inhibited proliferation and invasion by Alb/AEG-1/c-Myc hepatocytes. Our studies reveal a novel cooperative oncogenic effect of AEG-1 and c-Myc that might explain the mechanism of aggressive HCC. Alb/AEG-1/c-Myc mice provide a useful model to understand the molecular mechanism of cooperation between these two oncogenes and other molecules involved in hepatocarcinogenesis. This model might also be of use for evaluating novel therapeutic strategies targeting HCC.


Measurement properties of translated versions of the Scoliosis Research Society-22 Patient Questionnaire, SRS-22: a systematic review.
The Scoliosis Research Society-22 Patient Questionnaire (SRS-22) has been translated into various languages and tested in patients with scoliosis. However, the translations and their psychometric properties have never been systematically reviewed. This study aimed to evaluate the psychometric properties and to provide the current level of evidence of all the available translations of the SRS-22 using the "COnsensus-based Standards for the selection of health status Measurement INstruments" (COSMIN). A systematic review was performed. The PubMed, Medline, EMbase, and CINAHL databases were searched for articles concerning the translations of the SRS-22 and/or evaluating any of their measurement properties. Two reviewers independently assessed the methodological quality and the psychometric estimates of the selected studies by using the 4-point rating scale COSMIN checklist and a validated quality assessment criteria, respectively. The level of evidence of each psychometric property per language was determined combining COSMIN outcomes and psychometric results. The search strategy led to 24 articles evaluating the SRS-22 in 17 different languages. The methodological quality of the properties was mostly poor to fair, and there was a lack of information regarding them. The overall assessment was positive in 42.5 % of cases. The level of evidence resulted in a limited positive evidence in 11 languages. The Chinese (traditional), Dutch, Italian, Norwegian, and Spanish translations are advisable; the Greek, Japanese, Korean, Persian, Thai, and Turkish translations showed encouraging results but should be used with caution; the Brazilian, Chinese (simplified), Polish, and Swedish translations showed contradictory or scarce results, and no suggestions can be formulated; the French Canadian and German translations did not provide methodologically sound information. Further attention should be given to cross-cultural and structural validity, hypothesis testing, and responsiveness.


Child abuse and neglect and the brain--a review.
Developmental psychology and the study of behaviour and emotion have tended to be considered in parallel to the study of neurobiological processes. This review explores the effects of child abuse and neglect on the brain, excluding nonaccidental injury that causes gross physical trauma to the brain. It commences with a background summary of the nature, context, and some deleterious effects of omission and commission within child maltreatment. There is no post-maltreatment syndrome, outcomes varying with many factors including nature, duration, and interpersonal context of the maltreatment as well as the nature of later intervention. There then follows a section on environmental influences on brain development, demonstrating the dependence of the orderly process of neurodevelopment on the child's environment. Ontogenesis, or the development of the self through self-determination, proceeds in the context of the nature-nurture interaction. As a prelude to reviewing the neurobiology of child abuse and neglect, the next section is concerned with bridging the mind and the brain. Here, neurobiological processes, including cellular, biochemical, and neurophysiological processes, are examined alongside their behavioural, cognitive, and emotional equivalents and vice versa. Child maltreatment is a potent source of stress and the stress response is therefore discussed in some detail. Evidence is outlined for the buffering effects of a secure attachment on the stress response. The section dealing with actual effects on the brain of child abuse and neglect discusses manifestations of the stress response including dysregulation of the hypothalamic-pituitary-adrenal axis, and parasympathetic and catecholamine responses. Recent evidence about reduction in brain volume following child abuse and neglect is also outlined. Some biochemical, functional, and structural changes in the brain that are not reflections of the stress response are observed following child maltreatment. The mechanisms bringing about these changes are less clearly understood and may well be related to early and more chronic abuse and neglect affecting the process of brain development. The behavioural and emotional concomitants of their neurobiological manifestations are discussed. The importance of early intervention and attention to the chronicity of environmental adversity may indicate the need for permanent alternative caregivers, in order to preserve the development of the most vulnerable children.


The brainstem preproglucagon system in a non-human primate (Macaca mulatta).
The nucleus of the solitary tract (NTS) contains a small population of neurons expressing preproglucagon. In these neurons preproglucagon is processed to the glucagon-like-peptides 1 and 2 (GLP-1 and GLP-2) and oxyntomodulin. Whereas the neuroanatomy of these neurons is well characterized in rodents the location and projection of preproglucagon neurons have never been described in primates. The purpose of the present study was to characterize the location of preproglucagon neurons and their projections in the non-human primate using radioactive in situ hybridization and immunohistochemistry. In situ hybridization revealed preproglucagon mRNA expressing neurons in the caudal nucleus of the solitary tract extending laterally through the intermediate reticular nucleus into the A1 area. Using an antibody raised against rat GLP-2, GLP-2-immunoreactive (-ir) cell bodies were found in the same areas as the preproglucagon mRNA. Only very few GLP-2-ir nerve fibers were observed in the caudal brainstem and mostly in the same areas as the GLP-2-ir cell bodies. The most prominent GLP-2-ir terminal fields were detected in the hypothalamus and rostrally in the bed nucleus of the stria terminalis complex. In the hypothalamus, GLP-2-ir fibers arborized extensively in the paraventricular nucleus of the hypothalamus (PVN), the dorsomedial hypothalamic nucleus (DMH) and the arcuate nucleus (Arc), the latter containing the densest fiber-plexus. The findings indicate that the brainstem preproglucagon neuronal system is highly conserved between rat and non-human primate with the exception of a much denser innervation of the mediobasal hypothalamus in the primate brain.


Auditory event-related potential indices of fronto-temporal information processing in schizophrenia syndromes: valid outcome prediction of clozapine therapy in a three-year follow-up.
Reliability, specificity, and validity of three event-related potential (ERP) indices of non-attended and attended auditory information processing [the mismatch negativity (MMN), the novelty-P3a and the target-P3b] were assessed in 21 healthy subjects and 25 schizophrenic patients while performing a visual discrimination task (Ignore condition) and, subsequently, an auditory discrimination task (Attend condition). Re-test reliability, as measured in a subset of 10 healthy subjects and 9 patients respectively, ranged from r=0.4 to r=0.8. In both groups P3a was found to be smaller in the Ignore than in the Attend condition. Patients had significantly larger P3a amplitudes than healthy subjects while their MMN and P3b amplitudes were smaller. Two ERP factors were extracted in healthy subjects: (1) 'novelty reaction' with high loading scores for P3a and (2) 'deviant detection' with high loading scores for MMN. P3b was predominantly loading on the first factor thus confirming partly overlapping P3a and P3b generators. However, considerable variance was also shared by the second factor, particularly in patients. External validity of the ERP factors was confirmed post hoc. Particularly ERP indices of deviant detection were found to be associated with negative symptoms. In order to assess further clinical relevance, therapy response to clozapine was followed-up over 3 yr in a sub-sample of 17 patients. Poor treatment response was associated with high Novelty Factor scores and large P3a amplitudes whereas good response was associated with high Deviant Factor scores and relatively intact MMN. It is concluded that ERP abnormalities provide a severity index of brain impairment and a measure of predicting therapeutic outcome.


Expression, Purification, and Functional Characterization of Tectonin 2 from Laccaria bicolor: A Six-Bladed Beta-Propeller Lectin Specific for O-Methylated Glycans.
Tectonins are conserved defense proteins of innate immune systems featuring a β-propeller fold. Tectonin 2 from Laccaria bicolor, Lb-Tec2, is the first fungal representative of the tectonin superfamily that has been described. In-depth characterization revealed a specificity for O-methylated glycans and identified a unique sequence motif and binding site architecture underlying this unusual specificity. This chapter provides information on how to produce and purify recombinant Lb-Tec2, characterize its interaction with O-methylated glycans and demonstrate its biological function.


Fundamental Epidemiology Terminology and Measures: It Really Is All in the Name.
Epidemiology is the study of how disease is distributed in populations and the factors that influence or determine this distribution. Clinical epidemiology denotes the application of epidemiologic methods to questions relevant to patient care and provides a highly useful set of principles and methods for the design and conduct of quantitative clinical research. Validly analyzing, correctly reporting, and successfully interpreting the findings of a clinical research study often require an understanding of the epidemiologic terms and measures that describe the patterns of association between the exposure of interest (treatment or intervention) and a health outcome (disease). This statistical tutorial thus discusses selected fundamental epidemiologic concepts and terminology that are applicable to clinical research. Incidence is the occurrence of a health outcome during a specific time period. Prevalence is the existence of a health outcome during a specific time period. The relative risk can be defined as the probability of the outcome of interest (eg, developing the disease) among exposed individuals compared to the probability of the same event in nonexposed individuals. The odds ratio is a measure of risk that compares the frequency of exposure to a putative causal factor in the individuals with the health outcome (cases) versus those individuals without the health outcome (controls). Factors that are associated with both the exposure and the outcome of interest need to be considered to avoid bias in your estimate of risk. Because it takes into consideration the contribution of extraneous variables (confounders), the adjusted odds ratio provides a more valid estimation of the association between the exposure and the health outcome and thus is the preferably reported measure. The odds ratio closely approximates the risk ratio in a cohort study or a randomized controlled trial when the outcome of interest does not occur frequently (<10%). The editors, reviewers, authors, and readers of journal articles should be aware of and make the key distinction between the absolute risk reduction and the relative risk reduction. In assessing the findings of a clinical study, the investigators, reviewers, and readers must determine if the findings are not only statistically significant, but also clinically meaningful. Furthermore, in deciding on the merits of a new medication or other therapeutic intervention, the clinician must balance the benefits versus the adverse effects in individual patients. The number needed to treat and the number needed to harm can provide this needed additional insight and perspective.


Progressive alcohol-induced sperm alterations leading to spermatogenic arrest, which was reversed after alcohol withdrawal.
This is a report of a 6-year follow-up of a male patient's semen parameters during heavy chronic alcohol intoxication and after withdrawal. A slowly progressive negative impact of alcohol could be observed: isolated moderate teratozoospermia was firstly noted followed by oligoasthenoteratospermia. Then a severe worsening resulted in cryptozoospermia and ultimately in azoospermia. At this moment, the histological analysis of a testicular biopsy revealed a maturation arrest of the germinal cells at the pachytene stage with no mature sperm cells. Alcohol withdrawal was then obtained, allowing a very fast and drastic improvement of semen characteristics; strictly normal semen parameters were observed after no more than 3 months. Taking into consideration these data, patients should be questioned about their alcohol intake before assisted reproductive technology and should be informed about this adverse effect. Moreover, this case report emphasizes how quickly benefits can be obtained after withdrawal, even in the case of heavy chronic alcohol intake.


Mortality and Hospitalizations among Sickle Cell Disease Patients with End-Stage Kidney Disease Initiating Dialysis.
Sickle cell disease (SCD) is the most common inherited hematological disorder and a well-described risk factor for end-stage kidney disease (ESKD). Mortality and hospitalizations among patients with SCD who develop ESKD remain understudied. Furthermore, prior studies focused only on SCD patients where ESKD was caused by SCD. We aimed to describe mortality and hospitalization risk in all SCD patients initiating dialysis and explore risk factors for mortality and hospitalization. We performed a national observational cohort study of African American ESKD patients initiating dialysis (2000-2014) in facilities affiliated with a large dialysis provider. SCD was identified by diagnosis codes and matched to a reference population (non-SCD) by age, sex, dialysis initiation year, and geographic region of care. Sensitivity analyses were conducted by restricting to patients where SCD was recorded as the cause of ESKD. We identified 504 SCD patients (mean age: 47 ± 14 years; 48% females) and 1,425 reference patients (mean age: 46 ± 14 years; 49% females). The median follow-up was 2.4 (IQR 1.0-4.5) years. Compared to the reference, SCD was associated with higher mortality risk (hazard ratio 1.66; 95% confidence interval [CI]: 1.36-2.03) and higher hospitalization rates (incidence rate ratio 2.12; 95% CI: 1.88-2.38) in multivariable analyses. Exploratory multivariable mortality risk models showed the largest mortality risk attenuation with the addition of time-varying hemoglobin and high-dose erythropoietin, but the association of SCD with mortality remained significant. Sensitivity analyses (restricted to ESKD caused by SCD) also showed significant associations between SCD and mortality and hospitalizations, but with larger effect estimates. High-dose erythropoietin was associated with the highest risk for mortality and hospitalization in SCD. Among ESKD patients, SCD is associated with a higher risk for mortality and hospitalization, particularly in patients where SCD is identified as the cause of ESKD.


Association of Dilated Perivascular Spaces With Cognitive Decline and Incident Dementia.
To determine whether severe perivascular space (PVS) dilation is associated with longitudinal cognitive decline and incident dementia over 4 and 8 years, respectively, we analyzed data from a prospective cohort study. A total of 414 community-dwelling older adults aged 72-92 years were assessed at baseline and biennially for up to 8 years, with cognitive assessments, consensus dementia diagnoses, and 3T MRI. The numbers of PVS in 2 representative slices in the basal ganglia (BG) and centrum semiovale (CSO) were counted and severe PVS pathology defined as the top quartile. The effects of severe PVS pathology in either region or both regions and those with severe BG PVS and severe CSO PVS were examined. White matter hyperintensity volume, cerebral microbleed number, and lacune number were calculated. Participants with severe PVS pathology in both regions or in the CSO alone had greater decline in global cognition over 4 years, even after adjustment for the presence of other small vessel disease neuroimaging markers. The presence of severe PVS pathology in both regions was an independent predictor of dementia across 8 years (odds ratio 2.91, 95% confidence interval 1.43-5.95, p = 0.003). The presence of severe PVS pathology in all groups examined was associated with greater dementia risk at either year 4 or 6. Severe PVS pathology is a marker for increased risk of cognitive decline and dementia, independent of other small vessel disease markers. The differential cognitive associations for BG and CSO PVS may represent differences in their underlying pathology.


[Genetic study of plasmid-associated high-frequency mutations to streptomycin resistance in Escherichia coli].
Escherichia coli CTR1(RT1)RHfm1) carrying two H-factors and having unusually high frequency of mutation to high level streptomycin resistance is studied. The high frequency of mutation (about 10(-6) to streptomycin resistance is connected with the presence of R factor RHfm1, controlling the resistance to chloramphenicol and low level streptomacin resistance, but not with RT1, controlling the resistance to tetracycline. Spontaneous or ethidium bromide-induced loss of RHfm1 is accompanied by a decrease of the mutation frequency to 10(-9). RHfm1 is efficiently transmissible to other strains at 28 degrees C. The acquisition of RHfm1 by strains of E. coli K-12 ans S. typhimurium LT2 was followed by a 1000--10000-fold increase of the frequejcy of mutation to streptomycin resistance. Some streptomycin resistant mutants were isolated, and chromosome location of the mutations was demonstrated. The streptomycin resistant mutants were unable to transmit high level of resistance to streptomycin with R factor, but only low level one. The loss of RHfm1 by streptomycin resistant mutants was accompanied by the return to the streptomycin sensitivity of the initial R- strans (E. coli K-12 mutants) or by a decrease of the streptomycin resistance to the level, only 2-fold higher than that of R- wild type (E. coli CTR1 mutant). Thus, the mutantions had practically no effect on streptomycin resistance of R- strains, but could lead to high resistance phenotypes in the presence of RHfm1. The mutant loci in all three studied strains were found to be closely linked to the locus "fus" on the genetic map of E. coli.


Comparison between open-angle glaucoma and angle-closure glaucoma regarding the short-term optic disc vessel density changes after trabeculectomy.
To compare the microvasculature of the optic disc in open-angle glaucoma (OAG) and angle-closure glaucoma (ACG) after trabeculectomy. This study included 34 patients divided into two groups based on the angle: (1) the OAG Group, which included 24 eyes from 24 patients, and (2) the ACG Group, which included ten eyes from 10 patients. All patients were subjected to comprehensive ophthalmic examinations. It included best-corrected visual acuity (BCVA), Goldmann applanation tonometry, gonioscopy, slit-lamp biomicroscopy, dilated fundus examination, and stereoscopic examination of the optic disc. The central corneal thickness was measured using a Nidek AL scan optical biometer. The visual field was evaluated by standard automated perimetry using Humphrey Field Analyzer (24-2 Swedish interactive threshold algorithm; Carl-Zeiss Meditec, Dublin, CA). Moreover, optical coherence tomography angiography (OCT-A) was performed utilizing the RTVue XR Avanti scanner (Optovue Inc., Fremont, CA, USA) preoperatively as well as 1 month after surgery. There was a statistically significant increase in optic disc vessel density (VD) in the whole image, radial peripapillary, inferior, superior, temporal, and nasal quadrant in OAG after surgery. Regarding the change in VD after surgery in ACG patients, there was a statistically significant increase in optic disc VD in the whole image, radial peripapillary, inferior, superior, temporal, and nasal quadrant in ACG after surgery.Regarding the percentage of VD change following trabeculectomy surgery, there were highly significant differences between the two groups for the whole image, radial peripapillary, inferior quadrant, and temporal quadrant VD. Statistically significant changes were also observed in the superior and nasal quadrants of VD. However, no significant change in VD was detected within the disc. In conclusion, the optic disc VD improved after the reduction of intraocular pressure (IOP) by surgery in both OAG and ACG. However, ACG demonstrated a significant improvement than the OAG.


Pediatric postoperative cerebellar cognitive affective syndrome follows outflow pathway lesions.
To evaluate lesion location after pediatric cerebellar tumor resection in relation to the development of severe cognitive and affective disturbances, or cerebellar cognitive affective syndrome (CCAS). The postsurgical lesion location of 195 pediatric patients with cerebellar tumors was mapped onto a template brain. Individuals with CCAS were matched to 2 participants without CCAS by sex, age, and lesion volume. Lesion analyses included both a hypothesis-driven evaluation of the cerebellar outflow pathway (deep nuclei and superior cerebellar peduncles) and data-driven multivariate lesion symptom mapping. Lesion-associated networks were evaluated by comparing connectivity patterns between the lesion location of cases with and those without CCAS with resting-state functional connectivity MRI data from large normative adult and pediatric cohorts. CCAS was present in 48 of 195 participants (24.6%) and was strongly associated with cerebellar outflow tract lesions (p < 0.0001). Lesion symptom mapping also highlighted the cerebellar outflow pathway, with peak findings in the fastigial nuclei extending into the inferior vermis. Lesion network mapping revealed that the cerebellar region most associated with CCAS was functionally connected to the thalamic mediodorsal nucleus, among other sites, and that higher connectivity between lesion location and the mediodorsal nucleus predicts CCAS occurrence (p < 0.01). A secondary analysis of 27 participants with mutism revealed similar localization of lesions and lesion-associated networks. Lesions of the cerebellar outflow pathway and inferior vermis are associated with major cognitive and affective disturbances after pediatric cerebellar tumor resection, and disrupted communication between the cerebellum and the thalamic mediodorsal nucleus may be important.


Northern analysis of viral plus- and minus-strand RNAs.
Replication is a fundamental activity of viruses. Replication of positive-sense RNA viruses involves the synthesis of complementary minus-strand intermediates from the parental RNA template followed by synthesis of nascent plus strands. Negative-sense RNA genome and double-stranded RNA are copied into positive-sense mRNA before translation. To detect and estimate the abundance of plus- and minus-strand viral transcripts in the infected samples, northern analysis is the most commonly used method.


Surgical versus non-surgical management of early stage oropharyngeal squamous cell carcinoma.
National guidelines state that early-stage oropharyngeal carcinoma can be treated by either primary surgery or radiotherapy. There is a paucity of evidence comparing surgery versus non-surgical therapy within the same population. With the shift in head and neck cancer treatment towards primary chemoradiation, the aim of this observational cohort study was to help define whether surgery still has a role for early-stage oropharyngeal disease, using a national prospective audit of all new head and neck cancers recruited between 1999 and 2001 in Scotland. Patients with T1-2 N0 M0 tumours were identified. Patients were divided into those treated surgically (±adjuvant radiotherapy) or non-surgically. Five-year outcome data were calculated. Forty-two patients were treated surgically (13 received adjuvant radiotherapy) and 32 patients treated non-surgically. Disease-specific 5-year survival was 69 and 60%, respectively (p = 0.22). Locoregional failure occurred in seven of the surgical group and five of the non-surgical group. The success of chemoradiotherapy and the evidence for its use as adjuvant therapy may dissuade clinicians from considering surgical intervention. This study demonstrates the outcomes of surgical and non-surgical therapy within the same population. Where clear margins can be achieved, and in the absence of negative prognostic neck pathology, surgery remains a good option; allowing radiotherapy to be preserved for locoregional failures or second primary tumours. Although there are limitations to this study, it does demonstrate the benefit of prospective population data collection.


Outcomes of gestational weight gain outside the Institute of Medicine Guidelines.
To compare pregnancy outcomes between women who gave birth at Lerdsin Hospital having gestational weight gain (GWG) within and above or below Institute of Medicine (IOM) guidelines. All medical records of women who gave birth at Lerdsin Hospital between October 1, 2010 and September 30, 2013 were reviewed. Three thousands six hundred eighty three women who met inclusion criteria were divided into four categories according to pre-pregnancy body mass index (BMI) as underweight, normal weight, overweight and obese. Women in each categories were compared for outcomes (neonatal birth weight, cesarean birth, pregnancy induced hypertension (PIH), gestational diabetes (GDM), preterm birth, low birth weight (LBW), macrosomia, smallforgestational age (SGA) and largefor gestational age (LGA)), using logistic regression to calculate odds ratios (ORs) and 95% confidence intervals (Cls). Of3,683 pregnant women, 34.9% had weight gain within, 36.5% above, and 28.7% below IOM guidelines. Women with higher gestational weight gain in all BM7 categories had an increased risk of cesarean birth (except in obese group), macrosomia, LGA and a decreased riskforpreterm birth, LBW (exceptfor overweight group) and SGA. Women with lower gestational weight gain had an increased risk forpreterm birth, LBW SGA and a decreased risk for cesarean birth. Neonates deliveredfrom women whose gestational weight gains were above IOMguidelines were also heavier than those from neonates whose maternal weight gains during pregnancy were within IOM guidelines. The IOM guidelines are usefulfor monitoring gestational weight gain and if it were within guidelines, women could have decreased riskfor several adverse outcomes such as cesarean birth, macrosomia, LGA, preterm birth, LBW and SGA.


Reversible dissociation and inactivation of phosphofructokinase in the ischemic rat heart.
To determine if shifts in the ratio of active phosphofructokinase (PFK) tetramers to the inactive dimeric form of the enzyme occur in vivo in the ischemic rat heart, we have developed a rocket immunoelectrophoretic (IEP) assay that provides a sensitive means by which to measure relative differences in this ratio among crude heart extracts. In ischemic hearts, in the face of a drop in intracellular pH from 6.95 to 6.25, there is a time-dependent decrease (63%) in the ratio of tetramer to dimer IEP rocket height relative to perfused controls. Concomitant with this hysteretic depolymerization is a 50% loss of PFK catalytic activity. Realkalinizing extracts of ischemic hearts fosters a recovery of 86% of the activity lost during ischemia and a return of the tetramer-to-dinner ratio to near control value. The amount of reactivation is directly dependent on the degree of enzyme dissociation that occurred during ischemia. Importantly, ischemia-induced dimerization is also reversed in vivo by postischemic reperfusion. The data are consistent with those in the previous study [Hand and Carpenter, Am. J. Physiol. 250 (Regulatory Integrative Comp. Physiol. 19): R505-R511, 1986] that characterized the pH-dependent hysteretic dissociation of heart PFK in vitro, and together they represent the first demonstration that this molecular behavior is operative in intact tissue. Other vertebrate muscle systems in which this mechanism might be functioning during pH-dependent glycolytic inhibition are discussed.


Validation of DTI tractography-based measures of primary motor area connectivity in the squirrel monkey brain.
Diffusion tensor imaging (DTI) tractography provides noninvasive measures of structural cortico-cortical connectivity of the brain. However, the agreement between DTI-tractography-based measures and histological 'ground truth' has not been quantified. In this study, we reconstructed the 3D density distribution maps (DDM) of fibers labeled with an anatomical tracer, biotinylated dextran amine (BDA), as well as DTI tractography-derived streamlines connecting the primary motor (M1) cortex to other cortical regions in the squirrel monkey brain. We evaluated the agreement in M1-cortical connectivity between the fibers labeled in the brain tissue and DTI streamlines on a regional and voxel-by-voxel basis. We found that DTI tractography is capable of providing inter-regional connectivity comparable to the neuroanatomical connectivity, but is less reliable measuring voxel-to-voxel variations within regions.


Adapting Motor Imagery Training Protocols to Surgical Education: A Systematic Review and Meta-Analysis.
Objective. Motor imagery (MI) is widely used to improve technical skills in sports and has been proven to be effective in neurorehabilitation and surgical education. This review aims to identify the key characteristics of MI protocols for implementation into surgical curricula. Design. This study is a systematic review and meta-analysis. PubMed, MEDLINE, Embase and PsycINFO databases were systematically searched. The primary outcome was the impact of MI training on measured outcomes, and secondary outcomes were study population, MI intervention characteristics, study primary outcome measure and subject rating of MI ability (systematic review registration: PROSPERO CRD42019121895). Results. 456 records were screened, 60 full texts randomising 2251 participants were reviewed and 39 studies were included in meta-analysis. MI was associated with improved outcome in 35/60 studies, and pooled analysis also showed improved outcome on all studies with a standardised mean difference of .39 (95% CI: .12, .67, P = .005). In studies where MI groups showed improved outcomes, the median duration of training was 24 days (mode 42 days), and the median duration of each individual MI session was 30 minutes (range <1 minute-120 minutes). Conclusions. MI training protocols for use in surgical education could have the following characteristics: MI training delivered in parallel to existing surgical training, in a flexible format; inclusion of a brief period of relaxation, followed by several sets of repetitions of MI and a refocusing period. This is a step towards the development of a surgical MI training programme, as a low-cost, low-risk tool to enhance practical skills.


Granulocyte colony-stimulating factor promotes an aggressive phenotype of colon and breast cancer cells with biochemical changes investigated by single-cell Raman microspectroscopy and machine learning analysis.
Granulocyte colony-stimulating factor (G-CSF) is produced at high levels in several cancers and is directly linked with metastasis in gastrointestinal (GI) cancers. In order to further understand the alteration of molecular compositions and biochemical features triggered by G-CSF treatment at molecular and cell levels, we sought to investigate the long term treatment of G-CSF on colon and breast cancer cells measured by label-free, non-invasive single-cell Raman microspectroscopy. Raman spectrum captures the molecule-specific spectral signatures ("fingerprints") of different biomolecules presented on cells. In this work, mouse breast cancer line 4T1 and mouse colon cancer line CT26 were treated with G-CSF for 7 weeks and subsequently analyzed by machine learning based Raman spectroscopy and gene/cytokine expression. The principal component analysis (PCA) identified the Raman bands that most significantly changed between the control and G-CSF treated cells. Notably, here we proposed the concept of aggressiveness score, which can be derived from the posterior probability of linear discriminant analysis (LDA), for quantitative spectral analysis of tumorigenic cells. The aggressiveness score was effectively applied to analyze and differentiate the overall cell biochemical changes of G-CSF-treated two model cancer cells. All these tumorigenic progressions suggested by Raman analysis were confirmed by pro-tumorigenic cytokine and gene analysis. A high correlation between gene expression data and Raman spectra highlights that the machine learning based non-invasive Raman spectroscopy offers emerging and powerful tools to better understand the regulation mechanism of cytokines in the tumor microenvironment that could lead to the discovery of new targets for cancer therapy.


Bitches, queens and prostaglandins.
Luteolysis can be obtained in bitches by prolonged administration of PGF2 alpha resulting in abortion in pregnant bitches. A prostaglandin analogue (TPT) can induce fetal resorption or abortion depending upon the time of administration. In an investigation comprising a few bitches, PGF2 alpha has given encouraging results for treatment of uterine disorders. In the queen prostaglandin can induce abortion and parturition, and it has, when administered during a long period, been used for treatment of pyometra. Irrespective of the preparation and dosage the administration of prostaglandin is accompanied by side effects lasting for up to 3 hours, and therefore further investigations are needed before prostaglandins can be recommended for use in bitches and queens.


EvoEF2: accurate and fast energy function for computational protein design.
The accuracy and success rate of de novo protein design remain limited, mainly due to the parameter over-fitting of current energy functions and their inability to discriminate incorrect designs from correct designs. We developed an extended energy function, EvoEF2, for efficient de novo protein sequence design, based on a previously proposed physical energy function, EvoEF. Remarkably, EvoEF2 recovered 32.5%, 47.9% and 22.3% of all, core and surface residues for 148 test monomers, and was generally applicable to protein-protein interaction design, as it recapitulated 30.9%, 42.4%, 31.3% and 21.4% of all, core, interface and surface residues for 88 test dimers, significantly outperforming EvoEF on the native sequence recapitulation. We further used I-TASSER to evaluate the foldability of the 148 designed monomer sequences, where all of them were predicted to fold into structures with high fold- and atomic-level similarity to their corresponding native structures, as demonstrated by the fact that 87.8% of the predicted structures shared a root-mean-square-deviation less than 2 Å to their native counterparts. The study also demonstrated that the usefulness of physical energy functions is highly correlated with the parameter optimization processes, and EvoEF2, with parameters optimized using sequence recapitulation, is more suitable for computational protein sequence design than EvoEF, which was optimized on thermodynamic mutation data. The source code of EvoEF2 and the benchmark datasets are freely available at https://zhanglab.ccmb.med.umich.edu/EvoEF. Supplementary data are available at Bioinformatics online.


Aggregation versus inclusion complexes to solubilize drugs with cyclodextrins. A case study using sulphobutylether-β-cyclodextrins and remdesivir.
The formation of small hybrid aggregates between excipient and drug molecules is one of the mechanisms that contributes to the solubilization of active principles in pharmaceutical formulations. The characterization of the formation, governing interactions and structure of such entities is not trivial since they are highly flexible and dynamic, quickly exchanging molecules from one to another. In the case of cyclodextrins, this mechanism and the formation of inclusion complexes synergistically cooperate to favour the bioavailability of drugs. In a previous study we reported a detailed characterization of the possible formation of inclusion complexes with 1:1 stoichiometry between remdesivir, the only antiviral medication currently approved by the United States Food and Drug Administration for treating COVID-19, and sulphobutylether-β-cyclodextrins. Here we extend our study to assess the role of the spontaneous aggregation in the solubilization of the same drug, by molecular dynamics simulations at different relative concentrations of both compounds. The number of sulphobutylether substitutions in the cyclodextrin structure and two different protonation states of the remdesivir molecule are considered. We aim to shed light in the solubilization mechanism of sulphobutylether-β-cyclodextrins, broadly used as an excipient in many pharmaceutical formulations, in particular in the case of remdesivir as an active compound.


Male accessory gland infection frequency in infertile patients with chronic microbial prostatitis and irritable bowel syndrome: transrectal ultrasound examination helps to understand the links.
The aim of this study was to evaluate the frequency of male accessory gland infection (MAGI) in patients with chronic bacterial prostatitis (CBP) plus irritable bowel syndrome (IBS) and to compare the sperm parameters of patients with or without MAGI. In addition, another objective of this study was to evaluate the ultrasound characterization of the anatomical space between the posterior wall of the prostate and the anterior wall of the rectum using transrectal ultrasonography. Fifty consecutive patients with the following criteria were enrolled: 1) infertility, 2) diagnosis of CBP, and 3) diagnosis of IBS according to the Rome III criteria. The following 2 age-matched control groups were also studied: infertile patients with CBP alone (n = 56) and fertile men (n = 30) who had fathered a child within the previous 3 months. Patients and controls underwent an accurate patient history; administration of the National Institutes of Health-Chronic Prostatitis Symptom Index and the Rome III questionnaires for prostatitis and IBS, respectively; physical examination; semen analysis; and transrectal ultrasound evaluation (limited to patients with CBP and IBS or CBP alone). A significantly higher frequency of MAGI was found in patients with CBP plus IBS (82.0%) compared with patients with CBP alone (53.6%) or fertile men (0%). The presence of MAGI in patients with CBP plus IBS was associated with a significantly lower sperm concentration, total number, and forward motility, and with a higher seminal leukocyte concentration compared with patients with CBP alone and MAGI. Sperm normal morphology was similar in the groups of patients. All sperm parameters did not differ significantly in both groups of patients without MAGI. With ultrasound evaluation, a significantly higher frequency of dilatation of prostatic venous plexus was found in patients with CBP plus IBS (75%) compared with patients with CBP alone (10%). Patients with CBP plus IBS had a significantly higher frequency of MAGI compared with patients with CBP alone. This was associated with worse sperm parameters and, hence, poorer reproductive prognosis. We suggest searching for the presence of IBS in patients with prostatitis syndrome, in particular when CBP and/or worse sperm parameters are present. Finally, this is the first observation on ultrasound examination of the anatomical space between the posterior wall of the prostate and the anterior wall of the rectum reported in patients with CBP and IBS. Further studies should clarify the meaning of the ultrasound findings.


The Hippo Pathway and YAP/TAZ-TEAD Protein-Protein Interaction as Targets for Regenerative Medicine and Cancer Treatment.
The Hippo pathway is an important organ size control signaling network and the major regulatory mechanism of cell-contact inhibition. Yes associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) are its targets and terminal effectors: inhibition of the pathway promotes YAP/TAZ translocation to the nucleus, where they interact with transcriptional enhancer associate domain (TEAD) transcription factors and coactivate the expression of target genes, promoting cell proliferation. Defects in the pathway can result in overgrowth phenotypes due to deregulation of stem-cell proliferation and apoptosis; members of the pathway are directly involved in cancer development. The pharmacological regulation of the pathway might be useful in cancer prevention, treatment, and regenerative medicine applications; currently, a few compounds can selectively modulate the pathway. In this review, we present an overview of the Hippo pathway, the sequence and structural analysis of YAP/TAZ, the known pharmacological modulators of the pathway, especially those targeting YAP/TAZ-TEAD interaction.


[Smuggling of illegal drugs by body suffers].
Body packers are persons who smuggle illegal drugs by swallowing condoms or plastic cylinders containing such substances. Body stuffers are drug dealers or drug abusers who swallow illegal drugs in an effort to conceal evidence during an arrest or in fear of being arrested. We report four cases and discuss management. Asymptomatic body packers may be managed conservatively with laxatives and water-soluble contrast medium. This method allows an accurate follow-up with abdominal radiography. If patients develop abdominal pain or signs and symptoms of intoxication, surgical intervention should be considered. Both types of patients should be monitored carefully.


[High-dose brachytherapy in endobronchial neoplastic stenoses].
Form March, 1991, to September, 1995, twenty-nine patients with endobronchial neoplastic stenosis were treated with high dose rate (HDR) brachytherapy at the Casa Sollievo della Sofferenza Hospital in San Giovanni Rotondo (Foggia, Italy). Fifteen patients had hemoptysis, 10 dyspnea, 6 constant cough and 6 lung atelectasis. The total dose, specified at 1 cm from the source, ranged 5 to 21 Gy and the fraction doses 5 to 15 Gy. Fourteen of 29 patients (48%) died. The mean survival is 7 months, with the follow-up ranging 1 to 22 months. Subjective responses were achieved in 78.4% of cases, with 67.6% complete and 10.8% partial remission rates. Complete remission of hemoptysis was observed in 100% of patients. Dyspnea improved in 70%, cough in 46.4% and atelectasis in 83.2%. Endoscopic findings, 1 month after the end of brachytherapy, showed a response in 79.4% of patients. The complication rate was 13.8% (1 tracheoesophageal fistula, 2 pulmonary hemorrhages and 1 cavitary necrosis). Even though the number of treated patients is small, our experience confirms the efficacy of HDR endobronchial brachytherapy in the palliation of lung cancer-related symptoms. Literature data show that brachytherapy improves the quality of life in the patients with poor prognosis who are otherwise untreatable. The HDR technique is more accurate than the LDR technique and therapy is better tolerated also because execution time is shorter. Prospective clinical trials are needed to investigate the most effective total doses and fractionations and to better define the role of brachytherapy in the curative treatment of lung cancer.


SNP-Based Genetic Linkage Map and Quantitative Trait Locus Mapping Associated with the Agronomically Important Traits of Hypsizygus marmoreus.
White strains of Hypsizygus marmoreus are more difficult to cultivate than are brown strains; therefore, new white strain breeding strategies are required. Accordingly, we constructed the genetic map of H. marmoreus with 1996 SNP markers on 11 linkage groups (LGs) spanning 1380.49 cM. Prior to analysis, 82 backcrossed strains (HM8 lines) were generated by mating between KMCC03106-31 and the progenies of the F1 hybrid (Hami-18 × KMCC03106-93). Using HM8, the first 23 quantitative trait loci (QTLs) of yield-related traits were detected with high limit of detection (LOD) scores (1.98-9.86). The length, thickness, and hardness of the stipe were colocated on LG 1. Especially, length of stipe and thickness of stipe were highly correlated given that the correlation coefficients were negative (-0.39, p value ≤ .01). And a typical biomodal distribution was observed for lightness of the pileus and the lightness of the pileus trait belonged to the LG 8, as did traits of earliness and mycelial growth in potato dextrose agar (PDA) medium. Therefore, results for color traits can be suggested that color is controlled by a multi-gene of one locus. The yield trait was highly negatively correlated with the traits for thickness of the stipe (-0.45, p value ≤ .01). Based on additive effects, the white strain was confirmed as recessive; however, traits of mycelial growth, lightness, and quality were inherited by backcrossed HM8 lines. This new genetic map, finely mapped QTLs, and the strong selection markers could be used in molecular breeding of H. marmoreus.


Overview of the angiotensin-converting-enzyme inhibitors.
The pharmacology of angiotensin-converting-enzyme (ACE) inhibitors and their role in the renin-angiotensin system (RAS) are described, and pharmacokinetic properties and common adverse events are presented. ACE inhibitors play a vital role in the RAS by regulating the potent vasoconstrictor angiotensin II. All ACE inhibitors share the same basic structure; however, they can be separated on the basis of their functional (binding) group: carboxyl, sulfhydryl, or phosphinyl. These functional groups are, in part, responsible for differences in the pharmacokinetic and safety profiles of these agents. Captopril and lisinopril are the only ACE inhibitors that are not prodrugs requiring activation through hepatic biotransformation. Differences among the ACE inhibitors in lipophilicity are described; fosinopril has the greatest lipophilicity and lisinopril the least. ACE is found in numerous tissues, and there is increasing evidence of differences among ACE inhibitors in their ability to inhibit tissue ACE. Most ACE inhibitors are eliminated mainly by the kidneys and to a lesser extent through the liver. Lisinopril is the only ACE inhibitor that does not require hepatic metabolism. In the selection of an ACE inhibitor for once-daily use to treat hypertension, differences in trough-peak ratios are clinically relevant. Fosinopril, ramipril, and trandolapril have minimum trough-peak ratios of 50% or greater. ACE inhibitors are generally well tolerated, with hypotension, cough, and hyperkalemia being the most frequently reported adverse effects for the entire class. Drug interactions across the ACE inhibitor class as well as agent-specific interactions are described. Factors to be considered in the selection of an ACE inhibitor include differences in potency, affinity for ACE, pharmacokinetics, and toxicity that are related to structural properties of the drug; whether the trough-peak ratio enables use of a once-daily dose; and potential adverse effects related to a drug's functional (binding) group.


[Two forms of carbonic anhydrase from bean chloroplasts].
The intracellular localization of carboanhydrase from the bean (Vicia faba) leaves was investigated. The bulk of the enzyme activity (about 70%) is localized in the chloroplasts. The enzyme exists both in the soluble and in membrane-bound state. Disc electrophoresis in polyacrylamide gel with specific staining for the enzyme activity demonstrated that the soluble and membrane-bound carboanhydrases from bean chloroplasts are two molecular forms (presumably isoenzymes) differing in their electrophoretic mobilities. Protein fractionation with (NH4)2SO4 and a subsequent gel filtration on Sephadex G-200 and isoelectrofocusing resulted in separation of the two forms and their purification to homogeneity. Both carboanhydrases differ in pH, specific activity and stability.


A novel method for estimating solid fraction of roller-compacted ribbons.
A simple method has been developed to estimate solid fraction or relative density of compacts using the weight of ribbons produced during roller compaction. The method provides an alternative to the commonly used dimensional measurement, especially for formulations not amenable to forming quality ribbons. Surface texture of the compaction rolls has been taken into consideration in our mathematical treatment along with correction for ribbon relaxation. Ribbon relaxation occurring upon ribbon exiting the compaction zone is estimated using roll geometry, roll gap, and ribbon thickness. Detailed experimental runs have been carried out to confirm the validity of the proposed theory. The predicted solid fraction was found comparable to that from actual dimensional measurement by caliper. In the case of the microcrystalline cellulose/dicalcium phosphate one:one formulation, the predicted solid fraction had an error sum of squares (SSE) of 2.64E-03 when compared to the dimensional method. When relaxation was included, the SSE decreased by four folds. Similarly, for the microcrystalline cellulose/lactose monohydrate 2:1 formulation, the SSE decreased twelfth folds when relaxation was taken into consideration. These results further confirm the utility of the proposed throughput method for estimating the solid fraction of ribbons.


Scapula fracture incidence in reverse total shoulder arthroplasty using screws above or below metaglene central cage: clinical and biomechanical outcomes.
Reverse total shoulder arthroplasty (RTSA) is a viable treatment option for rotator cuff tear arthropathy but carries a complication risk of scapular fracture. We hypothesized that using screws above the central glenoid axis for metaglene fixation creates a stress riser contributing to increased scapula fracture incidence. Clinical type III scapular fracture incidence was determined with screw placement correlation: superior screw vs. screws placed exclusively below the glenoid midpoint. Cadaveric RTSA biomechanical modeling was employed to analyze scapular fractures. We reviewed 318 single-surgeon single-implant RTSAs with screw correlation to identify type III scapular fractures. Seventeen cadaveric scapula specimens were matched for bone mineral density, metaglenes implanted, and fixation with 2 screw configurations: inferior screws alone (group 1INF) vs. inferior screws with one additional superior screw (group 2SUP). Biomechanical load to failure was analyzed. Of 206 patients, 9 (4.4%) from the superior screw group experienced scapula fractures (type III); 0 fractures (0/112; 0%) were identified in the inferior screw group. Biomechanically, superior screw constructs (group 2SUP) demonstrated significantly (P < .05) lower load to failure (1077 N vs. 1970 N) compared with constructs with no superior screws (group 1INF). There was no significant age or bone mineral density discrepancy. Clinical scapular fracture incidence significantly decreased (P < .05) for patients with no screws placed above the central cage compared with patients with superior metaglene screws. Biomechanical modeling demonstrates significant construct compromise when screws are used above the central cage, fracturing at nearly half the ultimate load of the inferior screw constructs. We recommend use of inferior screws, all positioned below the central glenoid axis, unless necessary to stabilize the metaglene construct.


Building a durable response to HIV/AIDS: implications for health systems.
The remarkable rise in investments for HIV control programs in 2003-2010 enabled an unprecedented expansion of access to HIV services in low-income and middle-income countries. By the end of 2010, more than 5.2 million people were receiving antiretroviral therapy (ART), which transformed HIV infection, once a death sentence, into a long-term illness. The rapid expansion in the number of persons receiving ART means that health systems must continue to provide acute life-saving care for those with advanced HIV/AIDS although also providing chronic care services to expanding cohorts of more stable patients who are doing well on ART. This expansion also means a transition from an emergency response to the epidemic, characterized by a public health approach, to a more integrated and durable approach to HIV prevention, care, and treatment services that fosters individualized care for those requiring long-term antiretroviral treatment. Yet most low-income and middle-income countries, which have weak health systems, are poorly prepared to make this transition. In this article, we highlight the challenges health systems face in developing a sustained and durable response to HIV/AIDS. The article analyses the readiness of health systems to combine rapid expansion of ART access with long-term treatment and continuity of care for a growing cohort of patients. We argue that effective management of a transition from an emergency AIDS response to long-term programatic strategies will require a paradigm shift that enables leveraging investments in HIV to build sustainable health systems for managing large cohorts of patients receiving ART although meeting the immediate needs of those who remain without access to HIV treatment and care.


Is apolipoprotein-(a) an important indicator of vasculogenic erectile dysfunction?
We aimed to investigate whether high peripheral and cavernosal plasma levels of apolipoprotein-(a) [Lp (a)] is an indicator for vasculogenic erectile dysfunction. We determined Lp (a), total cholesterol (TC), triglyceride (TG) and high density lipoprotein (HDL) levels in peripheral and cavernosal blood in 39 patients with erectile dysfunction. Thirty-nine impotent patients have been divided into two groups: vasculogenic erectile dysfunction (VED) and nonvasculogenic erectile dysfunction (NVED), according to colour Doppler ultrasonic flowmetry, dynamic infusion cavernosometry, and the pressure difference between the brachial arterial systolic pressure and cavernosal arterial systolic pressure measurements. Biochemical values were compared in both groups. Lp (a) and TC levels were higher in both peripheral and cavernosal samples of VED group than in NVED group, with no differences between peripheral and cavernosal blood levels within the same groups. There were no significant changes in TG and HDL levels in either group. The detection of more than 31 mg/dl in Lp (a) level solely shows the vascular origin with a sensitivity and specificity of 95 and 82.3%, respectively. High Lp (a) levels can be considered an indicator of vasculogenic erectile dysfunction.


Costs for collagenase injections compared with fasciectomy in the treatment of Dupuytren's contracture: a retrospective cohort study.
To compare collagenase injections and surgery (fasciectomy) for Dupuytren's contracture (DC) regarding actual total direct treatment costs and short-term outcomes. Retrospective cohort study. Orthopaedic department of a regional hospital in Sweden. Patients aged 65 years or older with previously untreated DC of 30° or greater in the metacarpophalangeal (MCP) and/or proximal interphalangeal (PIP) joints of the small, ring or middle finger. The collagenase group comprised 16 consecutive patients treated during the first 6 months following the introduction of collagenase as treatment for DC at the study centre. The controls were 16 patients randomly selected among those operated on with fasciectomy at the same centre during the preceding 3 years. Treatment with collagenase was given during two standard outpatient clinic visits (injection of 0.9 mg, distributed at multiple sites in a palpable cord, and next-day finger extension under local anaesthesia) followed by night-time splinting. Fasciectomy was carried out in the operating room (day surgery) under general or regional anaesthesia using standard technique, followed by therapy and splinting. Actual total direct costs (salaries of all medical personnel involved in care, medications, materials and other relevant costs), and total MCP and PIP extension deficit (degrees) measured by hand therapists at 6-12 weeks after the treatment. Collagenase injection required fewer hospital outpatient visits to a therapist and nurse than fasciectomy. Total treatment cost for collagenase injection was US$1418.04 and for fasciectomy US$2102.56. The post-treatment median (IQR) total extension deficit was 10 (0-30) for the collagenase group and 10 (0-34) for the fasciectomy group. Treatment of DC with one collagenase injection costs 33% less than fasciectomy with equivalent efficacy at 6 weeks regarding reduction in contracture.


Challenges in neurologic prognostication after neonatal brain injury.
Parents often ask neonatologists and neurologists to determine neurologic prognosis in the preterm and term infant after neonatal brain injury. Prognostication in these populations remains rather full of uncertainties. Knowledge of available diagnostic tests and their limitations allows the clinician to synthesize the most likely outcomes after neurologic injury. In this review, we describe the diagnostic tools available to the clinician, active areas of research, and challenges in neurologic prognostication of the neonate.


Reconstructed human skin shows epidermal invagination towards integrated neopapillae indicating early hair follicle formation in vitro.
Application of reconstructed human Skin (RhS) is a promising approach for the treatment of extensive wounds and for drug efficacy and safety testing. However, incorporating appendages, such as hair follicles, into RhS still remains a challenge. The hair follicle plays a critical role in thermal regulation, dispersion of sweat and sebum, sensory and tactile functions, skin regeneration, and repigmentation. The aim of this study was to determine whether human neopapilla could be incorporated into RhS (differentiated epidermis on fibroblast and endothelial cell populated dermis) and whether the neopapillae maintain their inductive follicular properties in vitro. Neopapillae spheroids, constructed from expanded and self-aggregating dermal papilla cells, synthesized extracellular matrix typically found in follicular papillae. Compared with dermal fibroblasts, neopapillae showed increased expression of multiple genes (Wnt5a, Wnt10b, and LEF1) known to regulate hair development and also increased secretion of CXCL1, which is a strong keratinocyte chemoattractant. When neopapillae were incorporated into the dermis of RhS, they stimulated epidermal down-growth resulting in engulfment of the neopapillae sphere. Similar to the native hair follicle, the differentiated invaginating epidermis inner side was keratin 10 positive and the undifferentiated outer side keratin 10 negative. The outer side was keratin 15 positive confirming the undifferentiated nature of these keratinocytes aligning a newly formed collagen IV, laminin V positive basement membrane within the hydrogel. In conclusion, we describe a RhS model containing neopapillae with hair follicle-inductive properties. Importantly, epidermal invagination occurred to engulf the neopapillae, thus demonstrating in vitro the first steps towards hair follicle morphogenesis in RhS.


Defined metal atom aggregates precisely incorporated into metal-organic frameworks.
Nanosized metal aggregates (MAs), including metal nanoparticles (NPs) and nanoclusters (NCs), are often the active species in numerous applications. In order to maintain the active form of MAs in "use", they need to be anchored and stabilised, preventing agglomeration. In this context, metal-organic frameworks (MOFs), which exhibit a unique combination of properties, are of particular interest as a tunable and porous matrix to host MAs. A high degree of control in the synthesis towards atom-efficient and application-oriented MA@MOF composites is required to derive specific structure-property relationships and in turn to enable design of functions on the molecular level. Due to the versatility of MA@MOF (derived) materials, their applications are not limited to the obvious field of catalysis, but increasingly include 'out of the box' applications, for example medical diagnostics and theranostics, as well as specialised (bio-)sensoring techniques. This review focuses on recent advances in the controlled synthesis of MA@MOF materials en route to atom-precise MAs. The main synthetic strategies, namely 'ship-in-bottle', 'bottle-around-ship', and approaches to achieve novel hierarchical MA@MOF structures are highlighted and discussed while identifying their potential as well as their limitations. Hereby, an overview of standard characterisation methods that enable a systematic analysis procedure and state-of-art techniques that localise MA within MOF cavities are provided. While the perspectives of MA@MOF materials in general have been reviewed various times in the recent past, few atom-precise MAs inside MOFs have been reported so far, opening opportunities for future investigation.


Rivastigmine improves dual-task gait velocity in patients with Alzheimer's disease.
Gait impairments are common in patients with Alzheimer's disease. Cholinesterase inhibitors are used to treat the symptoms of patients with Alzheimer's disease, but they have not been shown to reduce the severity of Alzheimer's disease-related gait disorders. This was a prospective, single-arm, open-label, non-randomized study. The aim of the present study was to determine the effect of the acetylcholinesterase inhibitor rivastigmine on gait in 21 newly diagnosed patients with mild to moderate Alzheimer's disease. The outcome variables were velocity, stride length, and cadence during single-task and dual-task gait trials. The subjects were also assessed with the Mini-Mental State Examination, Alzheimer's Disease Cooperative Study Activities of Daily Living, Functional Assessment Staging, and Geriatric Depression Scale. After 12 weeks of treatment with rivastigmine, gait velocity was significantly improved in the dual-task gait trials; gait velocity was increased from 40.59 ± 13.59 m/min at baseline to 46.88 ± 12.73 m/min when counting backward from 100 in steps of 7 while walking, and gait velocity was increased from 37.06 ± 15.57 m/min at baseline to 42.03 ± 14.02 m/min when naming animals while walking. In the single-task gait trials, which consisted only of walking at their usual pace or at a fast pace, gait velocity was not increased by rivastigmine administration. Our findings indicated that rivastigmine improved gait in subjects with mild to moderate Alzheimer's disease during dual-task trials. The observed enhancement of dual-task gait might be caused by an improvement of cognitive function rather than motor function. UMIN, UMIN000025869. Registered December 16, 2016, https://upload.umin.ac.jp/cgi-open-bin/icdr/ctr_view.cgi?recptno=R000029744.


Modulation of RANTES production by human cytomegalovirus infection of fibroblasts.
Chemokines play a major role in inflammatory responses and affect hematopoiesis both negatively and positively. We show that fresh isolates and laboratory strains (Towne and Ad-169) of human cytomegalovirus (HCMV) induce production of the CC chemokine RANTES in fibroblasts. Induction of extracellular RANTES production occurred as early as 8 h after infection, peaked around 24 h after infection, and was almost undetectable by 48 and 72 h. Upregulation occurred in the absence of viral DNA synthesis, suggesting that it was due to immediate-early-early HCMV gene expression. CMV infection stimulated RANTES transcription, since reverse transcription-PCR detected a sharp increase in RANTES RNA which persisted even when extracellular RANTES was no longer detected. Induction of RANTES in fibroblasts was not due to prior induction of tumor necrosis factor alpha or interleukin 1 beta. Down-regulation required an active viral genome. Decrease of RANTES in culture supernatants may be associated with the appearance of the HCMV CC chemokine receptor US28, since we show that this gene is transcribed as early as 8 h after infection. Modulation of CC chemokine production early during CMV infection might have a regulatory effect on viral replication, as well as affect immune surveillance.


Single Gold Nanobipyramids Sensing the Chirality of Amyloids.
Plasmonic nanoparticles, due to their sensitivity to small changes in their closest environment and plasmon resonance, can sense the chirality of the surrounding molecules. Therefore, plasmonic nanoparticles can be applied as a next-generation biosensor for peptides or proteins. In this work, we explore the interaction between chiral, ordered protein aggregates (amyloids) and small gold nanobipyramids. We show how the morphology, structure, and chiroptical properties of amyloids induce circular dichroism in the plasmon resonance wavelengths from individual plasmonic nanoparticles upon binding to the chiral amyloid template. Moreover, using the data from microscopic and spectroscopic analyses of formed heterostructures, we propose the most probable mechanism behind the induction of chirality in this system and discuss which specific feature of insulin protein aggregates is sensed by nanobipyramids.


Echocardiographic abnormalities of tricuspid valve motion in pulmonary embolism.
Echocardiographic findings in five patients with pulmonary embolism were studied. Tricuspid echocardiograms showed abnormalities in valve motion, that is a monophasic triangular wave during diastole in all the patients as well as an increased dimension of the right ventricle. An "a' dip of the pulmonary valve echocardiogram was also recognised in all five. Later tricuspid echocardiograms regained the normal M-shaped configuration. The monophasic triangular pattern of the tricuspid valve during diastole may be related to the shorter duration of tricuspid valve opening compared with that of the mitral valve. Tachycardia cannot explain this difference between tricuspid and mitral valve motion, which seems to be caused by a prolonged isovolumic relaxation time of the right ventricle resulting in a delayed opening of the tricuspid valve. These results were obtained by comparing these data with those of control subjects and patients with chronic right ventricular overloading resulting from atrial septal defect.


Neural and endocranial anatomy of Triassic phytosaurian reptiles and convergence with fossil and modern crocodylians.
Phytosaurs are a clade of large, carnivorous pseudosuchian archosaurs from the Late Triassic with a near cosmopolitan distribution. Their superficial resemblance to longirostrine (long-snouted) crocodylians, such as gharials, has often been used in the past to infer ecological and behavioural convergence between the two groups. Although more than thirty species of phytosaur are currently recognised, little is known about the endocranial anatomy of this clade. Here, we describe the endocranial anatomy (including the brain, inner ear, neurovascular structures and sinus systems) of the two non-mystriosuchine phytosaurs Parasuchus angustifrons (="Paleorhinus angustifrons") and Ebrachosuchus neukami from the Late Triassic of Germany based on digital reconstructions. Results show that the endocasts of both taxa are very similar to each other in their rostrocaudally elongate morphology, with long olfactory tracts, weakly demarcated cerebral regions and dorsoventrally short endosseous labyrinths. In addition, several sinuses, including large antorbital sinuses and prominent dural venous sinuses, were reconstructed. Comparisons with the endocranial anatomy of derived phytosaurs indicate that Phytosauria is united by the presence of elongate olfactory tracts and longitudinally arranged brain architecture-characters which are also shared with Crocodyliformes. However, a substantial morphological variability is observed in the cephalic and pontine flexure and the presence of a pineal organ across the different phytosaur species. These results suggest that the endocranial anatomy in Phytosauria generally follows a plesiomorphic pattern, with moderate variation within the clade likely resulting from divergent sensory and behavioural adaptations.


Elevated serum neuropeptide Y levels are associated with carotid plaque formation in Chinese adults: a cross-sectional study.
Carotid plaque (CP) formation is an important consequence of atherosclerosis and leads to significant complications. Levels of neuropeptide Y (NPY), which is a sympathetic neurotransmitter, are elevated in cardiovascular diseases. It also has important roles in inflammatory conditions. This study aimed to explore the relationship between serum NPY and CP and to study further the influence of NPY and inflammatory factors on CP. This cross-sectional study was conducted among 300 adults who underwent a health examination at the Second Affiliated Hospital of Fujian Medical University in Fujian Province, of whom 177 were finally enrolled. The participants were divided into the CP (n = 120) and non-CP (NCP) or control (n = 57) groups according to the results of carotid artery color Doppler ultrasound. The CP group was further classified into stable plaque (SP, n = 80) and vulnerable plaque (VP, n = 40) groups based on plaque characteristics. Serum NPY and pro-inflammatory cytokine tumor necrosis factor-α (TNF-α) levels were examined. Univariate and correlation analyses were used to evaluate the correlation between serum NPY levels, pro-inflammatory cytokines, and the CP phenotype. The serum NPY and TNF-α levels of patients in the CP group were significantly higher than those in individuals from the NCP group [ (177.30 ± 43.29) pg.mL- 1 vs. (121.53 ± 40.16)pg.mL- 1, P < 0.001; (41.94 ± 14.19) pg.mL- 1 vs.(33.54 ± 13.37)pg.mL- 1, P = 0.003]. The serum NPY levels of the patients in the VP group were significantly higher than those in patients from the SP group [(191.67 ± 39.87)ng.L- 1 vs.(170.12 ± 43.37)ng.L- 1, P = 0.01, P < 0.05]. Serum TNF-α and NPY levels were positively correlated among patients from the CP group (r = 0.184, P = 0.044). The binary logistic regression analysis showed that serum NPY and TNF-α were independent influencing factors of CP [(OR = 1.029, P < 0.001);(OR = 1.030, P = 0.023)]. The area under the ROC curve of NPY predicting the CP showed statistical significance at a value of 0.819. Together, elevated serum NPY levels seem to be associated with the occurrence of coronary atherosclerosis in Chinese adults.


[Accidental methyl alcohol poisoning].
An accidental poisoning due to drinking methyl alcohol in Chaoyang county is reported, analysing the accident. The poison came from the "retail white spirit" which was contaminated with methyl alcohol. Twenty-nine persons drank the wine, fourteen of them died, two of them became blind. After drinking this "retail white spirit" the drinkers showed symptoms of vertigo, headache, weakness, vomiting, night sweat, dyspnea and blurring of vision etc. within 6-120 hours. On examining the remaining spirit, we found the content of methyl alcohol to be between 16.6 and 40.69 g/100 ml. Some of the patients' urine and blood also contained methyl alcohol. We reckoned that each one of the twenty patients had taken more than 27 g of methyl alcohol and each of the ten dead drank more than 40 ml of the alcohol.


Uncoupling of GTP hydrolysis from eIF6 release on the ribosome causes Shwachman-Diamond syndrome.
Removal of the assembly factor eukaryotic initiation factor 6 (eIF6) is critical for late cytoplasmic maturation of 60S ribosomal subunits. In mammalian cells, the current model posits that eIF6 release is triggered following phosphorylation of Ser 235 by activated protein kinase C. In contrast, genetic studies in yeast indicate a requirement for the ortholog of the SBDS (Shwachman-Bodian-Diamond syndrome) gene that is mutated in the inherited leukemia predisposition disorder Shwachman-Diamond syndrome (SDS). Here, by isolating late cytoplasmic 60S ribosomal subunits from Sbds-deleted mice, we show that SBDS and the GTPase elongation factor-like 1 (EFL1) directly catalyze eIF6 removal in mammalian cells by a mechanism that requires GTP binding and hydrolysis by EFL1 but not phosphorylation of eIF6 Ser 235. Functional analysis of disease-associated missense variants reveals that the essential role of SBDS is to tightly couple GTP hydrolysis by EFL1 on the ribosome to eIF6 release. Furthermore, complementary NMR spectroscopic studies suggest unanticipated mechanistic parallels between this late step in 60S maturation and aspects of bacterial ribosome disassembly. Our findings establish a direct role for SBDS and EFL1 in catalyzing the translational activation of ribosomes in all eukaryotes, and define SDS as a ribosomopathy caused by uncoupling GTP hydrolysis from eIF6 release.


[Low gastrointestinal bleeding due to ectopic varices as a result of adhesions].
Portal hypertension frequently causes the appearance of porto-systemic shunts, such as esophageal varices and also, but with much less frequency, other atypical shunts known as ectopic varices. Despite their infrequency/rarity, ectopic varices can cause serious gastrointestinal bleeding. Intraabdominal adhesions, especially post-operative ones, promote their appearance. The therapeutic management of ectopic varices is initially the same as that for esophageal varices but surgical treatment is usually necessary as a diagnostic and therapeutic procedure.


Hyperoxia and the cerebral hemodynamic responses to moderate hyperventilation.
A reduction in the arterial partial pressure of CO2 (PaCO2) leads to a rapid reduction in cerebral blood flow (CBF). However, despite continuing hypocapnia there is secondary recovery of CBF over time as a result of increases in lactic acid production. Hyperoxia is thought to modulate the production of lactic acid. This study examined the kinetics of middle cerebral artery flow velocity (MCA FV) reduction during hyperventilation, and its modulation by hyperoxia. Cerebral blood flow was assessed using transcranial Doppler ultrasound in nine healthy, awake human volunteers. Subjects were ventilated, via a mouthpiece, to achieve a stable end-tidal CO2 (PETCO2). After a 20-min baseline period the minute volume on the ventilator was passively increased by approximately 20% to reduce PETCO2 by 0.75-1 kPa. After a 10-min stabilization period the new PETCO2 level was maintained at a constant level for 20 min, and MCA FV recovery was measured during this 20-min period. Subjects undertook the protocol breathing air and breathing 100% oxygen. The PETCO2 level was (mean +/- SD) 4.9 +/- 0.4 kPa (normoxia baseline), 4.0 +/- 0.3 kPa (normoxia hyperventilation), 4.6 +/- 0.4 kPa (hyperoxia baseline) and 3.9 +/- 0.4 kPa (hyperoxia hyperventilation). CO2 reactivity was significantly lower with normoxia than hyperoxia (16.5 +/- 3.8 vs. 21.2 +/- 4.6 % kPa-1; P< 0.05). Middle cerebral artery FV recovery was significantly more rapid with normoxia than hyperoxia (0.23 +/- 0.17 vs. 0.08 +/- 0.1 % baseline min-1; P< 0.01). Our results suggest that cerebral hemodynamic responses to moderate hyperventilation are different in normoxic and hyperoxic conditions. Clinical assessment of CO2 reactivity and CBF recovery during hyperventilation should take the degree of arterial oxygenation into account.