Murine protein kinase CK2 alpha': cDNA and genomic cloning and chromosomal mapping.
Protein kinase CK2 (casein kinase II) is a heterotetrameric enzyme implicated in many essential regulatory pathways in cells. We have determined the sequence of the murine CK2 alpha' cDNA that encodes a 350-amino-acid protein that would have 99 and 98% homology with the human and chicken proteins, respectively, and is also highly homologous to murine CK2 alpha. To clarify the sequence of the 5' end of the cDNA and to elucidate the structure and regulation of the gene, we obtained a bacterial artificial chromosome clone that contains the 35-kb CK2 alpha' gene. The gene consists of 12 small exons; the 5' end, including the first exon and intron, is extremely GC rich and contains a CpG island. The putative promoter contains potential binding sites for a variety of transcriptional factors but appears to lack CCAAT- or TATA-like elements. A polymorphic dinucleotide repeat in the fifth intron allowed us to map the CK2 alpha' gene to murine Chromosome 8.


Myelofibrosis at diagnosis is associated with the failure of treatment-free remission in CML patients.
The management of patients with chronic myeloid leukemia (CML) has been revolutionized by the introduction of tyrosine kinase inhibitors (TKIs), which induce deep molecular responses so that treatment can eventually be discontinued, leading to treatment-free remission (TFR) in a subset of patients. Unfortunately, leukemic stem cells (LSCs) often persist and a fraction of these can again expand in about half of patients that attempt TKI discontinuation. In this study, we show that presence of myelofibrosis (MF) at the time of diagnosis is a factor associating with TFR failure. Fibrotic transformation is governed by the action of several cytokines, and interestingly, some of them have also been described to support LSC persistence. At the cellular level, these could be produced by both malignant cells and by components of the bone marrow (BM) niche, including megakaryocytes (MKs) and mesenchymal stromal cells (MSCs). In our cohort of 57 patients, around 40% presented with MF at diagnosis and the number of blasts in the peripheral blood and BM was significantly elevated in patients with higher grade of MF. Employing a CML transgenic mouse model, we could observe higher levels of alpha-smooth muscle actin (α-SMA) in the BM when compared to control mice. Short-term treatment with the TKI nilotinib, efficiently reduced spleen weight and BCR::ABL1 mRNA levels, while α-SMA expression was only partially reduced. Interestingly, the number of MKs was increased in the spleen of CML mice and elevated in both BM and spleen upon nilotinib treatment. Analysis of human CML-vs healthy donor (HD)-derived MSCs showed an altered expression of gene signatures reflecting fibrosis as well as hematopoietic support, thus suggesting MSCs as a potential player in these two processes. Finally, in our cohort, 12 patients qualified for TKI discontinuation, and here we observed that all patients who failed TFR had BM fibrosis at diagnosis, whereas this was only the case in 25% of patients with achieved TFR, further supporting the link between fibrosis and LSC persistence.


PD-1 pathway and its clinical application: A 20year journey after discovery of the complete human PD-1 gene.
Anti-PD-1 therapy is a novel immune-checkpoint inhibition therapy with tremendous potential in treating refractory/relapsed cancers. The 20year journey of human PD-1 research went through 3 phases: 1) discovering PD-1 gene structure and genomic organization, 2) understanding the mechanism of PD-1 mediated immune-checkpoint regulatory effects in coordination with its ligands (PD-L1 and L2), 3) and translating our knowledge of PD-1 gene into a robust clinical anticancer approach by targeting the PD-1 immune-checkpoint pathway. The success of human PD-1 gene study reflects the advancement and trends of modern biomedical research from the laboratory to the bedside. However, our journey of understanding the PD-1 gene is not yet complete. Clinical investigation data show a high variety of response rates among different types of cancers to PD-1 immune-checkpoint inhibition therapy, with a range of 18% to 87%. There is no reliable biomarker to predict an individual patient's response to PD-1 inhibitory immunotherapy. Patients can present with primary, adaptive, or even acquired resistance to PD-1 immune-checkpoint inhibition therapy. Furthermore, the emerging data demonstrates that certain patients experience hyperprogressive disease status after receiving PD-1 immune-checkpoint inhibition therapy. In conclusion, PD-1 immune-checkpoint inhibition therapy has opened up a new venue of advanced cancer immunotherapy. Meanwhile, further efforts are still warranted in both basic scientific mechanism studies and clinical investigation using the principles of personalized and precision medicine.


Cardiac condition during cooling and rewarming periods of therapeutic hypothermia after cardiopulmonary resuscitation.
Hypothermia has been used in cardiac surgery for many years for neuroprotection. Mild hypothermia (MH) [body temperature (BT) kept at 32-35°C] has been shown to reduce both mortality and poor neurological outcome in patients after cardiopulmonary resuscitation (CPR). This study investigated whether patients who were expected to benefit neurologically from therapeutic hypothermia (TH) also had improved cardiac function. The study included 30 patients who developed in-hospital cardiac arrest between September 17, 2012, and September 20, 2013, and had return of spontaneous circulation (ROSC) following successful CPR. Patient BTs were cooled to 33°C using intravascular heat change. Basal BT, systolic artery pressure (SAP), diastolic artery pressure (DAP), mean arterial pressure (MAP), heart rate, central venous pressure, cardiac output (CO), cardiac index (CI), global end-diastolic volume index (GEDI), extravascular lung water index (ELWI), and systemic vascular resistance index (SVRI) were measured at 36°C, 35°C, 34°C and 33°C during cooling. BT was held at 33°C for 24 hours prior to rewarming. Rewarming was conducted 0.25°C/h. During rewarming, measurements were repeated at 33°C, 34°C, 35°C and 36°C. A final measurement was performed once patients spontaneously returned to basal BT. We compared cooling and rewarming cardiac measurements at the same BTs. SAP values during rewarming (34°C, 35°C and 36°C) were lower than during cooling (P < 0.05). DAP values during rewarming (basal temperature, 34°C, 35°C and 36°C) were lower than during cooling. MAP values during rewarming (34°C, 35°C and 36°C) were lower than during cooling (P < 0.05). CO and CI values were higher during rewarming than during cooling. GEDI and ELWI did not differ during cooling and rewarming. SVRI values during rewarming (34°C, 35°C, 36°C and basal temperature) were lower than during cooling (P < 0.05). To our knowledge, this is the first study comparing cardiac function at the same BTs during cooling and rewarming. In patients experiencing ROSC following CPR, TH may improve cardiac function and promote favorable neurological outcomes.


Improving the quality of health care: using international collaboration to inform guideline programmes by founding the Guidelines International Network (G-I-N).
Clinical practice guidelines are regarded as powerful tools to achieve effective health care. Although many countries have built up experience in the development, appraisal, and implementation of guidelines, until recently there has been no established forum for collaboration at an international level. As a result, in different countries seeking similar goals and using similar strategies, efforts have been unnecessarily duplicated and opportunities for harmonisation lost because of the lack of a supporting organisational framework. This triggered a proposal in 2001 for an international guidelines network built on existing partnerships. A baseline survey confirmed a strong demand for such an entity. A multinational group of guideline experts initiated the development of a non-profit organisation aimed at promotion of systematic guideline development and implementation. The Guidelines International Network (G-I-N) was founded in November 2002. One year later the Network released the International Guideline Library, a searchable database which now contains more than 2000 guideline resources including published guidelines, guidelines under development, "guidelines for guidelines", training materials, and patient information tools. By June 2004, 52 organisations from 27 countries had joined the network including institutions from Oceania, North America, and Europe, and WHO. This paper describes the process that led to the foundation of the G-I-N, its characteristics, prime activities, and ideas on future projects and collaboration.


Endoscopic pediatric endonasal retrieval of transorbital projectile: An illustrative multimedia report.
Air guns, particularly BB (ball-bearing or bullet ball) guns, have gained significant power and velocity over the last few decades. More than 145,000 pediatric patients suffered injuries attributed to air guns in the United States between 2001 and 2011, and approximately 22,000 pediatric emergency department visits are attributed to air gun-related injuries annually (Hyak et al., 2020 [1]). This study aims to describe an effective surgical technique in addressing maxillofacial injuries caused by BB gun projectiles in the pediatric population. We present a detailed surgical approach for endoscopic endonasal retrieval of a transorbital projectile in a 13-year-old male who sustained a maxillofacial BB gun injury, with the goal of restoring sinonasal function in a minimally invasive fashion.


Sindbis virus glycoproteins are abnormally glycosylated in Chinese hamster ovary cells deprived of glucose.
We have previously demonstrated that Sindbis virus infection of Chinese hamster ovary (CHO) cells altered the protein glycosylation machinery of the cell, so that both normal, full-size (nine mannose-containing) oligosaccharides and abnormal, "truncated' (five mannose-containing) oligosaccharides are transferred from lipid-linked precursors to newly synthesized viral membrane glycoproteins. In the present studies, we have examined the precursor oligosaccharides on viral glycoproteins that were pulse-labelled with [3H]mannose in the presence or absence of glucose, since glucose starvation of uninfected CHO cells has been reported to induce synthesis of truncated precursor oligosaccharides. Pulse-labelling in the absence of glucose led to a greater than 10-fold increase in the relative amount of the truncated precursor oligosaccharides being transferred to the newly synthesized viral glycoproteins and to an apparent underglycosylation of some precursor viral polypeptides, with some asparaginyl sites not acquiring covalently linked oligosaccharides. The mature virion glycoproteins from CHO cells which were pulse-labelled in the absence of glucose and then 'chased' in the presence of glucose contained proportionately more unusual Man3GlcNAc2-size oligosaccharides. These small neutral-type oligosaccharides were apparently not as good a substrate for further processing into complex acidic-type oligosaccharides as the normal Man5GlcNAc2 intermediate that results from the full-size precursor oligosaccharides.


Systematic Review of the Relationships between 24-Hour Movement Behaviours and Health Indicators in School-Aged Children from Arab-Speaking Countries.
The Australian and Canadian 24-hour movement guidelines for children and youth synthesized studies in English and French or other languages (if able to be translated with Google translate) and found very few studies published in English from Arabic countries that examined the relationship between objectively measured sedentary behaviour (SB), sleep and physical activity (PA) and health indicators in children aged 5-12 years. The purpose of this systematic review was to investigate the relationships between 24-hour movement behaviours and health indicators in school-aged children from Arab-speaking countries. Online databases MEDLINE, EMBASE, SPORTdiscus, CINAHL, PsycINFO and Scopus were searched for English, French and Arabic studies (written in English), while Saudi Digital Library, ArabBase, HumanIndex, KSUP, Pan-Arab Academic Journal, e-Marefa, Al Manhal eLibrary and Google Scholar were searched for Arabic studies. The Grading of Recommendations Assessment, Development and Evaluation framework was used to assess the risk of bias and the quality of evidence for each health indicator. A total of 16 studies, comprising 15,346 participants from nine countries were included. These studies were conducted between 2000 and 2019. In general, low levels of PA and sleep and high SB were unfavourably associated with adiposity outcomes, behavioural problems, depression and low self-esteem. Favourable associations were reported between sleep duration and adiposity outcomes. SB was favourably associated with adiposity outcomes, withdrawn behaviour, attention and externalizing problems. PA was favourably associated with improved self-esteem and adiposity outcomes. Further studies to address the inequality in the literature in the Arab-speaking countries to understand the role of 24-hour movement behaviours and its positive influence on health outcomes across childhood are urgently needed.


Discriminatory capacity between HIV-1 and HIV-2 of the new rapid confirmation assay Geenius.
The currently used HIV confirmatory assays, Western blot and line immunoassay, are costly, complex and time-consuming. There is a need for cheaper, simpler and faster assays for use in high- and low-resource settings. Furthermore, it is necessary to differentiate between HIV-1 and HIV-2 infection due to differences in disease progression, monitoring and treatment options. Because the new Geenius HIV 1/2 Confirmatory Assay (Bio-Rad) has a European Community (CE) label, this study focused on its differentiation capacity using serum/plasma specimens from established HIV-1, HIV-2 and HIV untypable infections from the AIDS Reference Laboratory (ARL) of the Institute of Tropical Medicine (ITM) in Belgium. The results were compared with ARL's standard algorithm for diagnosis of HIV-infection and the new interpretation criteria for discrimination of the INNO-LIA HIVI/II Score, Fujirebio, Ghent, Belgium (LIA). The study showed a performance comparable to that of the reference LIA, with an overall sensitivity of 99.3% and specificity of 98%. Differentiation capacity was much better for the Geenius assay, with 93.8% of samples identified correctly as HIV-1 or HIV-2. When the new interpretation criteria for the LIA were used, the differentiation capacity of LIA increased to 98.5%. The results show that the Geenius assay is a reliable and fast alternative for the confirmation and differentiation of HIV-1 and HIV-2 infection in resource-rich and poor settings.


Impact of a pH 5 Oil-in-Water Emulsion on Skin Surface pH.
Human skin surface has a physiologically acidic pH (pHss). In cases of increased pHss, the acidity of the skin can be restored by topical formulations. We tested a pH 5 oil-in-water (O/W) emulsion for pHss regeneration and stabilization. We performed 2 experiments with 10 female study subjects in each. In both experiments, 2D imaging with luminescent sensor foils was used to determine pHss. Alkalization was reached by washing the volar forearm with a soap bar and warm running tap water for 20 min. Experiment 1: after defining the baseline pHss, we alkalized the respective area and measured pHss over a duration of 5 h, while applying emulsion every hour. Experiment 2: study subjects used the emulsion twice daily for 1 week. Then, pHss was measured before and after 5 min of washing a treated and an untreated area on the volar forearm. (1) 5 h after alkalization, the treated arm showed a significantly lower pHss than the untreated one (5.87 ± 0.03 vs. 6.05 ± 0.03); (2) after washing, the treated area had a significantly lower pHss than controls (6.13 ± 0.03 vs. 6.27 ± 0.05). The tested pH 5 O/W emulsion seems to improve regeneration and stabilization of pHss.


An atypical anatomical variation of palmar vascular pattern.
A complex variation in the pattern of blood supply to the palm of the hand was encountered during a routine dissection of a female adult cadaver. Findings were: (a) there was no communication between the superficial palmar branches of the radial and ulnar arteries (incomplete superficial palmar arch); (b) the superficial palmar branch of the radial artery coursed superficially to the thenar muscles supplying two common palmar digital arteries for adjacent sides of the thumb and index finger, thereby replacing the conventional arteria radialis indices; (c) the branch supplying the lateral side of the thumb was seen arising from the deep branch of the radial artery; (d) the superficial palmar branch of the ulnar artery supplied a branch to the medial side of the little finger, and two common palmar digital arteries for the adjacent sides of the little and ring fingers and ring and middle fingers, respectively. Familiarity with the variations in the vascular patterns resulting from a number of developmental errors remains the crucial issue for personnel engaged in reconstructive hand surgery, where these varied patterns act as pivotal points around which successful accomplishment of various advanced surgical procedures revolve.


Persistent effects of Libby amphibole and amosite asbestos following subchronic inhalation in rats.
Human exposure to Libby amphibole (LA) asbestos increases risk of lung cancer, mesothelioma, and non-malignant respiratory disease. This study evaluated potency and time-course effects of LA and positive control amosite (AM) asbestos fibers in male F344 rats following nose-only inhalation exposure. Rats were exposed to air, LA (0.5, 3.5, or 25.0 mg/m(3) targets), or AM (3.5 mg/m(3) target) for 10 days and assessed for markers of lung inflammation, injury, and cell proliferation. Short-term results guided concentration levels for a stop-exposure study in which rats were exposed to air, LA (1.0, 3.3, or 10.0 mg/m(3)), or AM (3.3 mg/m(3)) 6 h/day, 5 days/week for 13 weeks, and assessed 1 day, 1, 3, and 18 months post-exposure. Fibers were relatively short; for 10 mg/m(3) LA, mean length of all structures was 3.7 μm and 1% were longer than 20 μm. Ten days exposure to 25.0 mg/m(3) LA resulted in significantly increased lung inflammation, fibrosis, bronchiolar epithelial cell proliferation and hyperplasia, and inflammatory cytokine gene expression compared to air. Exposure to 3.5 mg/m(3) LA resulted in modestly higher markers of acute lung injury and inflammation compared to AM. Following 13 weeks exposure, lung fiber burdens correlated with exposure mass concentrations, declining gradually over 18 months. LA (3.3 and 10.0 mg/m(3)) and AM produced significantly higher bronchoalveolar lavage markers of inflammation and lung tissue cytokines, Akt, and MAPK/ERK pathway components compared to air control from 1 day to 3 months post-exposure. Histopathology showed alveolar inflammation and interstitial fibrosis in all fiber-exposed groups up to 18 months post-exposure. Positive dose trends for incidence of alveolar epithelial hyperplasia and bronchiolar/alveolar adenoma or carcinoma were observed among LA groups. Inhalation of relatively short LA fibers produced inflammatory, fibrogenic, and tumorigenic effects in rats which replicate essential attributes of asbestos-related disease in exposed humans. Fiber burden, inflammation, and activation of growth factor pathways may persist and contribute to lung tumorigenesis long after initial LA exposure. Fiber burden data are being used to develop a dosimetry model for LA fibers, which may provide insights on mode of action for hazard assessment.


[Virus in sheep's skin].
In a double sense, the ovine gamma herpesvirus type 2 (OvHV-2) is a virus in sheep's skin. Not only is it present world wide in all sheep breeds but also it causes malignant catarrhal fever (MCF) in cattle pigs, elk, and bison. OvHV-2 cannot be propagated in cell culture. Therefore, new results from OvHV-2 research are based on molecular techniques and may be summarized as follows. OvHV-2 is transmitted by respiratory routes as well as by sexual intercourse. Lambs are infected within the first few months of life. Leucocytes, primarily latently infected lymphocytes, are responsible for disseminating the virus over the entire organism. On rare occasions, virus particles could be visualized by electron microscopy in explanted lymphocyte cultures. Structural antigens were detected by immunohistology in M-cells of diseased rabbits. Immunologically and cell biologically active genes have been detected on the viral genome.The products arising from those are thought to fine balance, the number of latently infected cells in sheep and to keep them alive without causing harm. Thus, it seems that this balance has been found through co-evolution, favoring both virus and natural host. In contrast, other host species that were exclude from the process of co-evolution, are bound to fall from MCF.


Serum Leptin Levels, Nutritional Status, and the Risk of Healthcare-Associated Infections in Hospitalized Older Adults.
We aimed to determine whether serum leptin levels are predictive of the occurrence of healthcare-associated infections (HAIs) in hospitalized older patients. In a prospective cohort, 232 patients had available data for leptin and were monitored for HAIs for 3 months. Admission data included comorbidities, invasive procedures, the Mini Nutritional Assessment (MNA), BMI, leptin, albumin and C-reactive protein levels, and CD4 and CD8 T-cell counts. Multivariate logistic regression modelling was used to identify predictors of HAIs. Of the 232 patients (median age: 84.8; females: 72.4%), 89 (38.4%) experienced HAIs. The leptin level was associated with the BMI (p < 0.0001) and MNA (p < 0.0001) categories. Women who experienced HAIs had significantly lower leptin levels than those who did not (5.9 μg/L (2.6-17.7) and 11.8 (4.6-26.3), respectively; p = 0.01; odds ratio (OR) (95% confidence interval): 0.67 (0.49-0.90)); no such association was observed for men. In a multivariate analysis of the women, a lower leptin level was significantly associated with HAIs (OR = 0.70 (0.49-0.97)), independently of comorbidities, invasive medical procedures, and immune status. However, leptin was not significantly associated with HAIs after adjustments for malnutrition (p = 0.26) or albuminemia (p = 0.15)-suggesting that in older women, the association between serum leptin levels and subsequent HAIs is mediated by nutritional status.


Trends in total mortality and mortality from heart disease in 26 countries from 1950 to 1978.
Death rates for total mortality and for non-rheumatic heart disease and hypertension ('heart disease') are described for men and women ages 45-64 in six time periods during 1950-78 for 26 countries. Rates for men in high-rate countries are three times those in low-rate countries. This variation is more striking for men than women. There were marked increases for heart disease in men in most countries, but in 13 countries there was a slowing or reversal of that trend in the 1960's or 1970's or acceleration of an already downward trend. In 22 countries long-term declines for heart disease occurred in women. There was a widening of the north/south gradient in Europe and of the male/female ratio of heart disease mortality. Countries with high heart disease death rates in men had high ratios of heart disease to total death. Other countries experienced a rise in proportionate mortality. In women, proportionate mortality for heart disease remained flat or declined in most countries. In spite of these changes in rates, each country seems to have a range for heart disease mortality that is characteristic of its population and environmental setting so that profound changes in rates do not substantially alter their relative ranking. Our intent is to stimulate the search for reasons why heart disease mortality recently declined in some countries but not in others (already begun in the WHO-sponsored MONICA programme). Our forthcoming monograph on international mortality trends for the major causes of death will be a next step in this process.


UDP-glucuronosyltransferase (UGT1A1*28 and UGT1A6*2) polymorphisms in Caucasians and Asians: relationships to serum bilirubin concentrations.
Polymorphisms that alter UDP-glucuronosyltransferase (UGT) activities have been identified. Mutations in the promoter of the UGT1A1 gene (UGT1A1*28), resulting in 5, 7 or 8, instead of 6 thymine-adenine (TA) repeats, alter bilirubin conjugation. Two missense mutations on one allele of UGT1A6 (UGT1A6*2) result in T181A and R184S amino acid substitutions and reduced activity against phenolics, such as 4-nitrophenol, 4-hydroxycoumarin and butylated hydroxy anisole. We determined the frequency of these polymorphisms in 245 healthy men and women, aged 20-40 years and examined the relationship between TA repeat number and serum bilirubin concentrations in a subset of 24 Asians and 169 Caucasians. The frequencies of the UGT1A1*28 genotypes were 0.537, 0.348, 0.098, 0.008 and 0.008 for promoter TA repeats 6/6, 6/7, 7/7, 5/6 and 6/8, respectively. Both allele and genotype frequencies varied by race (P < 0.02), with 11% of the Caucasians and none of the Asians having the 7/7 genotype. Within both ethnic groups, serum bilirubin increased with increased numbers of UGT1A1 promoter TA repeats (P = 0.0001). However, a strong ethnic group-by-UGT1A1 genotype interaction suggests that additional ethnic differences in bilirubin metabolism contribute to observed bilirubin concentrations. Genotype frequencies for UGT1A6*2 were 0.478, 0.392, 0.029, 0.090, 0.012 for wild-type (wt)/wt, wt/T181A + R184S, wt/R184S, T181A + R184S/T181A + R184S and T181A + R184S/R184S, respectively. The co-occurrence of polymorphisms in UGT1A1 and UGT1A6 differed from that expected (P < 0.0001): individuals homozygous wild-type for UGT1A1 and UGT1A6 were observed at twice the expected frequency; individuals homozygous variant for both genes were ten-fold more frequent and individuals homozygous wild-type for one gene and homozygous variant for the other were ten-fold less frequent than expected. Overall, 8% were homozygous variant for both UGT1 polymorphisms and 43% had at least one variant allele for both UGT1A1*28 and UGT1A6*2. These highly prevalent polymorphisms, which result in modified expression and activity of UGTs, may influence susceptibility to cancers associated with altered metabolism of endogenous and xenobiotic compounds.


Relationship among interpersonal stressors in adolescence, social support buffers, and obesity in adulthood 14 years later.
Early life stress may be linked to adult obesity. Alternatively, social support can buffer the effects of stress. The study's objective was to examine in a nationally representative sample, whether adolescent interpersonal and financial stress predict later obesity in adulthood and whether social support and social cohesion might buffer this effect. The sample includes 6,504 participants across four waves in the Add Health dataset. Researchers created a structural equation model whereby latent measures of interpersonal stress and financial stress during adolescence were used to predict obesity (Body Mass Index, BMI ≥ 30) at Wave 4, 14 years later. Latent measures of social support and social cohesion were added to observe whether they buffered the effect of stress on adult BMI. Covariates included race/ethnicity, gender, self-rated health, smoking status, and age. In an initial model of interpersonal and financial stressors and covariates predicting BMI, interpersonal stress (p < .001) but not financial stress (p > .05) predicted adult BMI. In the full model including stressors, buffers and covariates, social support (p < .001) and social cohesion (p = .038) negatively predicted adult BMI, and they covaried with interpersonal stress in opposing directions, buffering the effects of interpersonal stress on adult BMI. Stressful interpersonal life events in adolescence such as having family members in jail or being the victim of a crime are linked to adult obesity 14 years later. However, these stress effects are buffered by the effects of social support and social cohesion, which are linked to lower adult BMI. (PsycInfo Database Record (c) 2022 APA, all rights reserved).


Differentiation of the peptidergic vasoregulatory response to standardized splanchnic hypoperfusion by acute hypovolaemia or sepsis in anaesthetized pigs.
This study was performed to integratively investigate the vasoregulatory response during standardized splanchnic hypoperfusion in pigs. Splanchnic perfusion was reduced to 50% of baseline by: haemorrhage by 20 and 40% of the estimated total blood volume; femoral venous infusion of live E. coli to establish sepsis of systemic origin; portal venous infusion of live E. coli to establish sepsis of splanchnic origin. Invasive haemodynamic monitoring and radioimmunoassay analyses of arterial plasma concentrations of angiotensin II, endothelin-1 and atrial natriuretic peptide were carried out. Acute hypovolaemia reduced systemic and splanchnic vascular resistances following transient increases and increased angiotensin II levels (+587%), whereas endothelin-1 and atrial natriuretic peptide levels did not change significantly. Systemic sepsis following femoral venous infusion of E. coli resulted in increased splanchnic vascular resistance and increased levels of angiotensin II (+274%), endothelin-1 (+134%) and atrial natriuretic peptide (+185%). Infusion of E. coli via the portal venous route induced an increase in splanchnic vascular resistance associated with particularly elevated levels of angiotensin II (+1770%) as well as increased endothelin-1 (+201%) and atrial natriuretic peptide (+229%) concentrations. Hypovolaemia and sepsis, although standardized with a predefined level of splanchnic hypoperfusion, elicited differentiated cardiovascular and vasopeptidergic responses. Sepsis, particularly of portal origin, notably increased splanchnic vascular resistance related to increased production of the vasoconstrictors angiotensin II and endothelin-1. The role of atrial natriuretic peptide as a vasodilator seems to be of subordinate importance in hypovolaemia and sepsis.


Matrix Gla protein inhibition of tooth mineralization.
Extracellular matrix (ECM) mineralization is regulated by mineral ion availability, proteins, and other molecular determinants. To investigate protein regulation of mineralization in tooth dentin and cementum, and in alveolar bone, we expressed matrix Gla protein (MGP) ectopically in bones and teeth in mice, using an osteoblast/odontoblast-specific 2.3-kb Col1a1 promoter. Mandibles were analyzed by radiography, micro-computed tomography, light microscopy, histomorphometry, and transmission electron microscopy. While bone and tooth ECMs were established in the Col1a1-Mgp mice, extensive hypomineralization was observed, with values of unmineralized ECM from four- to eight-fold higher in dentin and alveolar bone when compared with that in wild-type tissues. Mineralization was virtually absent in tooth root dentin and cellular cementum, while crown dentin showed "breakthrough" areas of mineralization. Acellular cementum was lacking in Col1a1-Mgp teeth, and unmineralized osteodentin formed within the pulp. These results strengthen the view that bone and tooth mineralization is critically regulated by mineralization inhibitors.


Electrical synapses and synchrony: the role of intrinsic currents.
Electrical synapses are ubiquitous in the mammalian CNS. Particularly in the neocortex, electrical synapses have been shown to connect low-threshold spiking (LTS) as well as fast spiking (FS) interneurons. Experiments have highlighted the roles of electrical synapses in the dynamics of neuronal networks. Here we investigate theoretically how intrinsic cell properties affect the synchronization of neurons interacting by electrical synapses. Numerical simulations of a network of conductance-based neurons randomly connected with electrical synapses show that potassium currents promote synchrony, whereas the persistent sodium current impedes it. Furthermore, synchrony varies with the firing rate in qualitatively different ways depending on the intrinsic currents. We also study analytically a network of quadratic integrate-and-fire neurons. We relate the stability of the asynchronous state of this network to the phase-response function (PRF), which characterizes the effect of small perturbations on the firing timing of the neurons. In particular, we show that the greater the skew of the PRF toward the first half of the period, the more stable the asynchronous state. Combining our simulations with our analytical results, we establish general rules to predict the dynamic state of large networks of neurons coupled with electrical synapses. Our work provides a natural explanation for surprising experimental observations that blocking electrical synapses may increase the synchrony of neuronal activity. It also suggests different synchronization properties for LTS and FS cells. Finally, we propose to further test our predictions in experiments using dynamic clamp techniques.


T cell senescence and cardiovascular diseases.
Age-related changes in the immune system, commonly termed "immunosenescence," contribute to deterioration of the immune response and fundamentally impact the health and survival of elderly individuals. Immunosenescence affects both the innate and adaptive immune systems; however, the most notable changes are in T cell immunity and include thymic involution, the collapse of T cell receptor (TCR) diversity, an imbalance in T cell populations, and the clonal expansion of senescent T cells. Senescent T cells have the ability to produce large quantities of proinflammatory cytokines and cytotoxic mediators; thus, they have been implicated in the pathogenesis of many chronic inflammatory diseases. Recently, an increasing body of evidence has suggested that senescent T cells also have pathogenic potential in cardiovascular diseases, such as hypertension, atherosclerosis, and myocardial infarction, underscoring the detrimental roles of these cells in various chronic inflammatory responses. Given that cardiovascular disease is the number one cause of death worldwide, there is great interest in understanding the contribution of age-related immunological changes to its pathogenesis. In this review, we discuss general features of age-related alterations in T cell immunity and the possible roles of senescent T cells in the pathogenesis of cardiovascular disease.


Trends in pregnancy rates among women with human immunodeficiency virus.
To describe factors associated with pregnancy and trends in pregnancy rates among women with human immunodeficiency virus (HIV) before and after the release of U.S. Public Health Service Guidelines for the Use of Zidovudine and the Increased Availability of Highly Active Antiretroviral Therapy. Human immunodeficiency virus (HIV)-infected women aged 15 to 44 years who were enrolled in the Adult/Adolescent Spectrum of HIV Disease Project, a medical records cohort study of HIV-infected persons conducted in more than 100 U.S. health care facilities. Among 8857 women, there were 1185 incident pregnancies during 21617 person-years of follow-up from 1992 through 2001. Pregnancy rate at enrollment was 16%; thereafter, an average of 5.5% of women became pregnant annually. Pregnancies were more likely to occur in women aged 15 to 24 years (adjusted rate ratio [RR] 9.2; 95% confidence interval [CI] 7.4, 11.3) and 25 to 34 years (adjusted RR 4.0; 95% CI 3.3, 4.9) than in women aged 35 to 44 years. Pregnancies were less likely to occur in women with a history of acquired immunodeficiency syndrome (AIDS)-opportunistic illness (adjusted RR 0.4; 95% CI 0.3, 0.5) or a CD4 count below 200 cells/microL and no opportunistic illness (adjusted RR 0.6; 95% CI 0.5, 0.7) than in women with HIV but not AIDS. Higher rates of pregnancy were observed for women prescribed highly active antiretroviral therapy (adjusted RR 1.3; 95% CI 1.0, 1.6) than women prescribed other regimens of antiretroviral therapy. There were significantly higher rates of pregnancy during 1997 through 2001. The increase in pregnancy rates during the era of widespread use of highly active antiretroviral therapy illustrates the continued need for comprehensive prevention and treatment services. II-2


Changes in lung ultrasound of symptomatic healthcare professionals with COVID-19 pneumonia and their association with clinical findings.
To evaluate ultrasound signs of coronavirus disease-19 (COVID-19) pneumonia in symptomatic healthcare professionals and to correlate those changes with clinical findings. All patients underwent real-time polymerase chain reaction (RT-PCR), lung ultrasound (LUS) and clinical evaluation on the same day. In each of the 12 areas evaluated in the LUS, the LUS signs were scored to generate the aeration score. A total of 409 participants had positive PCR, with a median age of 41 (35-51) years. All participants had clinical symptoms, with cough in 84.1%, fever in 69.7%, and dyspnea in 36.2% of cases. In the LUS, 72.6% of participants had B-lines >2, 36.2% had coalescent B-lines, and 8.06% had subpleural consolidations. The median aeration score was 3 (2-7). The aeration score differed significantly regarding the presence of cough (P = .002), fever (P = .001), and dyspnea (P < .0001). The finding of subpleural consolidations in the LUS showed significant differences between participants with or without dyspnea (P < .0001). In healthcare professionals with COVID-19, LUS plays a key role in the characterization of lung involvement. Although B-lines are the most common ultrasound sign, subpleural consolidations are those that most impact the respiratory condition.


Sentinel Node Procedure in Prostate Cancer: A Systematic Review to Assess Diagnostic Accuracy.
Extended pelvic lymph node dissection (ePLND) is the gold standard for detecting lymph node (LN) metastases in prostate cancer (PCa). The benefit of sentinel node biopsy (SNB), which is the first draining LN as assessed by imaging of locally injected tracers, remains controversial. To assess the diagnostic accuracy of SNB in PCa. A systematic literature search of Medline, Embase, and the Cochrane Library (1999-2016) was undertaken using PRISMA guidelines. All studies of SNB in men with PCa using PLND as reference standard were included. The primary outcomes were the nondiagnostic rate (NDR), sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and false positive (FP) and false negative (FN) rates. Relevant sensitivity analyses based on SN definitions, ePLND as reference standard, and disease risk were undertaken, including a risk of bias (RoB) assessment. Of 373 articles identified, 21 studies recruiting a total of 2509 patients were eligible for inclusion. Median cumulative percentage (interquartile range) results were 4.1% (1.5-10.7%) for NDR, 95.2% (81.8-100%) for sensitivity, 100% (95.0-100%) for specificity, 100% (87.0-100%) for PPV, 98.0% (94.3-100%) for NPV, 0% (0-5.0%) for the FP rate, and 4.8% (0-18.2%) for the FN rate. The findings did not change significantly on sensitivity analyses. Most studies (17/22) had low RoB for index test and reference standard domains. SNB appears to have diagnostic accuracy comparable to ePLND, with high sensitivity, specificity, PPV and NPV, and a low FN rate. With a low FP rate (rate of detecting positive nodes outside the ePLND template), SNB may not have any additional diagnostic value over and above ePLND, although SNB appears to increase nodal yield by increasing the number of affected nodes when combined with ePLND. Thus, in high-risk disease it may be prudent to combine ePLND with SNB. This literature review showed a high diagnostic accuracy for sentinel node biopsy in detecting positive lymph nodes in prostate cancer, but further studies are needed to explore the effect of sentinel node biopsy on complications and oncologic outcome.


Twelve fundamental life histories evolving through allocation-dependent fecundity and survival.
An organism's life history is closely interlinked with its allocation of energy between growth and reproduction at different life stages. Theoretical models have established that diminishing returns from reproductive investment promote strategies with simultaneous investment into growth and reproduction (indeterminate growth) over strategies with distinct phases of growth and reproduction (determinate growth). We extend this traditional, binary classification by showing that allocation-dependent fecundity and mortality rates allow for a large diversity of optimal allocation schedules. By analyzing a model of organisms that allocate energy between growth and reproduction, we find twelve types of optimal allocation schedules, differing qualitatively in how reproductive allocation increases with body mass. These twelve optimal allocation schedules include types with different combinations of continuous and discontinuous increase in reproduction allocation, in which phases of continuous increase can be decelerating or accelerating. We furthermore investigate how this variation influences growth curves and the expected maximum life span and body size. Our study thus reveals new links between eco-physiological constraints and life-history evolution and underscores how allocation-dependent fitness components may underlie biological diversity.


Biomaterial-Assisted Regenerative Medicine.
This review aims to show case recent regenerative medicine based on biomaterial technologies. Regenerative medicine has arousing substantial interest throughout the world, with "The enhancement of cell activity" one of the essential concepts for the development of regenerative medicine. For example, drug research on drug screening is an important field of regenerative medicine, with the purpose of efficient evaluation of drug effects. It is crucial to enhance cell activity in the body for drug research because the difference in cell condition between in vitro and in vivo leads to a gap in drug evaluation. Biomaterial technology is essential for the further development of regenerative medicine because biomaterials effectively support cell culture or cell transplantation with high cell viability or activity. For example, biomaterial-based cell culture and drug screening could obtain information similar to preclinical or clinical studies. In the case of in vivo studies, biomaterials can assist cell activity, such as natural healing potential, leading to efficient tissue repair of damaged tissue. Therefore, regenerative medicine combined with biomaterials has been noted. For the research of biomaterial-based regenerative medicine, the research objective of regenerative medicine should link to the properties of the biomaterial used in the study. This review introduces regenerative medicine with biomaterial.


Accuracy of an expanded early warning score for patients in general and trauma surgery wards.
Early warning scores (EWS) may aid the prediction of major adverse events in hospitalized patients. Recently, an expanded EWS was introduced in the Netherlands. The aim of this study was to assess the relationship between this EWS and the occurrence of major adverse clinical events during hospitalization of patients admitted to a general and trauma surgery ward. This was a prospective cohort study of consecutive patients admitted to the general and trauma surgery ward of a university medical centre (March-September 2009). Follow-up was limited to the time the patient was hospitalized. Logistic regression analysis was used to assess the relationship between the EWS and the occurrence of the composite endpoint consisting of death, reanimation, unexpected intensive care unit admission, emergency surgery and severe complications. Performance of the EWS was analysed using sensitivity, specificity, predictive values and receiver operating characteristic (ROC) curves. A total of 572 patients were included. During a median follow-up of 4 days, 46 patients (8.0 per cent) reached the composite endpoint (two deaths, two reanimations, 17 intensive care unit admissions, 44 severe complications, one emergency operation). An EWS of at least 3, adjusted for baseline American Society of Anesthesiology classification, was associated with a significantly higher risk of reaching the composite endpoint (odds ratio 11·3, 95 per cent confidence interval (c.i.) 5·5 to 22·9). The area under the ROC curve was 0·87 (95 per cent c.i. 0·81 to 0·93). When considering an EWS of at least 3 to be a positive test result, sensitivity was 74 per cent and specificity was 82 per cent. An EWS of 3 or more is an independent predictor of major adverse events in patients admitted to a general and trauma surgery ward.


Generation and properties of the glycoprotein E-related 32K/34K/35K and 55K/57K polypeptides encoded by herpes simplex virus type 1.
A hybridoma line was isolated which produced antibody reacting with polypeptides of apparent molecular weights 32,000, 34,000 and 35,000 (32K/34K/35K) and 55,000 and 57,000 (55K/57K). These were sulphated glycoproteins that have previously been found in the medium of herpes simplex virus type 1 (HSV-1)-infected cells. By tryptic peptide mapping and serological cross-reactions the polypeptides were shown to be related to HSV-1 glycoprotein E (gE-1) but they lacked the Fc binding function. The 32K/34K/35K and 55K/57K polypeptides were not found in the medium of HSV-1-infected cells incubated in serum-free medium. They could be generated in vitro from purified gE-1 in the presence of serum. It is likely that 32K/34K/35K and 55K/57K are derived from gE-1 by the action of serum proteases.


Bisphenol A reveals its obesogenic effects through disrupting glucose tolerance, oxidant-antioxidant balance, and modulating inflammatory cytokines and fibroblast growth factor in zebrafish.
Obesogens affect lipid metabolism, and genetic or epigenetic factors may also contribute to the progression of obesity. Endocrine-disrupting chemicals (EDCs) are the most striking among obesogens. Bisphenol A (BPA) is an estrogenic EDC used in food containers, adhesives, dye powders, and dental fillers. We aimed to elucidate molecular mechanisms of BPA's obesogenic effects focusing on obesogenic pathways in the liver including fibroblast growth factor (FGF) and Dnmt3a which is its epigenetic regulator, oxidant-antioxidant status, and inflammatory cytokines. Zebrafish were divided into three groups as control, low-dose BPA (1 μm BPA), and high-dose BPA groups (10 μm BPA). At the end of 30 days, oral glucose tolerance test (OGTT) was performed, fasting blood glucose levels were measured, and hepatopancreas tissues were taken. Malondialdehyde (MDA) levels, superoxide dismutase (SOD), glutathione S-transferase (GST), and nitric oxide (NO) activities were examined in the hepatopancreas. Inflammatory cytokines, lepa, fgf21, and dnmt3a expressions were determined by RT-PCR. BPA exposure increased the body weights, il1ß, tnfα, il6, lepa, fgf21, and dnmt3a expressions, impaired glucose tolerance, and oxidant-antioxidant status in a dose-dependent manner. Hepatocyte degeneration, lipid vacuolization, and vasocongestion were observed in both BPA-exposed groups. Our study suggests impaired glucose tolerance, oxidant-antioxidant balance, increased inflammatory response, fgf21 expression, and dnmt3a expressions as the possible mechanisms for the BPA-induced obesity model in zebrafish.


Linkage to chromosome 2q32.2-q33.3 in familial serrated neoplasia (Jass syndrome).
Causative genetic variants have to date been identified for only a small proportion of familial colorectal cancer (CRC). While conditions such as Familial Adenomatous Polyposis and Lynch syndrome have well defined genetic causes, the search for variants underlying the remainder of familial CRC is plagued by genetic heterogeneity. The recent identification of families with a heritable predisposition to malignancies arising through the serrated pathway (familial serrated neoplasia or Jass syndrome) provides an opportunity to study a subset of familial CRC in which heterogeneity may be greatly reduced. A genome-wide linkage screen was performed on a large family displaying a dominantly-inherited predisposition to serrated neoplasia genotyped using the Affymetrix GeneChip Human Mapping 10 K SNP Array. Parametric and nonparametric analyses were performed and resulting regions of interest, as well as previously reported CRC susceptibility loci at 3q22, 7q31 and 9q22, were followed up by finemapping in 10 serrated neoplasia families. Genome-wide linkage analysis revealed regions of interest at 2p25.2-p25.1, 2q24.3-q37.1 and 8p21.2-q12.1. Finemapping linkage and haplotype analyses identified 2q32.2-q33.3 as the region most likely to harbour linkage, with heterogeneity logarithm of the odds (HLOD) 2.09 and nonparametric linkage (NPL) score 2.36 (P = 0.004). Five primary candidate genes (CFLAR, CASP10, CASP8, FZD7 and BMPR2) were sequenced and no segregating variants identified. There was no evidence of linkage to previously reported loci on chromosomes 3, 7 and 9.


Incidence of Antimicrobial-Associated Acute Kidney Injury in Children: A Structured Review.
Acute kidney injury (AKI) is a commonly reported adverse effect of administration of antimicrobials. While AKI can be associated with poorer outcomes, there is little information available to understand rates of AKI in children exposed to various antimicrobials. We performed a structured review using the PubMed and Embase databases. Articles were included if they provided an AKI definition in patients who were < 19 years of age receiving an antimicrobial and reported the frequency of AKI. Author-defined AKI rates were calculated for each study and mean pooled estimates for each antimicrobial were derived from among all study participants. Pooled estimates were also derived for those studies that reported AKI according to pRIFLE (pediatric risk, injury, failure, loss, end stage criteria), AKIN (acute kidney injury network), or KDIGO (kidney disease improving global outcomes) creatinine criteria. A total of 122 studies evaluating 28 antimicrobials met the inclusion criteria. Vancomycin was the most commonly studied drug: 11,514 courses across 44 included studies. Among the 27,285 antimicrobial exposures, the overall AKI rate was 13.2% (range 0-42.1% by drug), but the rate of AKI varied widely across studies (range 0-68.8%). Cidofovir (42.1%) and conventional amphotericin B (37.0%) had the highest pooled rates of author-defined AKI. Eighty-one studies used pRIFLE, AKIN, or KDIGO AKI criteria and the pooled rates of AKI were similar to author-defined AKI rates. In conclusion, antimicrobial-associated AKI is reported to occur frequently in children, but the rates of AKI varies widely across studies and drugs. Most published studies examined hospitalized patients and heterogeneity in study populations and in author definitions of AKI are barriers to a comparison of nephrotoxicity risk among antimicrobials in children.


POPULATION DYNAMICS OF BRUCELLA ON SOLID MEDIA.
An examination is presented of the growth characteristics on solid media of one strain each of Brucella abortus and B. neotomae. It was observed that, during the exponential growth phase, generation times of approximately 100 min were measured for both organisms under a variety of conditions. The logarithmic growth phase did not extend beyond 18 hr in most instances. It was noted that erythritol added to Trypticase Soy Agar did not enhance the growth rate or the total viable yield of either organism. Phosphate buffer failed to exert a significant effect upon pH changes during culture. B. neotomae cultures on solid media produced markedly acidic reactions in 48 hr. If cells in an active growth phase are desired, it is suggested that solid media cultures of laboratory strains be harvested before 24 hr.


Mammalian tyrosinase catalyzes three reactions in the biosynthesis of melanin.
The biosynthesis of melanin is initiated by the catalytic oxidation of tyrosine to dopa by tyrosinase in a reaction that requires dopa as a cofactor. Tyrosine then catalyzes the dehydrogenation of dopa to dopaquinone. The subsequent reactions can proceed spontaneously in vitro. Tyrosinase, purified from murine melanomas and the skins of brown mice, has now been shown to catalyze a third reaction in mammalian melanogenesis, namely the conversion of 5,6-dihydroxyindile to melanochrome. This reaction requires dopa as a cofactor and is inhibited by tyrosine. Conversely, 5,6-dihydroxyindole inhibits the oxidation of tyrosine to dopa, so that the relative concentrations of tyrosine and 5,6-dihydroxyindole within the mammalian pigment cell are capable of regulating melanogenesis in a previously unrecognized fashion. Tyrosinase has the unusual property of catalyzing three distinct reactions within a single biochemical pathway: the hydroxylation of a monophenol, the dehydrogenation of a catechol, and the dehydrogenation of a dihydroxyindole. The first and third of these reactions require dopa as a cofactor; in the second reaction, dopa is a substrate.


Functional specializations in human cerebral cortex analyzed using the visible man surface-based atlas.
We used surface-based representations to analyze functional specializations in the human cerebral cortex. A computerized reconstruction of the cortical surface of the Visible Man digital atlas was generated and transformed to the Talairach coordinate system. This surface was also flattened and used to establish a surface-based coordinate system that respects the topology of the cortical sheet. The linkage between two-dimensional and three-dimensional representations allows the locations of published neuroimaging activation foci to be stereotaxically projected onto the Visible Man cortical flat map. An analysis of two activation studies related to the hearing and reading of music and of words illustrates how this approach permits the systematic estimation of the degree of functional segregation and of potential functional overlap for different aspects of sensory processing.


Basic considerations in organ perfusion physiology.
Owing to a severe shortage of organs for patients with end-stage diseases, novel techniques in organ preservation and perfusion need to be studied and reviewed to increase the number of available organs for transplant. Many patients will die while waiting for an organ. To make organs from extended-criteria donors feasible, optimal conditions for pulsatile perfusion and the potential for organ reconditioning at implantation need to be addressed. Many techniques in organ preservation and perfusion are being studied. Several laboratories are studying the effects of temperature for organ perfusion. Two areas being studied are hypothermic and normothermic machine perfusion. In the area of organ preservation, new solutions are being studied such as a substrate-enriched, oxygen-saturated, and leukocyte-depleted perfusate to help with organ quality. Even with the strides being made in organ preservation and perfusion, there are still many unanswered questions. More studies will need to be done to find the optimal conditions for duration of perfusion in the cold phase, optimal perfusion solution, degree of oxygenation, and the addition of pharmacologic agents, to improve organ function and expand the organ pool.


Rapid modulation of cortical proprioceptive activity induced by transient cutaneous deafferentation: neurophysiological evidence of short-term plasticity across different somatosensory modalities in humans.
Single cell recording in non-human primates shows plastic changes of cortical somatic representations across different types of somatic inputs originating from the same peripheral territory. In humans, muscle afferents from first dorsal interosseus are supplied by the ulnar nerve while the cutaneous territory overlying this muscle is supplied by the radial nerve. This peculiar anatomical nervous distribution allowed us to devise an experimental model which provided a unique opportunity to assess, in humans with a non-invasive technique, the functional relationships between cutaneous and muscle afferent inputs originating from the same peripheral territory. We recorded spinal, brainstem and cortical somatosensory potentials evoked by stimulation of muscle afferents of the right first dorsal interosseus before, during and after anaesthetic block of the sensitive branch of the ipsilateral radial nerve. Amplitude of parietal N20 and P27 and frontal N30 somatosensory evoked potential components showed an increase of amplitudes with more profound anaesthesia. Amplitudes returned to pre-anaesthetic values several minutes after anaesthesia. By contrast, spinal N13 and brainstem P14 potentials did not change throughout the experiment. Results show, for the first time in humans, that a transient cutaneous deafferentation may induce rapid modulation of cortical activity evoked by stimulation of muscle afferents originating in the anaesthetic territory.


Structural and biochemical analysis reveal pirins to possess quercetinase activity.
Pirin is a recently identified eukaryotic protein implicated in transcriptional activation and apoptosis. Homologues of Pirin are highly conserved in both prokaryotes and eukaryotes, but their function remains poorly understood. We present here the crystal structure of the yhhW gene product, a putative Pirin homologue, from Escherichia coli and confirm its structural similarity to Pirin. The YhhW protein displays a bicupin fold with a single N-terminal metal coordination site. Molecular surface comparisons of YhhW and Pirin with structurally similar proteins suggested quercetin as a potential ligand. We demonstrate that both bacterial and human Pirins have quercetinase activity, which is inhibited by the addition of typical inhibitors of the quercetin 2,3-dioxygenase reaction. We also demonstrate the release of carbon monoxide as a reaction product. This is the first report of enzymatic activity for any member of the Pirin family and may be an important connection to their roles in transcriptional regulation.


Plasma and Red Blood Cell PUFAs in Home Parenteral Nutrition Paediatric Patients-Effects of Lipid Emulsions.
Background: Mixed lipid emulsions (LE) containing fish oil present several advantages compared to the sole soybean oil LE, but little is known about the safety of essential fatty acids (EFA) profile in paediatric patients on long-term Parenteral Nutrition (PN). Aim of the study: to assess glycerophosfolipid polyunsaturated fatty acids (PUFA) levels on plasma and red blood cell (RBC) membrane of children on long term PN with composite LE containing fish oil (SMOF), and to compare it with a group receiving olive oil LE (Clinoleic®) and to the reference range for age, previously determined on a group of healthy children. Results: A total of 38 patients were enrolled, median age 5.56 (0.9-21.86) years, 15 receiving Clinoleic®, 23 receiving SMOF. Patients on SMOF showed significantly higher levels of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), lower levels of arachidonic acid (ARA) and Mead acid (MEAD)/ARA ratio in plasma and RBC compared with patients on Clinoleic® and with healthy children. Triene:tetraene (T:T) ratio of both groups of patients did not differ from that of healthy children-median plasma (MEAD/ARA: 0.01, interquartile rage (IQR) 0.01, p = 0.61 and 0.02, IQR 0.02, p = 0.6 in SMOF and Clinoleic® patients, respectively), and was considerably lower than Holman index (>0.21). SMOF patients showed no statistically significant differences in growth parameters compared with Clinoleic® patients. Patients of both groups showed stiffness class F0-F1 of liver stiffness measure (LSM) 5.6 (IQR 0.85) in SMOF patients and 5.3 (IQR 0.90) in Clinoleic® patients, p = 0.58), indicating absence of liver fibrosis. Conclusions: Fatty acids, measured as concentrations (mg/L), revealed specific PUFA profile of PN patients and could be an accurate method to evaluate nutritional status and eventually to detect essential fatty acid deficiency (EFAD). SMOF patients showed significantly higher EPA, DHA and lower ARA concentrations compared to Clinoleic® patients. Both LEs showed similar hepatic evolution and growth.


Zwitterionic and cationic bis(phosphine) platinum(II) complexes: structural, electronic, and mechanistic comparisons relevant to ligand exchange and benzene C-H activation processes.
Structurally similar but charge-differentiated platinum complexes have been prepared using the bidentate phosphine ligands [Ph(2)B(CH(2)PPh(2))(2)], ([Ph(2)BP(2)], [1]), Ph(2)Si(CH(2)PPh(2))(2), (Ph(2)SiP(2), 2), and H(2)C(CH(2)PPh(2))(2), (dppp, 3). The relative electronic impact of each ligand with respect to a coordinated metal center's electron-richness has been examined using comparative molybdenum and platinum model carbonyl and alkyl complexes. Complexes supported by anionic [1] are shown to be more electron-rich than those supported by 2 and 3. A study of the temperature and THF dependence of the rate of THF self-exchange between neutral, formally zwitterionic [Ph(2)BP(2)]Pt(Me)(THF) (13) and its cationic relative [(Ph(2)SiP(2))Pt(Me)(THF)][B(C(6)F(5))(4)] (14) demonstrates that different exchange mechanisms are operative for the two systems. Whereas cationic 14 displays THF-dependent, associative THF exchange in benzene, the mechanism of THF exchange for neutral 13 appears to be a THF independent, ligand-assisted process involving an anchimeric, eta(3)-binding mode of the [Ph(2)BP(2)] ligand. The methyl solvento species 13, 14, and [(dppp)Pt(Me)(THF)][B(C(6)F(5))(4)] (15), each undergo a C-H bond activation reaction with benzene that generates their corresponding phenyl solvento complexes [Ph(2)BP(2)]Pt(Ph)(THF) (16), [(Ph(2)SiP(2))Pt(Ph)(THF)][B(C(6)F(5))(4)] (17), and [(dppp)Pt(Ph)(THF)][B(C(6)F(5))(4)] (18). Examination of the kinetics of each C-H bond activation process shows that neutral 13 reacts faster than both of the cations 14 and 15. The magnitude of the primary kinetic isotope effect measured for the neutral versus the cationic systems also differs markedly (k(C(6)H(6))/k(C(6)D(6)): 13 = 1.26; 14 = 6.52; 15 approximately 6). THF inhibits the rate of the thermolysis reaction in all three cases. Extended thermolysis of 17 and 18 results in an aryl coupling process that produces the dicationic, biphenyl-bridged platinum dimers [[(Ph(2)SiP(2))Pt](2)(mu-eta(3):eta(3)-biphenyl)][B(C(6)F(5))(4)](2) (19) and [[(dppp)Pt](2)(mu-eta(3):eta(3)-biphenyl)][B(C(6)F(5))(4)](2) (20). Extended thermolysis of neutral [Ph(2)BP(2)]Pt(Ph)(THF) (16) results primarily in a disproportionation into the complex molecular salt [[Ph(2)BP(2)]PtPh(2)](-)[[Ph(2)BP(2)]Pt(THF)(2)](+). The bulky phosphine adducts [Ph(2)BP(2)]Pt(Me)[P(C(6)F(5))(3)] (25) and [(Ph(2)SiP(2))Pt(Me)[P(C(6)F(5))(3)]][B(C(6)F(5))(4)] (29) also undergo thermolysis in benzene to produce their respective phenyl complexes, but at a much slower rate than for 13-15. Inspection of the methane byproducts from thermolysis of 13, 14, 15, 25, and 29 in benzene-d(6) shows only CH(4) and CH(3)D. Whereas CH(3)D is the dominant byproduct for 14, 15, 25, and 29, CH(4) is the dominant byproduct for 13. Solution NMR data obtained for 13, its (13)C-labeled derivative [Ph(2)BP(2)]Pt((13)CH(3))(THF) (13-(13)()CH(3)()), and its deuterium-labeled derivative [Ph(2)B(CH(2)P(C(6)D(5))(2))(2)]Pt(Me)(THF) (13-d(20)()), establish that reversible [Ph(2)BP(2)]-metalation processes are operative in benzene solution. Comparison of the rate of first-order decay of 13 versus the decay of d(20)-labeled 13-d(20)() in benzene-d(6) affords k(13)()/k(13-d20)() approximately 3. The NMR data obtained for 13, 13-(13)()CH(3)(), and 13-d(20)() suggest that ligand metalation processes involve both the diphenylborate and the arylphosphine positions of the [Ph(2)BP(2)] auxiliary. The former type leads to a moderately stable and spectroscopically detectable platinum(IV) intermediate. All of these data provide a mechanistic outline of the benzene solution chemistries for the zwitterionic and the cationic systems that highlights their key similarities and differences.


MINDflex Training for Cognitive Flexibility in Chronic Pain: A Randomized, Controlled Cross-Over Trial.
Impairments in executive functioning are prevalent in chronic pain conditions, with cognitive inflexibility being the most frequently reported. The current randomized, cross-over trial, piloted a computerized cognitive training (CCT) program based on Relational Frame Theory, targeting improvement in cognitive flexibility. At baseline, 73 chronic pain patients completed testing on pre-selected outcomes of executive functioning, alongside IQ measures. When tested three times over the course of 5 months, there was a drop-out rate of 40% at the third time point, leaving 44 patients who had data at all time points. The results showed that there was a substantial learning effect from the MINDFLEX training and a substantial time-dependent improvement on the primary outcomes of increased flexibility, but that this could not be tied to active training. In conclusion, this small study indicated a learning effect as well as improvement on primary outcomes. Based on the current results, a larger trial with improved feasibility of training is warranted.


The actin/MKL1 signalling pathway influences cell growth and gene expression through large-scale chromatin reorganization and histone post-translational modifications.
In addition to soluble factors, mechanical constraints and extracellular matrix stiffness are important regulators of cell fate that are mediated by cytoskeletal modifications. The EMT (epithelial-mesenchymal transition) that occurs during normal development and malignant progression is a typical example of the phenotypic switch associated with profound actin remodelling and changes in gene expression. For instance, actin dynamics control motile cell functions in EMT, in part, through regulating the subcellular localization of the myocardin-related transcription factor MKL1 (megakaryoblastic leukaemia translocation 1), a co-activator of SRF (serum-responsive factor). In the present paper, we show that MKL1 participates also to the control of the cellular switch between growth and quiescence. Experimental disconnection between MKL1 and G-actin (globular actin), by using an MKL1 mutant or enhancing the F (filamentous)-/G-actin ratio, generates a widely open chromatin state and a global increase in biosynthetic activity, classically associated with cell growth. Conversely, G-actin accumulation favours nuclear condensation and cell quiescence. These large-scale chromatin changes rely upon extensive histone modifications, exemplified by that of H3K9 (H3 Lys9) shifting from trimethylation, a heterochromatin mark, to acetylation, a mark of euchromatin. The present study provides the first evidence for a global reversible hetero/euchromatinization phenomenon triggered by the actin/MKL1 signalling pathway.


Adipocyte studies: systems for investigating effects of growth hormone and other chronically acting hormones.
Adipose tissue is very amenable to study in vitro. Collagenase digestion yields free adipocytes which usually respond well to acute stimulation/inhibition by hormones and other factors. Chronic effects of hormones are best studied using explants of adipose tissue which, from some species (e.g. sheep), can be maintained in culture for up to a week without loss of function. Alternatively, preadipocytes can be readily isolated from adipose tissue and induced to proliferate and differentiate in culture, while various adipocyte-like cell-lines have been established, which can be used for chronic studies. Use of these various systems for investigating the mechanisms of action of growth hormone are described.


Comparison of antiviral activity of lambda-interferons against HIV replication in macrophages.
Lambda-interferons (IFN-λs) have been demonstrated as having the ability to inhibit HIV replication in macrophages. However, specific differences in signaling transduction and anti-HIV activity in macrophages between different IFN-λs are unclear. Here, we showed that although all 3 members of (IFN-λ1, λ2, and λ3) IFN-λ family induced the expression of a number of genes of janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling pathway in monocyte-derived macrophages, IFN-λ1 or IFN-λ3 induced higher levels of antiviral IFN-stimulated genes (ISGs) expression than did IFN-λ2. In addition, IFN-λ1 or IFN-λ3 induced higher levels of several pattern recognition receptors (PPRs) than did IFN-λ2. Incubation of IFN-λs with HIV-infected macrophages showed that IFN-λ1 or IFN-λ3 is more potent in anti-HIV activity than IFN-λ2. We also showed that IFN-λ treatment before HIV infection was more potent in HIV inhibition than that after HIV infection. Further investigations showed that the inductions of ISGs and PPRs expression by IFN-λs were largely compromised by HIV infection. These findings provide further experimental evidence that IFN-λs have therapeutic potential in treatment of HIV infection.


COVID-19 Marked a Change in the Scope of Occupational Medicine from Occupational to Work-Related Diseases and Total Worker Health®.
The COVID-19 pandemic challenged occupational medicine, while its focus had already shifted from occupational diseases to work-related illnesses. Such a broader scope allowed the inclusion of transmissible diseases among the causes for concern in working settings. COVID-19 has had a profound impact globally, resulting in millions of infections, often lethal. From its appearance, COVID-19 was found to affect specific groups of workers at higher risk of contracting the virus due to their occupation or workplace conditions, which accounts for its consideration as a potential work-related disease. This overview examines various aspects of COVID-19 based on articles published in our journal. Specifically, the epidemiology of COVID-19 is discussed, including mortality rates and groups at higher risk. The diagnosis, measures to prevent contagion, vaccination efforts, long-term effects, and psychosocial factors are also summarized. The emerging picture is that COVID-19 has been a trigger accelerating the change of paradigm of occupational medicine, which is more and more concerned with prevention. Occupational Health contributes to health promotion and Total Worker Health®.


The heart of new ulm: a vision for the future.
Coronary artery disease (CAD) continues to be a leading cause of death in the USA and throughout the world. Allina Health System, with the Minneapolis Heart Institute at Abbott Northwestern, recently announced a long-term study in the city of New Ulm, MN, to reduce risk factors for myocardial infarction and, ultimately, reduce myocardial infarction incidence. To achieve this goal, the focus will be on health promotion interventions and primary and secondary prevention strategies for CAD that are innovative, community-wide, and able to impact individuals at home, at work, in their community, and in their health care settings. Factors considered in selecting this city included the identification of health as a priority by the community, readiness and willingness of the community to change, the ability to provide and deliver systematic care, and partnerships established across multiple disciplines and sectors centered on improved health. The following stakeholders will be engaged: the community, employers, public health, health care, and health plans. Unique aspects of the intervention include centralized healthcare, including an automated medical record; genetic testing; integrated behavioral interventions; social environmental change and social circumstances; health promotion, primary prevention and secondary prevention interventions; advanced diagnostics and imaging; and state-of-the-art therapy.


Mass spectrometry-based discovery of circadian peptides.
A significant challenge to understanding dynamic and heterogeneous brain systems lies in the chemical complexity of secreted intercellular messengers that change rapidly with space and time. Two solid-phase extraction collection strategies are presented that relate time and location of peptide release with mass spectrometric characterization. Here, complex suites of peptide-based cell-to-cell signaling molecules are characterized from the mammalian suprachiasmatic nucleus (SCN), site of the master circadian clock. Observed SCN releasates are peptide rich and demonstrate the co-release of established circadian neuropeptides and peptides with unknown roles in circadian rhythms. Additionally, the content of SCN releasate is stimulation specific. Stimulation paradigms reported to alter clock timing, including electrical stimulation of the retinohypothalamic tract, produce releasate mass spectra that are notably different from the spectra of compounds secreted endogenously over the course of the 24-h cycle. In addition to established SCN peptides, we report the presence of proSAAS peptides in releasates. One of these peptides, little SAAS, exhibits robust retinohypothalamic tract-stimulated release from the SCN, and exogenous application of little SAAS induces a phase delay consistent with light-mediated cues regulating circadian timing. These mass spectrometry-based analyses provide a new perspective on peptidergic signaling within the SCN and demonstrate that the integration of secreted compounds with information relating time and location of release generates new insights into intercellular signaling in the brain.


Genetic and morphological evolution following a founder event in the dark-eyed junco, Junco hyemalis thurberi.
An isolated population of dark-eyed juncos, Junco hyemalis, became established on the campus of the University of California at San Diego (UCSD), probably in the early 1980s. It now numbers about 70 breeding pairs. Populations across the entire natural range of the subspecies J. h. thurberi are weakly differentiated from each other at five microsatellite loci (FST = 0.01). The UCSD population is significantly different from these populations, the closest of which is 70 km away. It has 88% of the genetic heterozygosity and 63% of the allelic richness of populations in the montane range of the subspecies, consistent with a harmonic mean effective population size of 32 (but with 95% confidence limits from four to > 70) over the eight generations since founding. Results suggest a moderate bottleneck in the early establishment phase but with more than seven effective founders. Individuals in the UCSD population have shorter wings and tails than those in the nearby mountains and a common garden experiment indicates that the morphological differences are genetically based. The moderate effective population size is not sufficient for the observed morphological differences to have evolved as a consequence of genetic drift, indicating a major role for selection subsequent to the founding of the UCSD population.


Evaluating wait times from screening to breast cancer diagnosis among women undergoing organised assessment vs usual care.
Timely coordinated diagnostic assessment following an abnormal screening mammogram reduces patient anxiety and may optimise breast cancer prognosis. Since 1998, the Ontario Breast Screening Program (OBSP) has offered organised assessment through Breast Assessment Centres (BACs). For OBSP women seen at a BAC, an abnormal mammogram is followed by coordinated referrals through the use of navigators for further imaging, biopsy, and surgical consultation as indicated. For OBSP women seen through usual care (UC), further diagnostic imaging is arranged directly from the screening centre and/or through their physician; results must be communicated to the physician who is then responsible for arranging any necessary biopsy and/or surgical consultation. This study aims to evaluate factors associated with diagnostic wait times for women undergoing assessment through BAC and UC. Of the 2 147 257 women aged 50-69 years screened in the OBSP between 1 January 2002 and 31 December 2009, 155 866 (7.3%) had an abnormal mammogram. A retrospective design identified two concurrent cohorts of women diagnosed with screen-detected breast cancer at a BAC (n=4217; 47%) and UC (n=4827; 53%). Multivariable logistic regression analyses examined associations between wait times and assessment and prognostic characteristics by pathway. A two-sided 5% significance level was used. Screened women with breast cancer were two times more likely to be diagnosed within 7 weeks when assessed through a BAC vs UC (OR=1.91, 95% CI=1.73-2.10). In addition, compared with UC, women assessed through a BAC were significantly more likely to have their first assessment procedure within 3 weeks of their abnormal mammogram (OR=1.25, 95% CI=1.12-1.39), ⩽3 assessment procedures (OR=1.54, 95% CI=1.41-1.69), ⩽2 assessment visits (OR=1.86, 95% CI=1.70-2.05), and ⩾2 procedures per visit (OR=1.41, 95% CI=1.28-1.55). Women diagnosed through a BAC were also more likely than those in UC to have imaging (OR=1.99, 95% CI=1.44-2.75) or a biopsy (OR=3.69, 95% CI=2.64-5.15) vs consultation only at their first assessment visit, and two times more likely to have a core or FNA biopsy than a surgical biopsy (OR=2.08, 95% CI=1.81-2.40). Having ⩽2 assessment visits was more likely to reduce time to diagnosis for women assessed through a BAC compared with UC (BAC OR=10.58, 95% CI=8.96-12.50; UC OR=4.47, 95% CI=3.94-5.07), as was having ⩽3 assessment procedures (BAC OR=4.97, 95% CI=4.26-5.79; UC OR=2.95, 95% CI=2.61-3.33). Income quintile affected wait times only in women diagnosed in UC, with those in the two highest quintiles more likely to receive a diagnosis in 7 weeks. Women with screen-detected breast cancer in OBSP were more likely to have shorter wait times if they were diagnosed through organised assessment. This might be as a result of women diagnosed through a BAC having more procedures per visit, procedures scheduled in shorter intervals, and imaging or biopsy on their first visit. Given the significant improvement in timeliness to diagnosis, women with abnormal mammograms should be managed through organised assessment.


Limited capacity of proximal tubular proteolysis in mice with proteinuria.
Albuminuria is associated with the additional loss in the urine of small molecular weight proteins normally degraded by the proximal convoluted tubule (PCT), and competition for binding to the megalin/cubilin reuptake system has been considered the likely cause. We have previously reported that deficiency of the intrinsic lysosomal protein Limp-2 causes tubular proteinuria due to reduced fusion of endosomes with lysosomes in the PCT leading to inadequate proteolysis. To determine whether this mechanism also contributes to the tubular proteinuria induced by albumin overload in normal mice, wild-type (WT) mice received daily BSA injections intraperitoneally for 10 days, using untreated Limp-2(-/-) mice as positive controls for inadequate proteolysis. BSA overload induced significant urinary loss of megalin and cubilin ligands in WT mice. Tubular uptake of Alexa-conjugated BSA, administered by intravenous injection, was not reduced in the PCT of mice receiving intraperitoneal BSA. Expression of the tubular protein receptor megalin was also unchanged. There was a delay in proteolysis of reabsorbed proteins in WT mice receiving BSA, evidenced by an increased quantity of retinol-binding protein (RBP) in the kidney cortex, increased basal distribution of endocytosed RBP in cells of the PCT, and persistence of exogenous Alexa-conjugated BSA and RBP after injection. Upregulation of cathepsin L and normal fusion of lysosomes with endosomes were apparently not sufficient to maintain normal clearance of endocytosed proteins. The data suggest that in the presence of competition from albumin overload, reabsorption of filtered proteins is limited by the capacity of lysosomal degradation rather than receptor-mediated endocytosis.


IgG4-related disease: a rheumatologist's perspective.
Given that the clinical features of several IgG4-related diseases (IgG4-RD) can mimic those of autoimmune disorders, the aim of this study was to find possible distinguishing characteristics that would help us identify such cases from the pool of patients in a rheumatology clinic. From our clinic's medical records, we identified patients who fulfilled the recently published diagnostic criteria for IgG4-RD. We recorded their presenting features, co-morbid conditions, laboratory, radiologic and histologic findings as well as their treatment and outcome. We identified 11 cases of IgG4-RD: 4 cases of IgG4-related autoimmune pancreatitis (AIP), 5 cases of IgG4-related retroperitoneal fibrosis (RPF)/ periaortitis, 2 cases of IgG4-related sialadenitis and one of IgG4-related interstitial nephritis. 5 out of the 11 patients had been diagnosed with an autoimmune disease, namely rheumatoid arthritis (RA), Sjogren's syndrome (SS) and antiphospholipid syndrome (APS). 3 out of 11 patients were subsequently diagnosed with neoplastic disorders. All patients with IgG4-related AIP had raised CRP levels at presentation. Presenting features of RPF/periaortitis patients were constitutional symptoms, abnormal renal function, hypertension and back pain. Patients with IgG4-related sialadenitis had clinical features mimicking SS. The majority of patients had a favourable response to steroids. We present common IgG4-RD presentations in the setting of a rheumatology clinic. Increased awareness may avoid delay in diagnosis.


Comparison of outcomes of patients with inpatient or outpatient onset ischemic stroke.
Reperfusion times for ischemic stroke occurring in the outpatient setting have improved significantly in recent years. However, quality improvement efforts have largely ignored ischemic stroke occurring in patients hospitalized for unrelated indications. We performed a cohort study involving patients with ischemic stroke (with inpatient or outpatient onset) from 2009 to 2013 who were registered in the Statewide Planning and Research Cooperative System (SPARCS) database. A propensity score-adjusted regression analysis was used to assess the association of location of onset and outcomes. Mixed effects methods were employed to control for clustering at the hospital level. Of the 176 571 ischemic strokes, 160 157 (90.7%) occurred outside of a hospital and 16 414 (9.3%) occurred in patients hospitalized for unrelated indications. Using a logistic regression model with propensity score adjustment, we demonstrated that inpatient stroke onset was associated with increased inpatient mortality (OR 3.09; 95% CI 2.81 to 3.38), rate of discharge to rehabilitation (OR 2.57; 95% CI 2.37 to 2.79), and length of stay (LOS) (β=11.58; 95% CI 10.73 to 12.42). In addition, it was associated with lower odds (OR 0.69; 95% CI 0.62 to 0.77) of undergoing stroke-related interventions (mechanical thrombectomy and intravenous tissue plasminogen activator) compared with outpatient stroke onset. Using a comprehensive all-payer cohort of patients with ischemic stroke in New York State, we identified an association of inpatient stroke onset with fewer stroke-related interventions and increased mortality, rate of discharge to rehabilitation, and LOS.


Differential expression of cell surface antigens on subsets of CD4+ and CD8+ T cells.
The assessment of relative antigen density on T cell subsets is a feature of antigen expression that is infrequently characterized. Defining phenotypic differences is a first step in understanding associated differences in function. Additionally, a better understanding of T cell heterogeneity may aid in clinical diagnoses. To further elucidate phenotypic differences of T cell subsets, and begin to determine what information relative antigen density contributes to immunology, we analyzed normal human peripheral blood T cells for a variety of immunophenotypic (CD2, CD3, CD4, CD5, CD7, CD8, CD45RA, CD45RO, TCR alpha beta) and light scatter characteristics using 6 color flow cytometry. T-cell leukemia specimens were also analyzed. Our data show that statistically significant immunophenotypic differences exist between subsets of human CD4 and CD8 T cells. Normal T cells express different levels of relative antigen density for some antigens compared to malignant T cells. Significant differences are seen in relative antigen density for several cell surface markers between CD4+ and CD8+ T cells. Neither donor source nor flow cytometric calibration account for these differences. The data are applied to specimens from patients with T-lineage acute lymphoblastic leukemia to show how antigen density can be used clinically in aiding to diagnose disease. The data presented here can be used to further investigate these cell populations for functional differences.


Longitudinal study on infants' temperament and physical development in Beijing, China.
The objective of this longitudinal study is to explore the relationship between temperament and physical development among infants in Beijing, China. A total of 1117 term, normal and singleton infants were followed regularly for 12 months. Body weight and horizontal length were measured at 42 days and monthly from the third to twelfth month of their lives. Infants' temperament was assessed using the revised Chinese infants' temperament scale when the infants were 6 months. There was a significant difference on temperament dimensions between infants' genders (P < 0.05). Infants' weight and length were significantly related to their parents' weight and height. Infants with positive temperaments (easy and intermediate) were heavier than those with negative temperaments (difficult and slow to warm up) (P < 0.05). The horizontal length of boys was related to their temperament categories (P < 0.05). Infants' weight and length were significantly related to their temperament category and parents' weight and height.


Cytotoxic T-cell lymphoma diffusely involving the entire gastrointestinal tract associated with Epstein-Barr virus and tubercle bacilli infection.
We describe a rare case of cytotoxic gastrointestinal T-cell lymphoma with protein-losing enteropathy. Initial examination revealed the coexistence of T-cell lymphoma and tuberculosis in the mesenteric lymph node and liver. Despite anti-tuberculosis and anti-cancer treatment, the patient experienced chronic diarrhea and malabsorption and died approximately 3 years after onset. Autopsy specimens revealed medium-sized lymphoma cells, with a phenotype of CD3+, CD4-, CD7+, CD8+, CD30-, CD56-, CD103 (HML-1)-, TIA-1+, and granzyme B+, proliferating primarily and consistently in the mucosa of the entire bowel tract from esophagus to rectum. Interestingly, Epstein-Barr virus (EBV)-encoded small nuclear RNAs were detected in the tumors by in situ hybridization. Southern blot analysis revealed monoclonal proliferation in the EBV-infected T cells. Although the present case can possibly be categorized as an intestinal T-cell lymphoma according to the Revised European-American Lymphoma Classification, the case showed a unique clinical course and distribution of lymphoma cells. We present here an interesting case of gastrointestinal cytotoxic T-cell lymphoma and examine the possible association with infectious agents.


Formation of plexiform lesions in experimental severe pulmonary arterial hypertension.
The plexiform lesion is the hallmark of severe pulmonary arterial hypertension. However, its genesis and hemodynamic effects are largely unknown because of the limited availability of lung tissue samples from patients with pulmonary arterial hypertension and the lack of appropriate animal models. This study investigated whether rats with severe progressive pulmonary hypertension developed plexiform lesions. After a single subcutaneous injection of the vascular endothelial growth factor receptor blocker Sugen 5416, rats were exposed to hypoxia for 3 weeks. They were then returned to normoxia for an additional 10 to 11 weeks. Hemodynamic and histological examinations were performed at 13 to 14 weeks after the Sugen 5416 injection. All rats developed pulmonary hypertension (right ventricular systolic pressure approximately 100 mm Hg) and severe pulmonary arteriopathy, including concentric neointimal and complex plexiform-like lesions. There were 2 patterns of complex lesion formation: a lesion forming within the vessel lumen (stalk-like) and another that projected outside the vessel (aneurysm-like). Immunohistochemical analyses showed that these structures had cellular and molecular features closely resembling human plexiform lesions. Severe, sustained pulmonary hypertension in a very late stage of the Sugen 5416/hypoxia/normoxia-exposed rat is accompanied by the formation of lesions that are indistinguishable from the pulmonary arteriopathy of human pulmonary arterial hypertension. This unique model provides a new and rigorous approach for investigating the genesis, hemodynamic effects, and reversibility of plexiform and other occlusive lesions in pulmonary arterial hypertension.


Parkinson's disease treatment may cause impulse-control disorder via dopamine D3 receptors.
In treating Parkinson's disease with dopaminergic agonists, such as pramipexole, ropinirole, pergolide, rotigotine, apomorphine, or bromocriptine, it has been observed that a significant number of patients develop impulse-control disorders, such as compulsive shopping, pathological gambling, or hypersexuality. Because the dopamine agonists have high affinities for the dopamine D2 and D3 receptors, the drug dissociation constants of these drugs at the functional high-affinity states of these receptors, namely D2High and D3High, were compared. The data show that, compared to the other dopamine agonist drugs, pramipexole has a relatively high selectivity for the dopamine D3 receptor, as compared to D2, suggesting that the D3 receptor may be a primary target for pramipexole. There is a trend showing that the proportion of impulse-control disorders is related to the selectivity for D3 receptors over D2 receptors, with pramipexole having the highest association with, or frequency of, impulse-control disorders. While the number of studies are limited, the proportion of patients with impulse-control disorder in Parkinson patients treated with an add-on agonist were 32% for pramipexole, 25% for ropinirole, 16% for pergolide, 22% for rotigotine, 10% for apomorphine, and 6.8% for bromocriptine. Clinically, temporary replacement of pramipexole by bromocriptine may provide relief or reversal of the impulsive behavior associated with selective D3 stimulation by either pramipexole or ropinirole, while maintaining D2 stimulation needed for the anti-Parkinson action.


Unique cellular events occurring during the initial interaction of macrophages with matrix-retained or methylated aggregated low density lipoprotein (LDL). Prolonged cell-surface contact during which ldl-cholesteryl ester hydrolysis exceeds ldl protein degradation.
A critical event in atherogenesis is the interaction of arterial wall macrophages with subendothelial lipoproteins. Although most studies have investigated this interaction by incubating cultured macrophages with monomeric lipoproteins dissolved in media, arterial wall macrophages encounter lipoproteins that are mostly bound to subendothelial extracellular matrix, and these lipoproteins are often aggregated or fused. Herein, we utilize a specialized cell-culture system to study the initial interaction of macrophages with aggregated low density lipoprotein (LDL) bound to extracellular matrix. The aggregated LDL remains extracellular for a relatively prolonged period of time and becomes lodged in invaginations in the surface of the macrophages. As expected, the degradation of the protein moiety of the LDL was very slow. Remarkably, however, hydrolysis of the cholesteryl ester (CE) moiety of the LDL was 3-7-fold higher than that of the protein moiety, in stark contrast to the situation with receptor-mediated endocytosis of acetyl-LDL. Similar results were obtained using another experimental system in which the degradation of aggregated LDL protein was delayed by LDL methylation rather than by retention on matrix. Additional experiments indicated the following properties of this interaction: (a) LDL-CE hydrolysis is catalyzed by lysosomal acid lipase; (b) neither scavenger receptors nor the LDL receptor appear necessary for the excess LDL-CE hydrolysis; and (c) LDL-CE hydrolysis in this system is resistant to cellular potassium depletion, which further distinguishes this process from receptor-mediated endocytosis. In summary, experimental systems specifically designed to mimic the in vivo interaction of arterial wall macrophages with subendothelial lipoproteins have demonstrated an initial period of prolonged cell-surface contact in which CE hydrolysis exceeds protein degradation.


PDK1 homologs activate the Pkc1-mitogen-activated protein kinase pathway in yeast.
PDK1 (phosphoinositide-dependent kinase 1) is a mammalian growth factor-regulated serine/threonine kinase. Using a genetic selection based on a mutant form of the yeast MAP kinase kinase Ste7, we isolated a gene, PKH2, encoding a structurally and functionally conserved yeast homolog of PDK1. Yeast cells lacking both PKH2 and PKH1, encoding another PDK1 homolog, were nonviable, indicating that Pkh1 and Pkh2 share an essential function. A temperature-sensitive mutant, pkh1(D398G) pkh2, was phenotypically similar to mutants defective in the Pkc1-mitogen-activated protein kinase (MAPK) pathway. Genetic epistasis analyses, the phosphorylation of Pkc1 by Pkh2 in vitro, and reduced Pkc1 activity in the pkh1(D398G) pkh2 mutant indicate that Pkh functions upstream of Pkc1. The Pkh2 phosphorylation site in Pkc1 (Thr-983) is part of a conserved PDK1 target motif and essential for Pkc1 function. Thus, the yeast PDK1 homologs activate Pkc1 and the Pkc1-effector MAPK pathway.


Rapid demountable platform (RDP)--a device for preventing fall from height accidents.
The prevention of fall from height accidents has long been a popular topic in the field of construction safety. Previous research has indicated one of the potential hazards was induced by the use of steel bracket as scaffold support. While researchers are focusing to improve the existing scaffolding system, this research introduces a newly developed device to minimize fall accidents. The working platform, namely Rapid Demountable Platform (RDP) can be applied across window frames without fixing anchor bolts. Emphasizing on the rapid installation/dismantling, the RDP provides another safer option for working at height. The development of the RDP has incorporated modular concept and aesthetic factor into the design, achieving a more user-friendly platform. Although the RDP is not intended to totally replace the traditional bamboo truss-out scaffold, it is designed to act as an alternative or a supplement to the existing bamboo truss-out scaffold. The RDP is the first of this kind to minimize fall from height accidents especially in cities similar to Hong Kong where external working at height is frequently encountered.


Modulation of porcine β-defensins 1 and 2 upon individual and combined Fusarium toxin exposure in a swine jejunal epithelial cell line.
Defensins are small antimicrobial peptides (AMPs) that play an important role in the innate immune system of mammals. Since the effect of mycotoxin contamination of food and feed on the secretion of intestinal AMPs is poorly understood, the aim of this study was to elucidate the individual and combined effects of four common Fusarium toxins, deoxynivalenol (DON), nivalenol (NIV), zearalenone (ZEA), and fumonisin B1 (FB1), on the mRNA expression, protein secretion, and corresponding antimicrobial effects of porcine β-defensins 1 and 2 (pBD-1 and pBD-2) using a porcine jejunal epithelial cell line, IPEC-J2. In general, upregulation of pBD-1 and pBD-2 mRNA expression occurred following exposure to Fusarium toxins, individually and in mixtures (P < 0.05). However, no significant increase in secreted pBD-1 and pBD-2 protein levels was observed, as measured by enzyme-linked immunosorbent assay (ELISA). Supernatants from IPEC-J2 cells exposed to toxins, singly or in combination, however, possessed significantly less antimicrobial activity against Escherichia coli than untreated supernatants. When single toxins and two-toxin combinations were assessed, toxicity effects were shown to be nonadditive (including synergism, potentiation, and antagonism), suggesting interactive toxin effects when cells are exposed to mycotoxin combinations. The results show that Fusarium toxins, individually and in mixtures, activate distinct antimicrobial defense mechanisms possessing the potential to alter the intestinal microbiota through diminished antimicrobial effects. Moreover, by evaluating toxin mixtures, this improved understanding of toxin effects will enable more effective risk assessments for common mycotoxin combinations observed in contaminated food and feed.


Joint Robust Imputation and Classification for Early Dementia Detection Using Incomplete Multi-modality Data.
It is vital to identify Mild Cognitive Impairment (MCI) subjects who will progress to Alzheimer's Disease (AD), so that early treatment can be administered. Recent studies show that using complementary information from multi-modality data may improve the model performance of the above prediction problem. However, multi-modality data is often incomplete, causing the prediction models that rely on complete data unusable. One way to deal with this issue is by first imputing the missing values, and then building a classifier based on the completed data. This two-step approach, however, may generate non-optimal classifier output, as the errors of the imputation may propagate to the classifier during training. To address this issue, we propose a unified framework that jointly performs feature selection, data denoising, missing values imputation, and classifier learning. To this end, we use a low-rank constraint to impute the missing values and denoise the data simultaneously, while using a regression model for feature selection and classification. The feature weights learned by the regression model are integrated into the low rank formulation to focus on discriminative features when denoising and imputing data, while the resulting low-rank matrix is used for classifier learning. These two components interact and correct each other iteratively using Alternating Direction Method of Multiplier (ADMM). The experimental results using incomplete multi-modality ADNI dataset shows that our proposed method outperforms other comparison methods.