National guidelines on the management of venous thromboembolism: Joint guideline of the Turkish Society of Cardiovascular Surgery, National Society of Vascular and Endovascular Surgery, and Phlebology Society.
These evidence-based guidelines from the Turkish Society of Cardiovascular Surgery, National Society of Vascular and Endovascular Surgery, and Phlebology Society intend to support clinicians in best decisions regarding the treatment of venous thromboembolism (VTE). The Editor was selected by the three national societies and was tasked with the recruitment of the recognized panel. All financial support was solely derived from the sponsoring societies without the direct involvement of industry or other external stakeholders. The panel prioritized clinical questions and outcomes according to their importance for clinicians in terms of VTE. The panel agreed on 42 recommendations under 15 headings for the diagnosis, initial management, secondary prevention of VTE, and treatment of recurrent VTE events. Important recommendations included the use of ultrasonography, preference for home treatment over hospital treatment for uncomplicated VTE, preference for direct oral anticoagulants (DOACs) over vitamin K antagonists for primary treatment of cancer and non-cancer-related VTE, extended or indefinite anticoagulation with DOACs in selected high-risk patients. Early catheter-directed thrombectomy was recommended in only young symptomatic patients with a diagnosis of fresh iliofemoral deep vein thrombosis.


Epidemiology of noise-induced hearing loss in New Zealand.
Hearing loss is a major cause of disability in the world. Occupational noise exposure is likely to contribute to a very high proportion of the cases of hearing loss in adults. Concern has been raised by the Accident Compensation Corporation (ACC) in New Zealand about the fact that the number of new cases of noise-induced hearing loss (NIHL) is not declining, despite the health and safety legislation and establishment of hearing conservation programmes in industry. To inform strategies for prevention, a review of the burden of NIHL in New Zealand was undertaken, particularly focusing on the trends in compensation claims and costs, and the associated sociodemographic patterns. A review of the peer-reviewed published literature was conducted to identify national and international estimates of NIHL prevalence. The ACC claims dataset (July 1995 to June 2006) was analysed to describe annual trends in new NIHL claims, cost to ACC, and claimants' age, gender and occupational group. There is currently no reliable information regarding the overall incidence and prevalence of NIHL in New Zealand. ACC data reveals a substantial increase in the number of new NIHL claims annually, rising from 2823 in July 1995-June 1996, to 5580 in July 2005-June 2006. Together with ongoing claims the overall costs of NIHL claims increased by an average of 20% each year (a six-fold increase over the decade) resulting in a total cost to ACC of $193.82M over the review period. Collectively, agriculture and fisheries workers, trades workers, machine operators, and assemblers accounted for 53% of new claims. Most claims were lodged in middle age or later, with the vast majority of claimants (95%) being men. The relationship of age with the probability of making a claim changed significantly over the study period with rates in older age groups increasing faster than in younger. The substantial and increasing societal costs despite decades of NIHL control legislation suggests that current strategies addressing this problem are not effective, inadequately implemented, or both.


Enhanced hydrogen storage properties of ZrTiVAl1-x Fe x high-entropy alloys by modifying the Fe content.
Lightweight ZrTiVAl high-entropy alloys have shown great potential as a hydrogen storage material due to their appreciable capacity, easy activation, and fast hydrogenation rates. In this study, transition metal Fe was used to improve the hydrogen storage properties of the equimolar ZrTiVAl alloy, and ZrTiVAl1-x Fe x (x = 0, 0.2, 0.4, 0.6, 0.8, 1) alloys were prepared to investigate the microstructure evolution and hydrogen storage properties. The results show that the ZrTiVAl1-x Fe x alloys are composed of a C14 Laves phase and Ti-rich HCP phase. With Fe substituting Al, the fraction of the C14 Laves phase increases and that of the HCP phase decreases. Besides, the interdendritic area fraction reaches the maximum when the Fe ratio is 0.2. The element V transferred to the C14 Laves phase from the HCP phase, which is caused by the strong affinity between V and Fe. The ZrTiVAl1-x Fe x alloys show enhanced hydrogenation kinetics and capacities. Notably, the ZrTiVFe alloy can reversely absorb 1.58 wt% hydrogen even at room temperature under 1 MPa H2. The reduced interdendritic phase is beneficial to shorten the H atom diffusion distance, thus improving the hydrogenation rates. Both the transfer of the hydrogen-absorbing element V to the C14 Laves phase and the increased fraction of the C14 Laves phase lead to the increase of hydrogen storage capacity with the addition of Fe. Moreover, the increased Fe content leads to an increase of average valence electron concentration (VEC), where a larger VEC destabilizes the hydrides, and the desorption temperature of ZrTiVAl1-x Fe x hydride decreases significantly.


Salivary gland involvement disparities in clinical characteristics of IgG4-related disease: a retrospective study of 428 patients.
IgG4-related disease (IgG4-RD) has recently been recognized as a fibro-inflammatory condition featuring tumefactive lesions in multiple organs, and the salivary gland is one of the most commonly involved sites. We undertook this study to compare detailed demographic, clinical and laboratory characteristics of IgG4-RD patients with salivary gland lesions (IgG4-RD SG+) and salivary-gland-free IgG4-RD (IgG4-RD SG-) in a large cohort. We carried out a retrospective review of the medical records of 428 cases of IgG4-RD diagnosed at Peking University People's Hospital between March 2006 and May 2018. Among 428 patients, 249 had salivary glands that were affected. IgG4-RD SG+ patients showed younger age at disease onset and diagnosis, and a longer interval between symptom onset and diagnosis. The IgG4-RD SG+ group involved more female patients, and allergic diseases were more common in this group. In terms of organ involvement, the IgG4-RD SG+ group were more frequently presented with lacrimal gland involvement, while lymph node, retroperitoneal fibrosis, pancreas, biliary system, kidney and aorta were more prominent in the IgG4-RD SG- group. In addition, the serum IgG4 level, IgG4/IgG ratio and IgE level were significantly higher in IgG4-RD SG+ patients. Patients with eosinophilia were more common in the IgG4-RD SG+ group, while elevated ESR, CRP and positive ANA were more common in the IgG4-RD SG- group. We have revealed demographic, clinical and laboratory differences between IgG4-RD SG+ and SG- patients, which indicated potential differences in pathogenesis and important implications for the diagnosis and management of these two phenotypes.


Increased bilateral occipitoparietal activity during retention of binary versus unary indexed lists in pair recognition.
Cognitive complexity has been characterized by relations processed, rather than items stored. Separating these factors is difficult, because processing more complex relations often involves holding more items in memory. Previous research, NeuroImage, 17, 1031-1055) identified parietal lobes with more item relationships, but not more items by varying index length-fewest number of positions having a unique combination of items. For example, AB CD EF is a unary (length one) indexed list of three pairs, because all items are unique at the first (or second) position; AB AD CB is a binary indexed list, because only pairs of items are unique. But, these lists also differ in number of associates. In this experiment, index length was varied independently of the numbers of items and associates. Subjects were asked to make a recognition judgment for each three-pair list: Was the test pair in the previous list? Random effects analysis contrasting two binary indexed lists (AB AC CB and AB AD CB) minus two unary indexed lists (AB BC CA and AB BC CD) revealed increased occipital and parietal activity (bilaterally) during the retention period for both binary indexed list types. This result is explained by index length, but not by item load or item fan, because the numbers of items and item associates were the same for the corresponding unary and binary list types. For peak voxels in left and right precuneus, activity during retention for both binary list types was also greater than for a third unary indexed list (AB CD EF). Because binary indexes require more positions (roles) to individuate pairs, we suggest that the increased activity in precuneus relates to spatial rehearsal in that more attention is directed to both positions to maintain the integrity of the memory trace.


IRE1 signaling is essential for ischemia-induced vascular endothelial growth factor-A expression and contributes to angiogenesis and tumor growth in vivo.
In solid tumors, cancer cells subjected to ischemic conditions trigger distinct signaling pathways contributing to angiogenic stimulation and tumor development. Characteristic features of tumor ischemia include hypoxia and glucose deprivation, leading to the activation of hypoxia-inducible factor-1-dependent signaling pathways and to complex signaling events known as the unfolded protein response. Here, we show that the activation of the endoplasmic reticulum stress sensor IRE1 is a common determinant linking hypoxia- and hypoglycemia-dependent responses to the up-regulation of vascular endothelial growth factor-A (VEGF-A). Tumor cells expressing a dominant-negative IRE1 transgene as well as Ire1alpha-null mouse embryonic fibroblasts were unable to trigger VEGF-A up-regulation upon either oxygen or glucose deprivation. These data correlated with a reduction of tumor angiogenesis and growth in vivo. Our results therefore suggest an essential role for IRE1-dependent signaling pathways in response to ischemia and identify this protein as a potential therapeutic target to control both the angiogenic switch and tumor development.


Condom Use, Pornography Consumption, and Perceptions of Pornography as Sexual Information in a Sample of Adult U.S Males.
Using survey data from heterosexual adult men in the U.S., the present study has two objectives. The first objective is to provide an additional data point on the overall, bivariate association between frequency of pornography consumption and condom use. The second objective is to test the theoretical proposition that the association between using pornography more frequently and using condoms less frequently will be stronger when pornography is seen as functionally important and weaker when pornography is not seen as functionally important. At the bivariate level, more frequent pornography consumption was associated with using condoms less consistently. At the level of contingency, pornography use predicted condom nonuse only when men perceived that pornography was a primary source of information about sex. When men did not perceive that pornography was a primary source of sexual information, their rate of condom use was unrelated to how much or how little they consumed pornography. Collectively, these results are consistent with the public health position that pornography can be a risk-factor for condomless sex and the theoretical position that the socializing impact of sexual media depends on the pedagogical value attributed to that media.


[The effect of millet oil on healing of purulent wounds in patients with diabetes mellitus and experimental animals].
In the studies on 64 rabbits with the model of a suppurating wound against the background of diabetes mellitus, and as well in treating 29 patients with diabetes mellitus and purulent-inflammatory soft tissue diseases, it was established that the millet oil had the antiinflammatory and stimulating tissue regeneration effect. The duration of wound treatment in rabbits with the use of millet oil was 16 days shorter than in use of the sea-buckthorn oil, and 21 day shorter--Wishnevsky's ointment. In patients with diabetes mellitus, the duration of wound treatment in use of the millet oil reduced by 16 days when compared to that in using the sea-buckthorn oil.


Analysis of maternal circulation and renal function in physiologic pregnancies; parallel examinations of the changes in the cardiac output and the glomerular filtration rate.
The aim of the study was to examine the temporal relations between the parameters of the maternal hemodynamics and homeostasis in different phases of pregnancy and the postpartum period. Eleven healthy pregnant women were involved in the study. The value of the peripheric vasodilatation was measured by the ratio I/A of the maternal sphygmogram (I: incisure point, A: amplitude of the carotid pressure curve). The change of the cardiac output was determined by the ejection angle composed from maternal carotid sphygmogram and its first electrical derivate (dP/dT). The glomerular filtration rate (GFR) was measured with the in vitro radiofluorescent method. The primary peripheral vasodilatation and GFR increase occur early in the first trimester of a normal pregnancy, start to decrease at the end of the third trimester, and return to the normal value in the postpartum period. The increase of GFR precedes the increase of cardiac output. The cardiac output increases progressively from the first trimester and starts to decrease in the third trimester of a normal pregnancy. The extracellular volume increases at the beginning of first trimester progressively until the end of pregnancy and returns to the normal value in the postpartum period. The increase of GFR and the cardiac output during pregnancy are contributed to volume-establishment and to the cessation of the special "underfilled" condition of the maternal circulation in the normal pregnancy. We suppose that the maximal increase of GFR precedes the maximal increase of the cardiac output because the GFR increase is caused by maximal renal vasodilatation. The increase of cardiac output is caused in the first trimester by the shunt effect of the enhanced renal blood flow of maternal kidneys, and in the second and third trimester by the shunt effect of the feto-placental unit and the shunt effect of the maternal kidneys.


Signet-ring cell change versus signet-ring cell carcinoma: a comparative analysis.
Signet-ring cell change (SCC) is a nonneoplastic condition that morphologically simulates signet-ring cell carcinoma (SRCA). The few case reports on SCC have focused on morphologic characteristics in distinguishing benign from malignant. In biopsy specimens, however, SCC can be easily confused with SRCA, which often demonstrates innocuous cytologic features. The object of this study is twofold: 1) to report 14 additional cases of SCC, comparing their morphologic and phenotypic features with that of SRCA; and 2) to evaluate the incidence of SCC in pseudomembranous colitis. Paraffin sections of biopsy or resection specimens containing focal or extensive SCC and 5 cases of colonic SRCA were stained with hematoxylin and eosin, periodic-acid Schiff stain with and without diastase digestion, and by standard ABC immunoperoxidase procedure using antibodies to E-cadherin, p53, and Ki-67. Both cells in SCC and SRCA were strongly positive for neutral mucins. Cells in SCC were strongly positive for E-cadherin and negative for p53 and Ki-67. In contrast, cells in SRCA were strongly positive for p53, exhibited high proliferation, and demonstrated absent or weak positivity for E-cadherin. Although SCC is not well recognized in pseudomembranous colitis, the incidence is fairly high: 14 of 50 (28%) cases showed variable numbers of signet-ring cells. Extensive SCC, although rare, can occur in different clinical conditions and can be easily mistaken for SRCA. When in doubt, routine immunohistochemical stains such as p53, Ki-67, and E-cadherin can help to differentiate SCC from SRCA.


Development and evaluation of a dynamic model that projects population biomarkers of methylmercury exposure from local fish consumption.
A dynamic model was developed to project Hg concentrations in common biomarkers of exposure in response to changes in Hg concentrations in predatory fish from local waters. The model predicts biomarkers in susceptible populations for intake rates representing the mean, 90th, 95th, and 99 th percentiles of populations of interest. The biomarkers the model calculates are blood methylmercury, total hair Hg, and fetal blood methylmercury. Decision makers can use the model to determine the degree of reduction in fish tissue Hg levels necessary to protect the health of susceptible populations. Biomarker output was calibrated with literature sources. Output was then compared to additional literature sources to evaluate model function. Projected biomarkers were not different from literature sources. The model can be used as a tool to understand the impact of local fish consumption on susceptible populations.


The Nephrologist's Tumor: Basic Biology and Management of Renal Cell Carcinoma.
Kidney cancer, or renal cell carcinoma (RCC), is a disease of increasing incidence that is commonly seen in the general practice of nephrology. However, RCC is under-recognized by the nephrology community, such that its presence in curricula and research by this group is lacking. In the most common form of RCC, clear cell renal cell carcinoma (ccRCC), inactivation of the von Hippel-Lindau tumor suppressor is nearly universal; thus, the biology of ccRCC is characterized by activation of hypoxia-relevant pathways that lead to the associated paraneoplastic syndromes. Therefore, RCC is labeled the internist's tumor. In light of this characterization and multiple other metabolic abnormalities recently associated with ccRCC, it can now be viewed as a metabolic disease. In this review, we discuss the basic biology, pathology, and approaches for treatment of RCC. It is important to distinguish between kidney confinement and distant spread of RCC, because this difference affects diagnostic and therapeutic approaches and patient survival, and it is important to recognize the key interplay between RCC, RCC therapy, and CKD. Better understanding of all aspects of this disease will lead to optimal patient care and more recognition of an increasingly prevalent nephrologic disease, which we now appropriately label the nephrologist's tumor.


Gestational diabetes mellitus, prenatal air pollution exposure, and autism spectrum disorder.
Ambient air pollution and maternal diabetes may affect common biological pathways underlying adverse neurodevelopmental effects. However, joint effects of maternal diabetes and air pollution on autism spectrum disorder (ASD) have not been studied. We evaluated whether prenatal and early-life air pollution exposure interacts with maternal diabetes status to affect ASD risk. This retrospective cohort study included 246,420 singleton children born in Kaiser Permanente Southern California hospitals in 1999-2009. Children were followed from birth until age 5, during which 2471 ASD cases were diagnosed. Ozone (O3), particulate matter < 2.5 μm (PM2.5) and <10 μm in aerodynamic diameter, and nitrogen dioxide measured at regulatory air monitoring stations were interpolated to estimate exposures during preconception and each pregnancy trimester, and first year of life at each child's birth address. Hazard ratios (HRs) for ASD were estimated adjusting for birth year, KPSC service areas, and relevant maternal and child characteristics. For each exposure window, interactions were tested between pollutants and a 4-category maternal diabetes variable (none, GDM ≥ 24 and <24 weeks' gestation, and pre-existing type 2 diabetes). For an exposure window with statistically significant global interaction between pollutant and diabetes (p < 0.05), pollutant-associated HRs were estimated separately for each category of maternal diabetes. There were associations of ASD with preconception, first and third trimesters, and first year of life PM2.5, but not with other pollutants. There were, however, interactions of maternal diabetes with first trimester and first year of life O3. Increased ASD risk was associated with first trimester O3 among mothers with GDM < 24 weeks' gestation [adjusted HR 1.50 per 15.7 ppb O3 (95% CI: 1.08-2.09)]. No O3 associations with ASD were observed in other categories of maternal diabetes. GDM onset early in pregnancy may increase children's susceptibility to prenatal O3-associated ASD risk. These novel findings merit further investigation.


GI Epidemiology: infection epidemiology and acute gastrointestinal infections.
Gastrointestinal infection is a major cause of morbidity and mortality worldwide. The World Health Organisation estimated that in 2001 diarrheal disease was the third most common cause of mortality from infectious diseases worldwide, accounting for some 1.9 million deaths. Gastrointestinal infection is also linked to chronic diseases, for example Helicobacter pylori infection and gastric cancer. To introduce the features of infection epidemiology that differentiates it from disease epidemiology in general. The epidemiologic study of infection is essential for disease control. Infection epidemiology requires consideration of micro-organisms (the infection process and transmission pathways) as well as the host (clinical presentation, behavior and immune status). Although infection epidemiologists often draw on methods used in chronic disease epidemiology there are some special features of infection epidemiology that require additional investigative approaches. We have highlighted these unique features and described some of the special methods available to track infection to its source. * The epidemiologic approach to the investigation of gastrointestinal infection is influenced by the interaction between micro-organisms and the host. * The infection epidemiologist can draw on "standard" epidemiologic techniques and on special methods. * Collaboration with microbiologists is essential for studying infection epidemiology. The purpose of this chapter is to introduce the features of infection epidemiology that differentiate it from disease epidemiology in general. Epidemiologic concepts covered in other chapters will not be repeated here, but readers should bear in mind that those methods are also available to use in the study of infection.


Family Physicians' Perceptions of Electronic Cigarettes in Tobacco Use Counseling.
Recent support has been shown for physicians to recommend e-cigarettes to patients who are trying to quit smoking. Supporters of this recommendation argue that e-cigarettes are not combustible products and are less harmful and more effective cessation products than regular cigarettes, with less inherent risk. Those who oppose this idea argue that little reliable evidence suggests that e-cigarettes are better cigarette cessation devices than currently available nicotine replacement therapies, and that they pose as much risk as cigarettes. This study was conducted to explore family physicians' perceptions of recommending e-cigarettes as smoking cessation aids to patients who smoke cigarettes. The study used a mixed-methods approach whereby a 12-item survey was sent to 154 family physicians throughout the state of Kansas. Data were collected from 117, a 76% response rate. A multidisciplinary team used an immersion-crystallization approach to analyze the content of respondents' qualitative data; contingency table analysis was used to evaluate the quantitative data. The results showed that family physicians have negative perceptions of e-cigarettes and do not recommend them for smoking cessation. Family physicians are concerned about the effectiveness of e-cigarettes and the uncertainty regarding safety. The results suggest that most family physicians do not recommend e-cigarettes for smoking cessation, citing lack of evidence on effectiveness and uncertainty regarding short- and long-term safety.


Patient-doctor depth-of-relationship scale: development and validation.
PURPOSE Because patient-doctor continuity has been measured in its longitudinal rather than its personal dimension, evidence to show that seeing the same doctor leads to better patient care is weak. Existing relational measures of patient-doctor continuity are limited, so we developed a new patient self-completion instrument designed to specifically measure patient-doctor depth of relationship. METHODS Draft versions of the questionnaire were tested with patients in face-to-face interviews and 2 rounds of pilot testing. The final instrument was completed by patients attending routine appointments with their general practitioner, and some were sent a follow-up questionnaire. Scale structure, validity, and reliability were assessed. RESULTS Face validity of candidate items was confirmed in interviews with 11 patients. Data from the pilot rounds 1 (n = 375) and 2 (n = 154) were used to refine and shorten the questionnaire. The final instrument comprised a single scale of 8 items and had good internal reliability (Cronbach's α = .93). In the main study (N = 490), seeing the same doctor was associated with deep patient-doctor relationships, but the relationship appeared to be nonlinear (overall adjusted odds ratio = 1.5; 95% CI, 1.2-1.8). Test-retest reliability in a sample of participants (n = 154) was good (intracluster correlation coefficient 0.87; 95% CI, 0.53-0.97). CONCLUSIONS The Patient-Doctor Depth-of-Relationship Scale is a novel, conceptually grounded questionnaire that is easy for patients to complete and is psychometrically robust. Future research will further establish its validity and answer whether patient-doctor depth of relationship is associated with improved patient care.


Pollinating bees (Hymenoptera: Apiformes) of U.S. alfalfa compared for rates of pod and seed set.
Alfalfa (=lucerne) flowers require visiting bees to trip the sexual column, thereby providing pollination and subsequent pod and seed set. Previous studies have compared the pollination values of different bee species solely by the speed with which they handle flowers and the proportion of visited flowers tripped. In this greenhouse study, five species of bees, including the three commercially managed U.S alfalfa pollinators, are likewise compared for their floral tripping frequencies. These bee species are also compared for the pod set and mature seed that results from their single visits to virgin flowers. Regardless of the identity of the pollinating bee, tripped flowers had the same probabilities of pod set and seed set. Thus, differences in the single-visit pollination efficiencies of the various bee species are entirely attributable to the proportion of visited flowers that they trip. Females of the alkali bee, Nomia melanderi Cockerell, and the alfalfa leafcutting bee, Megachile rotundata F, tripped 81 and 78% of visited flowers, respectively. Males of these species are significantly less effective (61 and 51%, respectively), but still significantly superior to the honey bee, Apis mellifera L. (22% of visited flowers tripped). These relationships are supported by field data for tripping frequencies. One candidate pollinator, Osmia sanrafaelae Parker, shows promise (44% tripped), but not the congeneric O. aglaia Sandhouse (13% tripped).


Comparison of three different techniques of extraction in laparoscopic donor nephrectomy.
We compare the outcome of three different methods of graft extraction after a laparoscopic donor nephrectomy. AFTER A CONVENTIONAL FIVE PORT LAPAROSCOPIC DONOR NEPHRECTOMY, SPECIMEN WAS EXTRACTED THROUGH ONE OF THREE APPROACHES: 1. Iliac fossa (IF) incision and hand extraction, 2. Midline (MD) periumbilical with a lower polar fat stitch incorporating gonadal vein for traction while retrieval, and 3. Pfannensteil (PF) with Gel port extraction. Estimated blood loss, operating time, warm ischemia time, incision length, pain score, analgesic consumption, hospital stay, wound complications, graft complications and recipient creatinine at 6 weeks were analyzed. Warm ischemia time was significantly reduced in PF group when compared to other groups. Length of the incision was less in the MD group compared to other groups. Wound complications were significantly less in PF group when compared to other groups. Graft extraction complications were significantly high in MD group compared to other two groups. Based on the results obtained, our current method of preference is by Pfannensteil incision. A controlled extraction with the use of a hand assist device would be best for donor safety and to avoid graft related complications.


A temporal distinctiveness theory of recency and modality effects.
A temporal distinctiveness theory of contextually cued retrieval from memory is presented and applied to recency and modality effects. According to this theory, one part of the mnemonic trace of an item is a representation of the item's time of presentation. Time of presentation may be encoded with a coarse grain (so that it is consistent with a wide range of times) or with a fine grain (so that it is consistent with a narrow range of times). Retrieval proceeds by constructing temporally defined search sets that include representations of items consistent with the temporal bounds of the search set. The temporal width of the search set increases as the retention interval increases. Recency effects arise from retrieval of recently presented items from narrow search sets that include representations of few items; within the context of the search set, these items are distinctive and recalled well. Superiority in recall of recently presented auditory information in comparison with recently presented visual information is attributed to differences in the grain of time of presentation representations for aurally (fine grain) and visually (coarse grain) presented information. Four experiments confirm qualitative and quantitative predictions of the theory, including the prediction of auditory superiority at the beginning of the list when the initial items are temporally distinct.


Tinea capitis in Germany. A survey in 1998.
Under the assignment of the ECMM (European Confederation of Medical Mycology) a survey regarding frequency, infectious spectrum and therapy of tinea capitis was conducted in Germany in 1998. In this survey 154 dermatology practitioners and 19 hospitals throughout Germany participated. There were 394 conditions reported, 377 with and 17 without identification of the infectious agent. The most frequent infectious agent was M. canis (n= 216; 54,8%) before T. mentagrophytes (n = 58; 14,7 %), T. verrucosum (n = 32; 8,1 %), T. violaceum (n = 24; 6, 1 %) and T. tonsurans (n = 15; 3,8%). Zoophilic dermatophytes (n = 306; 81,2%) predominated over anthropophilic species (n = 71; 18,8%) in the ratio of 4:1. Tinea capitis microsporica showed to be a more frequent infectious disease again which due to its high virulence and contagiosity of the infectious agent represents a therapeutical problem. Tinea capitis occured in an average age of 17,3 years. The preferred therapeutical regimen was a combination of systemic and topical antimycotics in 61,5% (n = 176) of the reported cases (n = 286). A solely topical or systemical monotherapy was reported in 25,2 % (n = 72) respectively 13,3 % (n = 38) of the patients. In case of systemic antimycotics the most frequent used drugs were griseofulvin (43,0%, n = 101), fluconazole (25,1%, n = 59) or itraconazole (18,7%; n = 44), in topical preparations ciclopiroxolamine dominated (53,3 %, n = 121) prior to clotrimazole (13,2%, n = 30) and terbinafine (7,1 %, n = 16). Different from the situation in Germany and in Southern Europe some of the western European countries show a tendency of an increase of anthropophilic agents in tinea capitis.


Use of fluorescence induction and sucrose counterselection to identify Mycobacterium tuberculosis genes expressed within host cells.
The identification of Mycobacterium tuberculosis genes expressed within host cells would contribute greatly to the development of new strategies to combat tuberculosis. By combining the natural fluorescence of the Aequoria victoria green fluorescent protein (GFP) with the counterselectable property of the Bacillus subtilis SacB protein, M. tuberculosis promoters displaying enhanced in vivo activity have been isolated. Macrophages were infected with recombinant Mycobacterium bovis bacille Calmette-Guérin containing a library of M. tuberculosis promoters controlling gfp and sacB expression, and fluorescent bacteria recovered by fluorescence-activated cell sorting. The expression of sacB was used to eliminate clones with strong promoter activity outside the macrophage, resulting in the isolation of seven clones containing M. tuberculosis promoters with greater activity intracellularly. The gene products identified displayed similarity to proteins from other organisms whose functions include nutrient utilization, protection from oxidative stress and defence against xenobiotics. These proposed functions are consistent with conditions encountered within the host cell and thus suggest that the augmented activity of the isolated promoters/genes may represent strategies employed by M. tuberculosis to enhance intracellular survival and promote infection.


Associations of lifestyle factors with quality of life (QOL) in Japanese children: a 3-year follow-up of the Toyama Birth Cohort Study.
To examine the associations between lifestyle factors and quality of life (QOL) among Japanese children. Participants were 7794 children (3869 boys and 3925 girls) aged 9-10. They completed a questionnaire regarding lifestyles at baseline survey and were followed up for 3 years. In the follow-up survey, QOL was evaluated using a Japanese version of the COOP charts. Children rated their QOL as one of five response categories. Subjects rated as 'very well' or 'pretty good' were considered to have good QOL, and the remainder was assumed to have poor QOL. Logistic regression analysis was performed to evaluate the relationship between lifestyles or changes in lifestyles and QOL. In the multivariate analysis model, age, sex, body mass index (BMI), and lifestyle factors were simultaneously entered. During the follow-up period, children became more sedentary. Compared to children participating in physical activity 'very often' at baseline, those who exercised 'almost never' were more likely to have poor QOL [OR (95% CI): 1.92 (1.26-2.93)]. Children who developed or maintained undesirable lifestyles had high OR for poor QOL. Compared to children taking breakfast 'often' during the follow-up period, those changing from 'often' to 'seldom' or those taking breakfast 'seldom' were more likely to have poor QOL [1.61 (1.24-2.07), 2.05 (1.03-4.09), respectively]. When compared with children maintaining their participation in physical activity 'often', those who changed from 'often' to 'seldom' and those who kept 'seldom' were more likely to have poor QOL [2.10 (1.84-2.39), 2.21 (1.88-2.59), respectively]. This study shows that unfavourable lifestyles in childhood are associated with poor QOL in early adolescence. Early intervention could be worth considering to keeping desirable lifestyles during childhood.


Id-1 as a molecular target in therapy for breast cancer cell invasion and metastasis.
Mammary epithelial cells constitutively expressing Id-1 protein are unable to differentiate, acquire the ability to proliferate, and invade the extracellular matrix. In addition, Id-1 is aberrantly over-expressed in aggressive and metastatic breast cancer cells, as well as in human breast tumor biopsies from infiltrating carcinomas, suggesting Id-1 might be an important regulator of breast cancer progression. We show that human metastatic breast cancer cells become significantly less invasive in vitro and less metastatic in vivo when Id-1 is down-regulated by stable transduction with antisense Id-1. Expression of the matrix metalloproteinase MT1-MMP is decreased in proportion to the decrease in Id-1 protein levels, representing a potential mechanism for the reduction of invasiveness. Further, to more accurately recapitulate the biology of and potential therapeutic approaches to tumor metastasis, we targeted Id-1 expression systemically in tumor-bearing mice by using a nonviral approach. We demonstrate significant reduction of both Id-1 and MT1-MMP expressions as well as the metastatic spread of 4T1 breast cancer cells in syngeneic BALB/c mice. In conclusion, our studies have identified Id-1 as a critical regulator of breast cancer progression and suggest the feasibility of developing novel therapeutic approaches to target Id-1 expression to reduce breast cancer metastasis in humans.


Hypoxia increases group IIA phospholipase A(2) expression under inflammatory conditions in rat renal mesangial cells.
Hypoxia evokes a common mechanism of oxygen sensing mediated by hypoxia-inducible transcription factors (HIF) in many mammalian cells. This study investigated the effect of hypoxia on group-IIA secretory phospholipase A(2) (sPLA(2)-IIA) expression in renal mesangial cells. Stimulation of cells with IL-1beta under normoxic conditions (21% O(2)) is known to induce expression and secretion of the group sPLA(2)-IIA. This induction is further enhanced by constantly reducing the O(2) concentration to 1% O(2), and is accompanied by increased sPLA(2) activity. To see whether hypoxia potentiates IL-1beta-induced sPLA(2)-IIA gene expression, a 2.67-kb fragment of the rat sPLA(2)-IIA promoter was fused to a luciferase reporter construct and used to transfect mesangial cells. Hypoxia alone is not able to activate the sPLA(2) promoter, whereas it significantly enhances IL-1beta-stimulated promoter activity. A deletion mutant of the promoter that lacks the two putative hypoxia responsive elements (HRE) is devoid of the potentiating effect of hypoxia. Moreover, site-directed mutagenesis of either of the two HRE is sufficient to abolish the potentiating effect of hypoxia. Electrophoretic mobility shift assays show that HIF-2alpha, which is the only HIF subtype expressed in mesangial cells, binds to both HRE in the sPLA(2)-IIA promoter. In summary, the data show that in an inflammatory setting hypoxia is able to potentiate sPLA(2)-IIA expression and activity in renal mesangial cells, and thereby may critically contribute to enhanced formation of inflammatory lipid mediators seen in a diverse range of kidney diseases.


Measurement and outcomes of co-production in health and social care: a systematic review of empirical studies.
Co-production is promoted as an effective way of improving the quality of health and social care but the diversity of measures used in individual studies makes their outcomes difficult to interpret. The objective is to explore how empirical studies in health and social care have described the outcomes of co-production projects and how those outcomes were measured. A scoping review forms the basis for this systematic review. Search terms for the concepts (co-produc* OR coproduc* OR co-design* OR codesign*) and contexts (health OR 'public service* OR "public sector") were used in: CINAHL with Full Text (EBSCOHost), Cochrane Central Register of Controlled trials (Wiley), MEDLINE (EBSCOHost), PsycINFO (ProQuest), PubMed (legacy) and Scopus (Elsevier). There was no date limit. Papers describing the process, original data and outcomes of co-production were included. Protocols, reviews and theoretical, conceptual and psychometric papers were excluded. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guideline was followed. The Mixed Methods Appraisal Tool underpinned the quality of included papers. 43 empirical studies were included. They were conducted in 12 countries, with the UK representing >50% of all papers. No paper was excluded due to the Mixed Methods Quality Appraisal screening and 60% of included papers were mixed methods studies. The extensive use of self-developed study-specific measures hampered comparisons and cumulative knowledge-building. Overall, the studies reported positive outcomes. Co-production was reported to be positively experienced and provided important learning. The lack of common approaches to measuring co-production is more problematic than the plurality of measurements itself. Co-production should be measured from three perspectives: outputs of co-production processes, the experiences of participating in co-production processes and outcomes of co-production. Both self-developed study-specific measures and established measures should be used. The maturity of this research field would benefit from the development and use of reporting guidelines.


The outer membrane phospholipase A is essential for membrane integrity and type III secretion in Shigella flexneri.
Outer membrane phospholipase A (OMPLA) is an enzyme located in the outer membrane of Gram-negative bacteria. OMPLA exhibits broad substrate specificity, and some of its substrates are located in the cellular envelope. Generally, the enzymatic activity can only be induced by perturbation of the cell envelope integrity through diverse methods. Although OMPLA has been thoroughly studied as a membrane protein in Escherichia coli and is constitutively expressed in many other bacterial pathogens, little is known regarding the functions of OMPLA during the process of bacterial infection. In this study, the proteomic and transcriptomic data indicated that OMPLA in Shigella flexneri, termed PldA, both stabilizes the bacterial membrane and is involved in bacterial infection under ordinary culture conditions. A series of physiological assays substantiated the disorganization of the bacterial outer membrane and the periplasmic space in the ΔpldA mutant strain. Furthermore, the ΔpldA mutant strain showed decreased levels of type III secretion system expression, contributing to the reduced internalization efficiency in host cells. The results of this study support that PldA, which is widespread across Gram-negative bacteria, is an important factor for the bacterial life cycle, particularly in human pathogens.


Reinforced Glass-ceramics: Parametric Inspection of Three-Dimensional Wear and Volumetric Loss after Chewing Simulation.
The aim of this study was to investigate the three-dimensional wear, volumetric loss and surface roughness after chewing simulation of two glass ceramics. Lithium disilicate (LD, Emax CAD, Ivoclar) and Zirconia reinforced lithium silicate (ZLS, Vita Suprinity, Vita Zhanfabrick) discs (n=20/g) were scanned to obtain stereolithography (STL) files for each sample. All discs were submitted to chewing simulation with sliding configuration (30 N, 300,000 cycles, 6 mm and 1.7 Hz) with steatite as antagonist. The samples were then scanned again and the volume loss and the deepest defect depth was measured using the superimposed file from the baseline using three-dimensional digital parametric inspection software (GOM Inspect, Braunschweig, Germany). Surface roughness (Ra and Rz) was analyzed with a contact profilometer. Data were analyzed by one-way ANOVA and Tukey test (α=0.5%). ANOVA showed significant differences among the groups. Considering the ceramic volume loss, wear depth defect length and Rz roughness, LD (-22.09±5.57%; 0.80±0.06 µm; 3.08±1.02 µm) showed higher mean values than ZLS (-15.67±4.51%; 0.56±0.09 µm; 1.51±0.90 µm). Ra mean values were similar for both materials (p=0.064). All discs exhibited slight surface scratches along with the sliding direction with pitted wear patterns, while large cracks were observed on wear traces. These same areas can be identified in blue, overlapping the STL files before and after chewing simulation in inspection software. The linear reduction generated by sliding contact shows a graph with a similar wear pattern shape. ZLS was more resistant to wear than LD, with less volume loss and shallower surface defects.


Impact of reticular pseudodrusen on microperimetry and multifocal electroretinography in intermediate age-related macular degeneration.
To examine the influence of reticular pseudodrusen (RPD) on retinal and visual function in intermediate AMD using multifocal electroretinography (mfERG) and microperimetry. In a prospective cross-sectional study, microperimetry and mfERG testing, followed by color fundus photography, near-infrared reflectance imaging and spectral-domain optical coherence tomography (SD-OCT) scans were performed in 120 eyes from 60 participants with bilateral intermediate AMD. The number of subfields with pigmentary changes and RPD within the central 3-mm diameter of the Early Treatment of Diabetic Retinopathy Study (ETDRS) grid and drusen cube root volume within the central 3-mm diameter was determined. The influence of these pathological features on microperimetry and mfERG in this region were examined. Microperimetric sensitivity was not significantly associated with the presence and extent of RPD (P = 0.068), but with drusen volume and extent of pigmentary changes (P < 0.001 for both). However, the presence and extent of RPD was independently and significantly associated with mfERG implicit time, along with drusen volume and the extent of pigmentary changes (P ≤ 0.023). The mfERG response amplitude was not significantly associated with the presence and extent of RPD (P = 0.130). The presence and extent of RPD was associated with functional changes on mfERG implicit time, but not mfERG response amplitude or microperimetry. These findings suggest that the presence of RPD in eyes with intermediate AMD has a significant influence on cone-mediated neuroretinal function, without a significant influence on mesopic visual function as determined on microperimetry.


Surgical treatment for biliary lithiasis in patients associated with chronic renal failure on hemodialysis.
Incidences of the variety of postoperative complications in surgical treatment for patients with chronic renal failure on hemodialysis is the clinically accepted opinion. The aim of this study was to ascertain the safety of surgical treatment for patients of biliary lithiasis with chronic renal failure on hemodialysis. Eleven consecutive patients with biliary lithiasis, who had a history of chronic renal failure treated with hemodialysis, were selected. The peri-operative course in-each of these cases was investigated. There was no incidence of peri-operative problems and postoperative complications in cases treated with laparoscopic cholecystectomy. One case treated with cholecystectomy with laparotomy had a slight degree of postoperative pneumonia, which soon improved after administration of antibiotics. Only one case, treated with choledochotomy, resulted in operative death due to accidental septic shock from an unknown origin. Surgical treatment of patients with biliary lithiasis and chronic renal failure on hemodialysis can be safely performed with appropriate operative indications and noninvasive surgical techniques.


[Cellular organization of the vestibular nucleus of the frog medulla oblongata].
Ventral vestibular nucleus of frogs is composed by multipolar cells of isodendritic type. Three basic kinds of cells are found in the nucleus-large, medium and small ones which differ mainly by the number of synaptic contacts on their perikaryon. The neuropile of the vestibular nucleus contains a large number of unmyelinated nervous fibers and exhibits numerous contacts formed along each of the fibers. Similar features in the organization of ventral vestibular nucleus in frogs and Deuters nucleus in rats and cats are noted. Functional role of cellular elements composing the nucleus is discussed.


Survival after somatostatin based radiopeptide therapy with (90)Y-DOTATOC vs. (90)Y-DOTATOC plus (177)Lu-DOTATOC in metastasized gastrinoma.
We aimed to explore the effects of (90)Y-DOTATOC and (90)Y-DOTATOC plus (177)Lu-DOTATOC on survival of patients with metastasized gastrinoma. Patients with progressive metastasized gastrinoma were treated with repeated cycles of (90)Y-DOTATOC or with cycles alternating between (90)Y-DOTATOC and (177)Lu-DOTATOC until tumor progression or permanent toxicity. Multivariable Cox regression analyses were used to study predictors of survival. A total of 36 patients were enrolled; 30 patients received (90)Y-DOTATOC (median activity per patient 11.8GBq; range: 6.1-62.2GBq) and 6 patients received (90)Y-DOTATOC plus (177)Lu-DOTATOC (median activity per patient: 14.8GBq; range: 7.4-14.8GBq). Response was found in 26 patients (72.2%), including morphological (n=12, 33.3%), biochemical (n=14, 38.9%) and/or clinical response (n=6, 16.2%). A total of 21 patients (58.3%) experienced hematotoxicity grade 1/2, while 1 patient (2.8%) experienced hematotoxicity grade 3; no grade 4 hematotoxicity occurred. Furthermore, 2 patients (5.6%) developed grade 4 renal toxicity; no grade 5 renal toxicity occurred. Responders had a significantly longer median survival from time of enrollment than non-responders (45.1 months, range: 37.1-53.1 months vs. 12.6 months, range: 11.0-14.2, hazard ratio: 0.12 (0.027-0.52), p=0.005). Additionally, there was a trend towards longer median survival with (90)Y-DOTATOC plus (177)Lu-DOTATOC as compared to (90)Y-DOTATOC alone (60.2 months, range: 19.8-100.6 months vs. 27.0 months, range: 4.0-50.0, hazard ratio: 0.21 (0.01-3.98), p=0.16). Response to (90)Y-DOTATOC and (90)Y-DOTATOC plus (177)Lu-DOTATOC therapy is associated with a longer survival in patients with metastasized gastrinoma. Both treatment regimens are promising tools for management of progressive gastrinoma.


[Special features of mild cognitive impairment in patients with metabolic syndrome].
Aim: to establish special features of mild cognitive impairment (MCI) in patients with chronic insufficiency of cerebral circulation (CICC) with metabolic syndrome (MS) depending on the age of patients. Investigation involved 282 patients aged 45-89 with CICC. All the patients also were divided into three groups depending on age; each group was divided into two subgroups: with MS and without it. Total MMSE score in patients with MS and without it of all age groups was not significantly different. We found significant difference between groups of patients in some MMSE tests: orientation in time, orientation in space, remembering of three words, attention and count, words reproduction. Presence of MS in patients with MCI syndrome of all age groups negatively influenced on such cognitive functions as: storage and reproduction of information, attention, orientation in time (processes depicting state of executive functions). In patients with MS, comparing with those without MS, we found significantly worse characteristics of immediate and delayed memory for verbal stimuli, especially in old aged patients, the rate of sensorimotor reactions, mental capacity, the amount of active attention of patients on tables Schulte, information processing speed and attention according to SCWT for all age groups.


CLASH-A Compliant Sensorized Hand for Handling Delicate Objects.
Automation of logistic tasks, such as object picking and placing, is currently one of the most active areas of research in robotics. Handling delicate objects, such as fruits and vegetables, both in warehouses and in plantations, is a big challenge due to the delicacy and precision required for the task. This paper presents the CLASH hand, a Compliant Low-Cost Antagonistic Servo Hand, whose kinematics was specifically designed for handling groceries. The main feature of the hand is its variable stiffness, which allows it to withstand collisions with the environment and also to adapt the passive stiffness to the object weight while relying on a modular design using off-the-shelf low-cost components. Due to the implementation of differentially coupled flexors, the hand can be actuated like an underactuated hand but can also be driven with different stiffness levels to planned grasp poses, i.e., it can serve for both model-based grasp planning and for underactuated or model-free grasping. The hand also includes self-checking and logging processes, which enable more robust performance during grasping actions. This paper presents key aspects of the hand design, examines the robustness of the hand in impact tests, and uses a standardized fruit benchmarking test to verify the behavior of the hand when different actuator and sensor failures occur and are compensated for autonomously by the hand.


Harnessing innate immunity in cancer therapy.
New therapies that promote antitumour immunity have been recently developed. Most of these immunomodulatory approaches have focused on enhancing T-cell responses, either by targeting inhibitory pathways with immune checkpoint inhibitors, or by targeting activating pathways, as with chimeric antigen receptor T cells or bispecific antibodies. Although these therapies have led to unprecedented successes, only a minority of patients with cancer benefit from these treatments, highlighting the need to identify new cells and molecules that could be exploited in the next generation of immunotherapy. Given the crucial role of innate immune responses in immunity, harnessing these responses opens up new possibilities for long-lasting, multilayered tumour control.


Identification of S1PR3 gene signature involved in survival of sepsis patients.
Sepsis is a life-threatening complication of infection that rapidly triggers tissue damage in multiple organ systems and leads to multi-organ deterioration. Up to date, prognostic biomarkers still have limitations in predicting the survival of patients with sepsis. We need to discover more prognostic biomarkers to improve the sensitivity and specificity of the prognosis of sepsis patients. Sphingosine-1-phosphate (S1P) receptor 3 (S1PR3), as one of the S1P receptors, is a prospective prognostic biomarker regulating sepsis-relevant events, including compromised vascular integrity, antigen presentation, and cytokine secretion. Until now, no S1PR3-related prognostic gene signatures for sepsis patients have been found. This study intends to obtain an S1PR3-associated gene signature from whole blood samples to be utilized as a probable prognostic tool for patients with sepsis. We obtained an 18-gene S1PR3-related molecular signature (S3MS) from the intersection of S1PR3-associated genes and survival-associated genes. Numerous important immunity pathways that regulate the progression of sepsis are enriched among our 18 genes. Significantly, S3MS functions greatly in both the discovery and validation cohort. Furthermore, we demonstrated that S3MS obtains significantly better classification performance than random 18-gene signatures. Our results confirm the key role of S1PR3-associated genes in the development of sepsis, which will be a potential prognostic biomarker for patients with sepsis. Our results also focus on the classification performance of our S3MS as biomarkers for sepsis, which could also provide an early warning system for patients with sepsis.


Applications of Prodigiosin Extracted from Marine Red Pigmented Bacteria Zooshikella sp. and Actinomycete Streptomyces sp.
This study is aimed to determine the distribution, diversity and bioprospecting aspects of marine pigmented bacteria (MPB) isolated from pristine Andaman Islands, India. A total of 180 samples including seawater, sediment, marine plants, invertebrates, and vertebrates were collected and investigated for isolating pigmented bacteria. Results revealed that sediment, invertebrates, and seawater samples were colonized with a greater number of pigmented bacteria pertains to 27.9 × 103 CFU/mL, 24.1 × 103 CFU/mL and 6.7 × 103 CFU/mL respectively. Orange (21.6 × 103 CFU/mL) and red (8.0 × 103 CFU/mL) MPB were predominant than other pigmented bacteria. Fourteen potential MPB were selected based on their intense pigmentation and tested for bioactive nature and food colorant applications. Out of 14, two red pigmented strains BSE6.1 & S2.1 displayed potential multifaceted applications, such as antibacterial, antioxidant, food colorant, and staining properties. Brown pigmented strains CO8 and yellow pigmented strain SQ2.3 have displayed staining properties. Chemical characterization of red pigment using TLC, HP-LC, GC-MS, FT-IR and 1H-NMR analysis revealed prodigiosin as a main chemical constituent. Pure form of prodigiosin compound fractions obtained from both the strains displayed effective antibacterial activity against different human pathogens. MIC and MBC assays revealed that S2.1 requires 300 µg and 150 µg, respectively, and BSE6.1 require 400 µg concentrations of pigment compound for complete inhibition of S. aureus subsp. aureus. On the basis of 16S rRNA sequence analysis, strains S2.1 and BSE6.1 were identified as Zooshikella sp. and Streptomyces sp. and assigned under the GenBank accession numbers: MK680108 and MK951781 respectively.


Specific cross-talk between epidermal growth factor receptor and integrin alphavbeta5 promotes carcinoma cell invasion and metastasis.
Tyrosine kinase receptors and integrins play essential roles in tumor cell invasion and metastasis. Previously, we showed that epidermal growth factor (EGF) stimulation of pancreatic carcinoma cells led to invasion and metastasis that was blocked by antagonists of integrin alpha(v)beta(5). Here, we show that EGF stimulates metastasis of carcinoma cells via a Src-dependent phosphorylation of p130 CAS leading to activation of Rap1, a small GTPase involved in integrin activation. Specifically, EGF receptor (EGFR)-induced Src activity leads to phosphorylation of a region within the CAS substrate domain, which is essential for Rap1 and alpha(v)beta(5) activation. This pathway induces alpha(v)beta(5)-mediated invasion and metastasis in vivo yet does not influence primary tumor growth or activation of other integrins on these cells. These findings show cross-talk between a tyrosine kinase receptor and an integrin involved in carcinoma cell invasion and metastasis and may explain in part how inhibitors of EGFR affect malignant disease.


Does selective use of computed tomography scan reduce the rate of "white" (negative) appendectomy?
Appendectomies are the most common operations performed on an emergency basis. The accepted rate of "white" appendectomies is around 20%. In recent years, computed tomography (CT) scanning has been recognized as a valuable tool with high sensitivity and specificity in the diagnosis of acute appendicitis. The use of CT scans in the management of patients with suspected acute appendicitis is increasing worldwide. To assess whether introducing more liberal use of CT in the management of patients presenting to the emergency room with right lower quadrant pain or suspected acute appendicitis would reduce the rate of "white" appendectomies. We conducted a retrospective study of the pathology reports and CT scans of all patients who underwent appendectomy during a 3 year period. We examined the correlation between the rate of CT scans performed and the rate of "white" appendectomies. Overall, we performed 797 appendectomies during the study period. In 2004, we performed 272 appendectomies and CT in 34 patients (12.5%). In 2005, we performed 275 appendectomies and CT in 83 patients (30.2%). In 2006, we performed 250 appendectomies and CT in 88 patients (35.2%). The percentage of "white" appendectomies decreased from 29% in 2004 to 21.1% in 2005 and to 18.8% in 2006. It appears that a more selective use of CT scans in the management of suspected appendicitis could reduce the rate of "white" appendectomies.


Recruitment for a hospital-based pragmatic clinical trial using volunteer nurses and students.
Recruitment of subjects is critical to the success of any clinical trial, but achieving this goal can be a challenging endeavor. Volunteer nurse and student enrollers are potentially an important source of recruiters for hospital-based trials; however, little is known of either the efficacy or cost of these types of enrollers. We assessed volunteer clinical nurses and health science students in their rates of enrolling family members in a hospital-based, pragmatic clinical trial of cardiopulmonary resuscitation education, and their ability to achieve target recruitment goals. We hypothesized that students would have a higher enrollment rate and are more cost-effective compared to nurses. Volunteer nurses and student enrollers were recruited from eight institutions. Participating nurses were primarily bedside nurses or nurse educators while students were pre-medical, pre-nursing, and pre-health students at local universities. We recorded the frequency of enrollees recruited into the clinical trial by each enroller. Enrollers' impressions of recruitment were assessed using mixed-methods surveys. Cost was estimated based on enrollment data. Overall enrollment data were analyzed using descriptive statistics and generalized estimating equations. From February 2012 to November 2014, 260 hospital personnel (167 nurses and 93 students) enrolled 1493 cardiac patients' family members, achieving target recruitment goals. Of those recruited, 822 (55%) were by nurses, while 671 (45%) were by students. Overall, students enrolled 5.44 (95% confidence interval (CI): 2.88, 10.27) more subjects per month than nurses (p < 0.01). After consenting to participate in recruitment, students had a 2.85 (95% CI: 1.09, 7.43) increased chance of enrolling at least one family member (p = 0.03). Among those who enrolled at least one subject, nurses enrolled a mean of 0.51(95% CI: 0.42, 0.59) subjects monthly, while students enrolled 1.63 (95% CI: 1.37, 1.90) per month (p < 0.01). Of 198 surveyed hospital personnel (127 nurses, 71 students), 168/198 (85%) felt confident conducting enrollment. The variable cost per enrollee recruited was $25.38 per subject for nurses and $23.30 per subject for students. Overall, volunteer students enrolled more subjects per month at a lower cost than nurses. This work suggests that recruitment goals for a pragmatic clinical trial can be successfully obtained using both nurses and students.


Nosocomial infection in an intensive-care unit: identification of risk factors.
To identify risk factors predictive of nosocomial infection in an intensive-care unit (ICU) and to identify patients with a higher risk of nosocomial infection using a predictive model of nosocomial infection in our ICU. Prospective study; daily concurrent surveillance of intensive-care-unit patients. All patients admitted for at least 24 hours to the ICU of a tertiary-level hospital from February to November 1994 were followed daily. Variables measuring extrinsic and intrinsic risk factors for nosocomial infection were collected on each patient during their ICU stay, and the Cox Proportional Hazards multivariable technique was used to identify the variables significantly associated with infection. The population studied consisted of 944 patients. The main risk factors identified were intrinsic; the significant extrinsic risk factors identified were head of the bed in a horizontal (< 30 degrees) position (this variable presented the highest increase of the infection hazard ratio) and the use of sedative medication. Patients presenting the highest risk scores using the predictive model are those with the highest risk of nosocomial infection. The important preventive measures derived from our results are that underlying conditions suffered by the patient at the ICU admission should be corrected promptly, the depression of the patient's level of consciousness with sedatives should be monitored carefully, and the horizontal position of the head of the bed should be avoided totally. Patients with a high risk of infection can be the target of special preventive measures.


Baseline factors predicting the need for corneal crosslinking in patients with keratoconus.
The primary purpose of crosslinking is to halt the progression of ectasia. We retrospectively assessed the condition of keratoconus patients who were followed-up at least twice after the initial examination to evaluate keratoconus progression, to identify definitive factors to predict a later need for corneal crosslinking (CXL). The medical charts of 158 eyes of 158 keratoconus patients (112 males and 46 females; mean age, 27.8 ± 11.7 years), who were followed up at the Department of Ophthalmology, Keio University School of Medicine at least twice after the initial examination to evaluate keratoconus progression were retrospectively reviewed. Best-spectacle corrected visual acuity, intraocular pressure, steepest corneal axis on the anterior float (Ks), thinnest corneal thickness according to Pentacam® HR, and corneal endothelial cell density were assessed. Gender, age, onset age of keratoconus, history of atopic dermatitis, and Pentacam® indices were also recorded. CXL was performed when the eye showed significant keratoconus progression, an increase in the steepest keratometric value, or an increase in the spherical equivalent or cylinder power of the manifest refraction by more than 1.0 D versus the respective values 2 years prior. Predictor variables and the requirement for CXL were analyzed using logistic regression. Fifty-eight eyes required CXL treatment. The best predictor of the requirement for CXL was patient age, followed by the Pentacam® Rmin (the minimum sagittal curvature evaluated by Pentacam®) value. The incidence of CXL was 86.4% in the < 20 years age group, with an Rmin of ≤ 5.73 mm, whereas 10.8% in the ≥ 27 years age group with an Rmin > 5.73 mm underwent treatment. An age of < 20 years and an Rmin value of ≤ 5.73 mm predicted keratoconus progression and the requirement for CXL treatment in the near future.


The Mind Body Connection in Dermatologic Conditions: A Literature Review.
Psychodermatology pertains to the relationship between the skin and brain. This review aims to summarize the evidence of the mind body connection in four psychophysiological conditions: rosacea, atopic dermatitis (AD), acne vulgaris (AV), and psoriasis. A literature search was conducted using several English language databases. All four conditions share similar psychiatric co-morbidities, including but not limited to anxiety, depression, and suicidality. In rosacea, the upregulation of transient receptor potential vanilloid type 1, Toll like receptor 2, and Th17 cells releases downstream products that are simultaneously implicated in mood disorders. Stress exacerbates AV through the hypothalamic-pituitary-adrenal (HPA) system, which alters functioning of sebocytes and Cutibacterium acnes. In AD and psoriasis, the HPA axis influences Th1, Th2, Th22, and Th1, Th17 immune mediated responses, respectively. This leads to the secretion of pro-inflammatory cytokines which are also involved in the pathogenesis of anxiety and depression. Neurotransmitters implicated in mental illness, such as gamma-aminobutyric acid and serotonin, may also play a role in the development of AD and psoriasis. The management of cutaneous disease may mitigate psychological distress, and future research may show the corollary to also be true.


[Frontal extranasal glioma].
Extranasal gliomas are very rare tumours, being difficult to diagnose preoperatively due to the unspecific nature of symptoms and, at times, of the test. A newborn baby, prenatally diagnosed with frontal tumour, which on exploration showed a mass at the root of the nose, red-violet in colour and which seemed to become tenser. Skull x-ray and brain ultra-sound were normal. Ultra-sound of the tumour area and TAC showed a mass with solid content, with possible intracraneal communication. Faced with this possibility, removal by neurosurgical procedures was performed with no communications with SNC being observed. Histological diagnosis: extra-nasal glioma. Tumours situated at the root of the nose can have normal skin covering whose aspect is similar to the tumour mentioned above. Test carried out may not show accurately whether the tumour communicates with SNC or not, which may lead to surgical errors. We recommend that these malformations be treated directly by surgical teams which include neurosurgical specialists.


L-Leucine In Ovo Administration Causes Growth Retardation and Modifies Specific Amino Acid Metabolism in Broiler Embryos.
L-Leucine (L-Leu) in ovo administration was demonstrated to afford thermotolerance and modified amino acids metabolism in post-hatched broiler chicks under heat stress. This study aimed to investigate the changes in embryonic growth and amino acid metabolism after in ovo injection of L-Leu. Fertilized broiler eggs were subjected to in ovo injection of sterile water or L-Leu on embryonic day (ED) 7. The weight of embryos and yolk sacs were measured on ED 12, 14, 16, and 18. Plasma and livers were collected on ED 14 and 18 for free amino acid analysis. The weight and relative weight of embryos were significantly lowered by in ovo administration of L-Leu, but those of yolk sacs were not altered. Moreover, L-Leu in ovo injection significantly reduced the plasma proline concentration during embryogenesis and increased the plasma concentrations of tyrosine (Tyr) and lysine (Lys) in ED 18. Hepatic Lys concentration was also significantly increased by L-Leu in ovo injection. Interestingly, Leu concentrations in the plasma and liver were not affected by L-Leu administration. These results indicated that in ovo administered L-Leu was metabolized before ED 14 and affected embryonic growth and amino acid metabolism during embryogenesis.


Two subunits specific to the PBAP chromatin remodeling complex have distinct and redundant functions during drosophila development.
Chromatin remodeling complexes control the availability of DNA binding sites to transcriptional regulators. Two distinct conserved forms of the SWI/SNF class of complexes are characterized by the presence of specific accessory subunits. In Drosophila, the core Brahma complex associates either with Osa to form the BAP complex or with Bap170 and Bap180 to form the PBAP complex. osa mutations reproduce only a subset of the developmental phenotypes caused by mutations in subunits of the core complex. To test whether the PBAP complex performs the remaining functions, we generated mutations in bap170 and bap180. Surprisingly, we found that Bap180 is not essential for viability, although it is required in ovarian follicle cells for normal eggshell development. Bap170 is necessary to stabilize the Bap180 protein, but a mutant form that retains this function is sufficient for both survival and fertility. The two subunits act redundantly to allow metamorphosis; using gene expression profiling of bap170 bap180 double mutants, we found that the PBAP complex regulates genes involved in tissue remodeling and immune system function. Finally, we generated mutants lacking Bap170, Bap180, and Osa in the germ line to demonstrate that the core Brahma complex can function in oogenesis without any of these accessory subunits.


Anomalous alterations affecting microglia in the central nervous system of a fetus at 12 weeks of gestation: case report.
We report here on the first documented case of profound alterations specifically affecting the microglial population within the nervous system during the fetal period. This case, derived at gestational week 12, was one amongst a series of second trimester brains currently being investigated with respect to microglial colonization of the human fetal brain. No significant pathological alterations could be identified upon gross macroscopy or following microscopic analysis of serial brain sections stained with cresyl fast violet (Nissl). By contrast, sections stained immunohistochemically to detect MHC class II (CR3/43) and CD68 (PG-M1) antigens revealed a marked pathological change in the morphology and density of microglia within the CNS. Specifically, labeled cells within the rostral telencephalon were clearly hypertrophied and emitted numerous, branched processes in all directions, appearing in an atypical 'hyper-ramified' state uncharacteristic of microglia found in normal brains at this age. However, cells located elsewhere in the CNS (for example in the thalamus and internal capsule) appeared in a less differentiated state (small, rounded cells lacking processes) when compared to those within normal age-matched control brains. The total density and distribution of these labeled cells far outnumbered that seen in normal development. As far as we are aware, such an anomaly specifically affecting microglia, has not been documented previously. Consequently, this case represents the first of its kind, and the remarkable observations outlined in this study bear considerable significance from a neuropathological standpoint for future investigations into pathological changes affecting microglia in the central nervous system during the fetal period.


[Spironolactone in the treatment of portal hypertension in liver cirrhosis. A new therapeutic principle?].
Five patients with liver cirrhosis, portal hypertension and oesophageal varices received spironolactone in daily doses of 50-200 mg. Measurements of hepatic vein occlusion pressure at intervals of 1 to 5 months showed a pressure reduction of between 9 and 11 mm Hg. Thus the pressure lowering effect of spironolactone is about the same as that of beta-blockers. Since spironolactone is without the well known side effects of beta-blockers this therapeutic approach has wide application in the long term drug therapy of portal hypertension.


More is less: a disinhibited prefrontal cortex impairs cognitive flexibility.
The prefrontal cortex (PFC) is critical for decision making, and it becomes dysfunctional in many neuropsychiatric disorders. Studies in schizophrenia patients and relevant animal models suggest loss of PFC inhibitory interneuron function. For instance, rats with a neonatal ventral hippocampal lesion (NVHL) show a deficient modulation of PFC interneurons by dopamine (DA). Whether the PFC becomes disinhibited in this model and alters decision making remains to be determined. Here, we recorded neural activity in the medial PFC of NVHL rats during a reward-discounting choice task that activated DA systems. Rats were trained to sample odors that instructed them to select one of two feeders that delivered unequal amounts of liquid. Putative pyramidal neurons in the PFC were hyperactive whereas task-related field potential oscillations were significantly reduced in NVHL rats, consistent with impaired interneuron activation by DA during odor sampling leading to disorganized processing. Cognitive flexibility was tested by examining response bias and errors after reversing reward outcomes. NVHL rats demonstrated impaired flexibility as they were less able to track changes in reward outcome and made more response errors than controls did. Reducing cortical excitability with the metabotropic glutamate receptor 2/3 agonist LY379268 (1 mg/kg, i.p.) improved behavioral flexibility in NVHL rats but not controls. Furthermore, D2 dopamine receptors were involved, as the antagonist eticlopride (0.02 mg/kg, i.p.) reduced the ability to switch only in control animals. We conclude that NVHL rats present PFC disinhibition, which affects neural information processing and the selection of appropriate behavioral responses.


Fertility intentions: are the undecided more like those who want more or want no more children?
In fertility surveys often women (and sometimes men) are asked their fertility desires, i.e. whether they want a/nother birth or not. Some respond that they are undecided. This study examines whether these persons are more like those who say they want more births or like those who say they want no more births. Data on married men and women in 29 Demographic and Health Surveys with sample sizes ranging from 300 to 3000 are used. A logistic regression equation is estimated within each country for those with known desires and then used to classify each person who was undecided. In all sub-Saharan African countries (n=20) and for both sexes, 50% or more of the undecided persons are classified as wanting more children (with one exception of wives in Kenya). By contrast in all five Latin American countries for both sexes less than 50% of the undecided were classified in the 'want more' group (with an exception of husbands in the Dominican Republic). Generally, the undecided tend to be classified the same as the majority among those in the survey with stated desires.


Spina bifida children attending ordinary schools.
From September 1971 to September 1973 a policy was actively followed in South Gloucestershire of placing spina bifida children in ordinary schools wherever possible. This was achieved successfully in 14 cases out of a possible 24. Special attention was paid to the selection of children and schools. The main contraindications to attendance at ordinary school were: below average intelligence, special perceptual problems, the need for intensive physiotherapy, and problem incontinence-particularly infaecal continence. Success often depended on special provisions-for example, transport, aids to mobility, peripatetic physiotherapists. Personal attendants (welfare assistants) could be allocated to each of the more severely handicapped children. The lack of facilities for handicapped pupils in comprehensive schools is a matter needing urgent review.


Bradykinesia-akinesia incoordination test: validating an online keyboard test of upper limb function.
The Bradykinesia Akinesia Incoordination (BRAIN) test is a computer keyboard-tapping task that was developed for use in assessing the effect of symptomatic treatment on motor function in Parkinson's disease (PD). An online version has now been designed for use in a wider clinical context and the research setting. Validation of the online BRAIN test was undertaken in 58 patients with Parkinson's disease (PD) and 93 age-matched, non-neurological controls. Kinesia scores (KS30, number of key taps in 30 seconds), akinesia times (AT30, mean dwell time on each key in milliseconds), incoordination scores (IS30, variance of travelling time between key presses) and dysmetria scores (DS30, accuracy of key presses) were compared between groups. These parameters were correlated against total motor scores and sub-scores from the Unified Parkinson's Disease Rating Scale (UPDRS). Mean KS30, AT30 and IS30 were significantly different between PD patients and controls (p≤0.0001). Sensitivity for 85% specificity was 50% for KS30, 40% for AT30 and 29% for IS30. KS30, AT30 and IS30 correlated significantly with UPDRS total motor scores (r = -0.53, r = 0.27 and r = 0.28 respectively) and motor UPDRS sub-scores. The reliability of KS30, AT30 and DS30 was good on repeated testing. The BRAIN test is a reliable, convenient test of upper limb motor function that can be used routinely in the outpatient clinic, at home and in clinical trials. In addition, it can be used as an objective longitudinal measurement of emerging motor dysfunction for the prediction of PD in at-risk cohorts.


Surgical management of pneumothorax in patients with acquired immunodeficiency syndrome.
Pneumocystis carinii pneumonia in a patient with acquired immunodeficiency syndrome may cause severe alveolar damage, resulting in pneumothoraces that are often bilateral, recurrent, and refractory to accepted methods of treatment. The clinical features, management, and follow-up results were assessed in 22 consecutive patients who presented with a pneumothorax and acquired immunodeficiency syndrome. Seventeen patients died within the time frame of this study. Their average survival time was 147 days. Five surviving patients have lived an average of 366 days. We proposed an algorithm to assist in the management of pneumothoraces in these patients. We concluded that pneumothorax in patients with acquired immunodeficiency syndrome is prognostic of short-term survival. The results in the treatment of pneumothorax in the patient with acquired immunodeficiency syndrome are related to the pathologic lesions of the lung that are associated with Pneumocystis pneumonia and not to the surgical treatment that is employed.


The spectrum of left ventricular hypertrophy in a general population sample: the Framingham Study.
To assess the prevalence, characteristics, and correlates of echocardiographically determined left ventricular hypertrophy (echo LVH) in a free-living population, 510 men and 855 women from the original Framingham cohort (age 59 to 90 years) were studied by M-mode echocardiography. Offspring and offspring spouses (1718 men and 1892 women; age 17 to 75 years) were similarly studied. The severity of echo LVH, as reflected by left ventricular mass indexed to body surface area, ranged from 101 g/m2 (women) and 132 g/m2 (men) to more than 400 g/m2. The prevalence of electrocardiographically assessed LVH increased proportionately with increased echocardiographic left ventricular mass. Women with echocardiographic left ventricular mass indexes exceeding 200 g/m2 were three to four times more likely to have electrocardiographic LVH than men with similar elevations of echocardiographic left ventricular mass index. The prevalence of echo LVH ranged from 6.6% in the younger (offspring study) women to 33% in the older (original cohort) women (8.6% and 23.7%, respectively, for men) and included a spectrum of forms--eccentric-dilated, eccentric-nondilated, concentric, and disproportionate septal thickness--which varied in prevalence in the various age-sex groups. Each of these forms of echo LVH was associated with higher systolic blood pressures at the time of echocardiographic examination and over the previous 30 years when compared with blood pressures of Framingham subjects without echo LVH.


Methodological aspects of whole-genome bisulfite sequencing analysis.
The combination of DNA bisulfite treatment with high-throughput sequencing technologies has enabled investigation of genome-wide DNA methylation beyond CpG sites and CpG islands. These technologies have opened new avenues to understand the interplay between epigenetic events, chromatin plasticity and gene regulation. However, the processing, managing and mining of this huge volume of data require specialized computational tools and statistical methods that are yet to be standardized. Here, we describe a complete bisulfite sequencing analysis workflow, including recently developed programs, highlighting each of the crucial analysis steps required, i.e. sequencing quality control, reads alignment, methylation scoring, methylation heterogeneity assessment, genomic features annotation, data visualization and determination of differentially methylated cytosines. Moreover, we discuss the limitations of these technologies and considerations to perform suitable analyses.


Primary production and rain use efficiency across a precipitation gradient on the Mongolia Plateau.
Understanding how the aboveground net primary production (ANPP) of arid and semiarid ecosystems of the world responds to variations in precipitation is crucial for assessing the impacts of climate change on terrestrial ecosystems. Rain-use efficiency (RUE) is an important measure for acquiring this understanding. However, little is known about the response pattern of RUE for the largest contiguous natural grassland region of the world, the Eurasian Steppe. Here we investigated the spatial and temporal patterns of ANPP and RUE and their key driving factors based on a long-term data set from 21 natural arid and semiarid ecosystem sites across the Inner Mongolia steppe region in northern China. Our results showed that, with increasing mean annual precipitation (MAP), (1) ANPP increased while the interannual variability of ANPP declined, (2) plant species richness increased and the relative abundance of key functional groups shifted predictably, and (3) RUE increased in space across different ecosystems but decreased with increasing annual precipitation within a given ecosystem. These results clearly indicate that the patterns of both ANPP and RUE are scale dependent, and the seemingly conflicting patterns of RUE in space vs. time suggest distinctive underlying mechanisms, involving interactions among precipitation, soil N, and biotic factors. Also, while our results supported the existence of a common maximum RUE, they also indicated that its value could be substantially increased by altering resource availability, such as adding nitrogen. Our findings have important implications for understanding and predicting ecological impacts of global climate change and for management practices in arid and semiarid ecosystems in the Inner Mongolia steppe region and beyond.


Association Between Rome Classification Among Hospitalized Patients With COPD Exacerbations and Short-Term and Intermediate-Term Outcomes.
Recently, the Rome proposal updated the definition of exacerbation of COPD (ECOPD). However, such severity grade has not yet demonstrated intermediate-term clinical relevance. What is the association between the Rome severity classification and short-term and intermediate-term clinical outcomes? We retrospectively grouped hospitalized patients with ECOPD according to the Rome severity classification (ie, mild, moderate, severe). Baseline, clinical, microbiologic, gas analysis, and laboratory variables were collected. In addition, data about the length of hospital stay and mortality (in-hospital and a follow-up time line from 6 months until 3 years) were assessed. Of the 347 hospitalized patients, 39% were categorized as mild, 31% were categorized as moderate, and 30% were categorized as severe. Overall, patients with severe ECOPD had an extended length of hospital stay. Although in-hospital mortality was similar among groups, patients with severe ECOPD presented a worse prognosis in all follow-up time points. The Kaplan-Meier curves show the role of the severe classification in the cumulative survival at 1 and 3 years (Gehan-Breslow-Wilcoxon test, P = .032 and P = .004, respectively). The multivariable Cox regression analysis showed a higher risk of death at 1 year when patients presented a severe (hazard ratio, 1.99; 95% CI, 1.49-2.65) or moderate grade (hazard ratio, 1.47; 95% CI, 1.10-1.97) compared with a mild grade. Older patients (aged ≥ 80 years), patients requiring long-term oxygen therapy, or patients reporting previous ECOPD episodes had a higher mortality risk. A BMI between 25 and 29 kg/m2 was associated with a lower risk. The Rome classification makes it possible to discriminate patients with a worse prognosis (severe or moderate) until a 3-year follow-up.


Device comparison study to measure nasal nitric oxide in relation to primary ciliary dyskinesia.
Primary ciliary dyskinesia (PCD) is a genetic respiratory disease characterized by chronic cough, recurrent respiratory infections, and rhinosinusitis. The measurement of nasal nitric oxide (nNO) against resistance has been suggested as a sensitive screening method. However, current recommendations argue for the use of expensive, chemiluminescence devices to measure nNO. This study aimed to compare nNO measurement using three different devices in distinguishing PCD patients from healthy controls and cystic fibrosis (CF) patients and to evaluate their diagnostic precision. The study included 16 controls, 16 PCD patients, and 12 CF patients matched for age and sex. nNO measurements were performed using a chemiluminescence device (Eco Medics CLD 88sp), and two devices based on electrochemical sensors (Medisoft FeNO+ and NIOX Vero) following standardized guidelines. Correlation estimation, Bland-Altman, ROC curve, and one-way ANOVA were used to assess device differences and diagnostic performance. Significantly lower nNO output values were observed in PCD and CF patients compared to controls during exhalation against resistance. The correlation analysis showed high agreement among the three devices. ROC curve analysis demonstrated 100% sensitivity and specificity at different cut-off values for all devices in distinguishing PCD patients from controls (optimal cut-offs: EcoMedics 73, Medisoft 92 and NIOX 87 (nl min-1)). Higher nNO output values were obtained with the Medisoft and NIOX devices as compared to the EcoMedics device, with a bias of-19 nl min-1(95% CI: -73-35) and -21 nl min-1(-73-31) accordingly. These findings indicate that all three tested devices can potentially serve as diagnostic tools for PCD if device specific cut-off values are used. This last-mentioned aspect warrants further studies and consideration in defining optimal cut-offs for individual device.


Origins and Evolution of Stomatal Development.
The fossil record suggests stomata-like pores were present on the surfaces of land plants over 400 million years ago. Whether stomata arose once or whether they arose independently across newly evolving land plant lineages has long been a matter of debate. In Arabidopsis, a genetic toolbox has been identified that tightly controls stomatal development and patterning. This includes the basic helix-loop-helix (bHLH) transcription factors SPEECHLESS (SPCH), MUTE, FAMA, and ICE/SCREAMs (SCRMs), which promote stomatal formation. These factors are regulated via a signaling cascade, which includes mobile EPIDERMAL PATTERNING FACTOR (EPF) peptides to enforce stomatal spacing. Mosses and hornworts, the most ancient extant lineages to possess stomata, possess orthologs of these Arabidopsis (Arabidopsis thaliana) stomatal toolbox genes, and manipulation in the model bryophyte Physcomitrella patens has shown that the bHLH and EPF components are also required for moss stomatal development and patterning. This supports an ancient and tightly conserved genetic origin of stomata. Here, we review recent discoveries and, by interrogating newly available plant genomes, we advance the story of stomatal development and patterning across land plant evolution. Furthermore, we identify potential orthologs of the key toolbox genes in a hornwort, further supporting a single ancient genetic origin of stomata in the ancestor to all stomatous land plants.


Blocking IL-1 in systemic inflammation.
A growing number of systemic inflammatory diseases characterized in part by recurrent fevers, leukocytosis, anemia, and elevated acute phase proteins are linked to interleukin (IL)-1 activity since rapid and sustained resolution is observed upon specific blockade of IL-1 receptors. Rapid resolution of systemic and local inflammation is now also reported in systemic onset juvenile idiopathic arthritis (SoJIA). Loss of control of the secretion of IL-1beta might be a common mechanism explaining the aberrant activity of IL-1 in these diseases.


CETP expression reverses the reconstituted HDL-induced increase in VLDL.
Human data suggest that reconstituted HDL (rHDL) infusion can induce atherosclerosis regression. Studies in mice indicated that rHDL infusion adversely affects VLDL levels, but this effect is less apparent in humans. This discrepancy may be explained by the fact that humans, in contrast to mice, express cholesteryl ester transfer protein (CETP). The aim of this study was to investigate the role of CETP in the effects of rHDL on VLDL metabolism by using APOE*3-Leiden (E3L) mice, a well-established model for human-like lipoprotein metabolism. At 1 h after injection, rHDL increased plasma VLDL-C and TG in E3L mice, but not in E3L mice cross-bred onto a human CETP background (E3L.CETP mice). This initial raise in VLDL, caused by competition between rHDL and VLDL for LPL-mediated TG hydrolysis, was thus prevented by CETP. At 24 h after injection, rHDL caused a second increase in VLDL-C and TG in E3L mice, whereas rHDL had even decreased VLDL in E3L.CETP mice. This secondary raise in VLDL was due to increased hepatic VLDL-TG production. Collectively, we conclude that CETP protects against the rHDL-induced increase in VLDL. We anticipate that studies evaluating the anti-atherosclerotic efficacy of rHDL in mice that are naturally deficient for CETP should be interpreted with caution, and that treatment of atherogenic dyslipidemia by rHDL should not be combined with agents that aggressively reduce CETP activity.


Municipal regulation of cannabis and public health in Canada: A comparison of Alberta, Ontario, and Québec.
Canada legalized nonmedical cannabis in October 2018, but significant variations in municipal regulations exist. This study explored the variations that exist and pondered their potential public health consequences. A comparative analysis was completed on the regulations and guidelines that addressed retailers' location and public consumption in the municipalities of Alberta, Ontario, and Québec. Municipal regulations that addressed the location of retailers were more numerous and extensive in Alberta and Ontario (in the context of provincial private retail models) than in Québec (government-based model). Municipalities in Alberta added more restrictions to public consumption laws as compared to municipalities in Ontario and in Québec. These additions were made to Alberta's and Ontario's provincial-level smoking and vaping bans which used tobacco-inspired frameworks, and to Québec's ban on smoking and vaping in all public spaces. The comparative analysis showed the importance of considering municipal cannabis regulations when studying the impact of legalization, given the significant variations that exist. Policy makers should be made aware of these variations in the regulation of cannabis in order to limit health harms and further social inequalities.


Molecular basis of inward rectification: structural features of the blocker defined by extended polyamine analogs.
Polyamines cause inward rectification of Kir K(+) channels by blocking deep within the channel pore. We investigated structural constraints of polyamine block of strongly rectifying mutant K(ATP) channels (Kir6.2[L164C,N160D,C166S] + SUR1). We studied three groups of polyamine analogs: 1) conformationally restricted linear tetra-amines with a cycloalkyl or alkene group between the second and third amines (CGC-11047, CGC-11093, CGC-11099, and CGC-11098), 2) conformationally restricted linear deca-amines with a cycloalkyl or alkene group between the fifth and sixth amines (CGC-11150, CGC-11179, and CGC-11241), and 3) cyclic tetra-amines (CGC-11174, CGC-11197, CGC-11199, and CGC-11254). All linear analogs cause a voltage-dependent block similar to that of spermine, but slightly weaker (at 1 microM, V(1/2) for spermine block = -10 +/- 1 mV, Z = 2.9 +/- 0.1, n = 19; V(1/2) for analogs varies from polyamine -7 to +10 mV, Z = 2.6-3.9). These data indicate tolerance for conformational restriction and an upper limit to the voltage dependence of the blocking process. There was no voltage-dependent block by the cyclic compounds; instead, they induce irreversible rundown of the current. Structural models of Kir channels suggest that a narrow entry at the top of the cytoplasmic pore may exclude cyclic analogs from the inner cavity, thereby explaining the structure-activity relationship that we observe.


Left Ventricular Assist Device as a Bridge to Recovery for Patients With Advanced Heart Failure.
Left ventricular assist devices (LVADs) have been used as an effective therapeutic option in patients with advanced heart failure, either as a bridge to transplantation, as destination therapy, or in some patients, as a bridge to recovery. This study evaluated whether patients undergoing an LVAD bridge-to-recovery protocol can achieve cardiac and physical functional capacities equivalent to those of healthy controls. Fifty-eight male patients-18 implanted with a continuous-flow LVAD, 16 patients with LVAD explanted (recovered patients), and 24 heart transplant candidates (HTx)-and 97 healthy controls performed a maximal graded cardiopulmonary exercise test with continuous measurements of respiratory gas exchange and noninvasive (rebreathing) hemodynamic data. Cardiac function was represented by peak exercise cardiac power output (mean arterial blood pressure × cardiac output) and functional capacity by peak exercise O2 consumption. All patients demonstrated a significant exertional effort as demonstrated with the mean peak exercise respiratory exchange ratio >1.10. Peak exercise cardiac power output was significantly higher in healthy controls and explanted LVAD patients compared with other patients (healthy 5.35 ± 0.95 W; explanted 3.45 ± 0.72 W; LVAD implanted 2.37 ± 0.68 W; and HTx 1.31 ± 0.31 W; p < 0.05), as was peak O2 consumption (healthy 36.4 ± 10.3 ml/kg/min; explanted 29.8 ± 5.9 ml/kg/min; implanted 20.5 ± 4.3 ml/kg/min; and HTx 12.0 ± 2.2 ml/kg/min; p < 0.05). In the LVAD explanted group, 38% of the patients achieved peak cardiac power output and 69% achieved peak O2 consumption within the ranges of healthy controls. The authors have shown that a substantial number of patients who recovered sufficiently to allow explantation of their LVAD can even achieve cardiac and physical functional capacities nearly equivalent to those of healthy controls.


Development rates of male bovine nuclear transfer embryos derived from adult and fetal cells.
This study compared the nuclear transfer (NT) embryo development rates of adult and fetal cells within the same genotype. The adult fibroblast cells were obtained from a 21-yr-old Brahman bull. The fetal cells were derived from a Day 40 NT fetus previously cloned using cells from the Brahman bull. Overall, similar numbers of blastocysts developed from both adult (53 of 190; 28%) and fetal (39 of 140; 28%) donor cells. Improved blastocyst development rates were observed when fetal cells were serum-starved (serum-fed 12% vs. serum-starved 43%; P < 0.01) whereas there was no similar benefit when adult cells were serum-starved (both serum-fed and serum-starved 28%). Day 30 pregnancy rates were similar for blastocysts derived from adult (6 of 26; 23%) or fetal (5 of 32; 16%) cells. Day 90 pregnancy rates were 3 of 26 for adult and 0 of 32 for the fetal cell lines. One viable bull calf derived from a 21-yr-old serum-starved adult skin fibroblast was born in August 1999. In summary, somatic NT embryo development rates were similar whether adult or fetal cells, from the same genotype, were used as donor cells. Serum starvation of these adult donor cells did not improve development rates of NT embryos to blastocyst, but when fetal cells were serum-starved, there was a significant increase in development to blastocyst.