Single-site colectomy with miniature in vivo robotic platform.
There has been a continuing push to reduce the invasiveness of surgery by accessing the abdominal cavity through a single incision, such as with laparoendoscopic single-site (LESS) surgery. Although LESS procedures offer significant benefits, added complexities still inhibit the procedures. Robotic surgery is proving to be an excellent option to overcome these limitations. This paper presents the experimental results of the single-incision in vivo surgical robot (SISR), a multifunctional, dexterous, two-armed robot capable of performing surgical tasks while overcoming the issues associated with manual LESS operations. In vivo surgical procedures have been used to demonstrate the efficacy of using a robotic platform over traditional laparoscopic tools. The most recent experimental test resulted in the first successful in vivo robotic LESS colectomy utilizing a robot completely contained within the abdominal cavity. In this test, SISR showed significant benefits including access to all quadrants in the peritoneal cavity and improved dexterity.


Pharmaceutical industry payments and delivery of non-recommended and low value cancer drugs: population based cohort study.
To estimate the association between oncologists' receipt of payments from the pharmaceutical industry and delivery of non-recommended or low value interventions among their patients. Cohort study. Fee-for-service Medicare claims. Medicare beneficiaries with a diagnosis of incident cancer (new occurrence of a cancer diagnosis code in proximity to claims for cancer treatment, and no such diagnosis codes during a ≥1 year washout period) during 2014-19, who met additional requirements identifying them as at risk for one of four non-recommended or low value interventions: denosumab for castration sensitive prostate cancer, granulocyte colony stimulating factors (GCSF) for patients at low risk for neutropenic fever, nab-paclitaxel for cancers with no evidence of superiority over paclitaxel, and a branded drug in settings where a generic or biosimilar version was available. Receipt of the non-recommended or low value drug for which the patient was at risk. The primary association of interest was the assigned oncologist's receipt of any general payments from the manufacturer of the corresponding non-recommended or low value drug (measured in Open Payments) within 365 days before the patient's index cancer date. The two modeling approaches used were general linear model controlling for patients' characteristics and calendar year, and general linear model with physician level indicator variables. Oncologists were in receipt of industry payments for 2962 of 9799 patients (30.2%) at risk for non-recommended denosumab (median $63), 76 747 of 271 485 patients (28.3%) at risk for GCSF (median $60); 18 491 of 86 394 patients (21.4%) at risk for nab-paclitaxel (median $89), and 4170 of 13 386 patients (31.2%) at risk for branded drugs (median $156). The unadjusted proportion of patients who received non-recommended denosumab was 31.4% for those whose oncologist had not received payment and 49.5% for those whose oncologist had (prevalence difference 18.0%); the corresponding values for GCSF were 26.6% v 32.1% (5.5%), for nab-paclitaxel were 7.3% v 15.1% (7.8%), and for branded drugs were 88.3% v 83.5% (-4.8%). Controlling for patients' characteristics and calendar year, payments from industry were associated with increased use of denosumab (17.5% (95% confidence interval 15.3% to 19.7%)), GCSF (5.8% (5.4% to 6.1%)), and nab-paclitaxel (7.6% (7.1% to 8.1%)), but lower use of branded drugs (-4.6% (-5.8% to -3.3%)). In physician level indicator models, payments from industry were associated with increased use of denosumab (7.4% (2.5% to 12.2%)) and nab-paclitaxel (1.7% (0.9% to 2.5%)), but not with GCSF (0.4% (-0.3% to 1.1%)) or branded drugs (1.2% (-6.0 to 8.5%)). Within some clinical scenarios, industry payments to physicians are associated with non-recommended and low value drugs. These findings raise quality of care concerns about the financial relationships between physicians and industry.


[The place of the first trocar setting in laparoscopic cholecystectomy].
At the department of endovideosurgery the comparative evaluation of paraumbilical trocar intervention technique at the laparoscopic cholecystectomy was conducted at two groups of patients with calculous cholecystitis. There were 600 patients under supervision. It is discovered that the essential drawback of trocar intervention higher or lower than umbilical ring along the middle line is that while taking the gallbladder out the abdominal cavity, additionally the aponeurosis of the abdomen white line is dissected and later it has to be sutured. After such interventions during early postoperative period sensation of pain in the umbilical point appears, infiltrates are formed; ligature fistulas, seromas, hypodermic hematomas and later postoperative hernia may appear. A new technique of trocar intervention is proposed (patent of RF for invention # 2267300 of November 19, 2004). By topographic and anatomic, ultrasonic examination of anterior abdominal wall it was discovered, that the most acceptable area for trocar intervention at laparoscopic cholecystectomy is the medial border of the right musculus rectus abdominis in the umbilical area. The right-side transrectal access in the umbilical area at laparoscopic cholecystectomy allows to avoid postoperative complications connected with traditional trocar intervention through the white abdomen line in the form of pain syndrome and its continuity, presence of hematomas and accumulation of tissue fluid (seromas) in the wound.


Intravesical Bacillus Calmette-Guérin therapy for murine bladder tumors: initiation of the response by fibronectin-mediated attachment of Bacillus Calmette-Guérin.
Intravesical Bacillus Calmette-Guérin (BCG) is considered to be one of the most effective treatments for superficial bladder cancer. Although the mechanisms by which BCG inhibits tumor growth are not known, previous studies have shown that systemic immunization to BCG and the local expression of the immune response in the bladder are associated with a favorable response to BCG therapy. We have investigated the conditions required for the initiation of an immunological response after the intravesical instillation of BCG. Initial histological studies showed that BCG attached to the bladder wall only in areas where the urothelium was damaged by electrocautery and suggested that attachment was associated with the fibrin clot. Quantitative studies verified the histological observations. Minimal BCG attachment (mean less than 10(2) colony forming units) was observed in normal bladders in contrast with a mean of 1.42 X 10(4) colony forming units/bladder in bladders damaged by electrocautery (10 separate experiments). BCG attachment to the bladder wall was durable since organisms were observed in bladders 48 h after instillation. To investigate the proteins to which BCG attached, we tested the binding of BCG to extracellular matrix and inflammatory proteins which comprise a significant portion of the fibrin clot. BCG bound in vitro to coverslips coated in vivo with extracellular matrix proteins but did not bind to control albumin-coated coverslips. BCG also bound to coverslips coated with purified plasma fibronectin but not to coverslips coated with other purified extracellular matrix proteins including laminin, fibrinogen, and type IV collagen. BCG attachment to coverslips coated with either extracellular matrix proteins or purified fibronectin was inhibited by antibodies specific for fibronectin. Moreover, BCG attachment to cauterized bladders in vivo was inhibited by antifibronectin antibodies. These results demonstrate that fibronectin mediates the attachment of BCG to surfaces and suggest that it is the primary component mediating attachment within the bladder. Moreover, the data suggest that the BCG-fibronectin interaction may be a requisite first step for the initiation of the antitumor activity in intravesical BCG for bladder cancer.


Do endogenous prostaglandins modulate noradrenergic transmission in the rat isolated perfused vas deferens?
The effects of the prostaglandin synthetase inhibitors aspirin, indomethacin and meclofenamic acid have been studied on the response of the rat isolated perfused vas deferens. None of these drugs, up to a concentration of 5 x 10(-5) M affected either phase of the biphasic constrictor response to 30 s periods of field stimulation. In the same preparations an inhibition of the response to field stimulation was seen in the presence of prostaglandin E1 at concentrations of 1 to 5 ng ml-1. All three prostaglandin synthetase inhibitors, at 5 x 10(-5) M, caused significant reduction of prostaglandin biosynthesis by homogenates of rat vas deferens. It is, therefore, suggested that stimuli which activate directly the noradrenergic nerves in the rat vas do not activate simultaneously a release of endogenous prostaglandins.


Are sensory phenomena present in Sydenham's Chorea? Evaluation of 13 cases.
Sydenham's Chorea (SC) is an early complication of rheumatic fever caused by group A beta-hemolytic streptococcal infection that manifests itself with adventitious choreatic movements and behavioral problems. Sensory phenomena are the premonitory sensory experiences that are described prior to tics. Tic disorders and SC share common underlying neurobiological substrates, yet sensory phenomena have not previously been examined in SC. We aimed to explore the presence of sensory phenomena associated with choreatic movements in children with SC. Thirteen SC patients are examined on measures of sensory phenomena using a semi-structured instrument. 10 out of 13 patients described sensory phenomena. Five of the SC patients described sensory phenomena as "between physical and mental". The patients described physical feelings of tension in joints, tingling and trembling sensations on skin. 69 % of them described movements as "completely involuntary". Sites of choreatic movements that were consistently preceded by sensory phenomena were upper and lower extremities, and trunk. Children may have difficulty in articulating sensory phenomena due to the subjective nature of premonitory feelings in SC. We recommend exploring the sensory experiences that might accompany the choreatic movements in children with SC.


[Architecture of physiological functions: the same basis but new aspects].
The principles of physiological functions formulated by J. Barckroft (constancy of the internal medium, reserves, any adaptation as an integration, principle of antagonism, doubling of mechanisms) are compared with principles of modern physiology. The place and role of physiology in the life sciences are discussed. The necessity of taking into consideration 4 level of regulation of functions (the nervous system, hormones, autacoids, physicochemical factors of the extracellular fluid) is substantiated, as well as the necessity of identification of 4 levels of organization of physiological systems. The main role of the water-salt homeostasis in maintaining the cell volume is suggested. Significance of various types of receptors and second messengers in regulation and modulation of functions is shown.


Vitamin K in neonates: how to administer, when and to whom.
Vitamin K-dependent factors are lower in neonates than in adults, and these anomalies are more prevalent in preterm neonates and in breast-fed infants. Vitamin K deficiency can account for vitamin K deficiency bleeding (VKDB) which occurs in 3 forms--early, classic and late. Vitamin K should be administered to all neonates at birth or immediately afterwards. However, the protocols for administration (route of administration, dosage, number of doses) remain a subject of discussion. Oral administration of a single dose of vitamin K protects against classical and early VKDB, but is less effective than intramuscular (IM) prophylaxis for the prevention of late VKDB. Although an increased risk of solid tumour, associated vitamin K administration, can be definitively excluded, a low potential risk of lymphoblastic leukaemia in childhood can not be ruled out. For formula-fed neonates without risk of haemorrhage, a 2 mg oral dose of vitamin K at birth, followed by a second 2 mg oral dose between day 2 and 7, is probably sufficient to prevent VKDB. For infants who are exclusively or nearly exclusively breast-fed, weekly oral administration of 2mg (or 25 microg/day) vitamin K after the initial 2 oral doses is justified at completion of breast-feeding. For neonates at high risk of haemorrhage (premature, neonatal disease, birth asphyxia, difficult delivery, any illness which will delay feeding, known hepatic disease, maternal drugs inhibiting vitamin K activity), the first dose must be administered by the IM or slow intravenous route. Doses should be repeated, particularly in premature infants, by a route of administration decided for each dose according to the clinical state of the infant. For infants of mothers treated with drugs inhibiting vitamin K activity, antenatal maternal prophylaxis (10 to 20 mg/day orally for 15 to 30 days before delivery) prevents early VKDB. After neonatal prophylaxis, as for infants at high risk of haemorrhage, doses need to be repeated at a rate and route of administration decided for each dose, according to the clotting factor profile specific for each infant.


Mortality rates for common respiratory diseases in an English population 1979-1998: artefact and substantive trends.
We analysed a mortality database in which all causes of death on each death certificate were coded, as well as underlying cause, to study trends from 1979 to 1998. Multiple-cause-coded death rates for pneumonia and acute bronchitis fell steadily and consistently. There were complementary rises and falls in death rates for individual chronic obstructive pulmonary diseases (COPD)--chronic bronchitis, emphysema, chronic obstructive airways disease--attributable to changes in clinical terminology. Judged by underlying cause, death rates for COPD were lower than those for lung cancer; but, judged by all mentions, death rates for COPD were appreciably higher than for lung cancer. Death rates for COPD, like lung cancer, fell over time in women under 65 years of age and in men; and increased in older women. For all respiratory diseases studied, except lung cancer, the underlying cause of death alone considerably underestimated the extent of their certification on death certificates.


Multiple conformational changes in enzyme catalysis.
Understanding the molecular mechanisms of enzyme catalysis and allosteric regulation has been a primary goal of biochemistry for many years. The dynamics of these processes, approached through a variety of kinetic methods, are discussed. The results obtained for many different enzymes suggest that multiple intermediates and conformations are general characteristics of the catalytic process and allosteric regulation. Ribonuclease, dihydrofolate reductase, chymotrypsin, aspartate aminotransferase, and aspartate transcarbamoylase are considered as specific examples. Typical and maximum rates of conformational changes and catalysis are also discussed, based on results obtained from model systems. The nature and rates of interconversion of the intermediates, along with structural information, can be used as the bases for understanding the incredible catalytic efficiency of enzymes. Potential roles of conformational changes in the catalytic process are discussed in terms of static and environmental effects, and in terms of dynamic coupling within the enzyme-substrate complex.


Etiology of severe mastitis in French dairy herds.
Severe clinical mastitis is not so frequent in dairy cows, but it can have a significant economic impact due to its high mortality rate and adverse effects on milk production. Surveys about the cause of mastitis typically provide overall findings without connecting them to a specific medical condition. There are few studies on the specific etiology of severe mastitis. Only etiological results obtained during field studies are available in France, and the number of mastitic milk samples analyzed is always low. In recent years, veterinary clinics have improved their ability to identify bacteria causing bovine mastitis using a widely used method. This in-clinic milk culture made it possible to better understand the etiology of mastitis according to the symptoms observed. Regarding clinical mastitis, veterinarians treat severe cases differently than less severe ones. Based on data from nineteen veterinary clinics in France and over 2000 severe mastitis cases, the current study revealed that Enterobacteriaceae, particularly Escherichia coli, is the most common cause, isolated on average from 53.9% of milk samples. This information is highly reliable for practitioners to quickly and effectively treat the condition, because early and targeted treatment is crucial to avoid the complication of endotoxic shock.


Self-assembled traditional Chinese nanomedicine modulating tumor immunosuppressive microenvironment for colorectal cancer immunotherapy.
Colorectal cancer (CRC), mostly categorized as a low immunogenic microsatellite-stable phenotype bearing complex immunosuppressive tumor microenvironment (TME), is highly resistant to immunotherapy. Seeking safe and efficient alternatives aimed at modulating tumor immunosuppressive TME to improve outcome of CRC is highly anticipated yet remains challenging. Methods: Enlightened from the drug complementary art in traditional Chinese medicine, we designed a self-assembled nanomedicine (termed LNT-UA) by the natural active ingredients of ursolic acid (UA) and lentinan (LNT) through a simple nano-precipitation method, without any extra carriers, for CRC immunotherapy. Results: UA induces immunogenic cell death (ICD), while LNT further promotes dendritic cell (DC) maturation and repolarizes tumor-associated macrophage (TAM) from a protumorigenic M2 to an antitumor M1 phenotype. Co-delivery of UA and LNT by LNT-UA effectively reshapes the immunosuppressive TME and mobilizes innate and adaptive immunity to inhibit tumor progression in the CT26 CRC tumor model. Following the principle of integrative theoretical system of traditional Chinese medicine (TCM) on overall regulation, the further combination of LNT-UA and anti-CD47 antibody (αCD47) would reinforce the antitumor immunity by promoting phagocytosis of dying tumor cells and tumor-associated antigens (TAAs), leading to effective suppression of both primary and distant tumor growth with 2.2-fold longer of median survival time in the bilateral tumor model. Most notably, this combination effect is also observed in the spontaneous CRC model induced by chemical carcinogens, with much less and smaller size of tumor nodules after sequential administration of LNT-UA and αCD47 through gavage and intraperitoneal injection, respectively. Conclusions: This study provides a promising self-assembled traditional Chinese nanomedicine to improve immunotherapy for CRC, which might be applicable for future clinical translation.


In situ fNIRS measurements during cognitive behavioral emotion regulation training in rumination-focused therapy: A randomized-controlled trial.
Repetitive negative thinking (RNT), including rumination, plays a key role in various psychopathologies. Although several psychotherapeutic treatments have been developed to reduce RNT, the neural correlates of those specific treatments and of psychotherapy in general are largely unknown. Functional near-infrared spectroscopy (fNIRS) offers the potential to investigate the neural correlates of psychotherapeutic techniques in situ. Therefore, in this study we investigated the efficacy and neural correlates of a fNIRS adapted Mindfulness-based Emotion Regulation Training (MBERT) for the treatment of depressive rumination in 42 subjects with major depressive disorder (MDD) in a cross-over designed randomized controlled trial. Using psychometric measures, subjective ratings and fNIRS, we analyzed in situ changes in depressive symptom severity, ruminative thoughts and cortical activity in the Cognitive Control Network (CCN). Our results show that MBERT is effective in treating depressive symptoms and rumination. On a neural level, we found consistently higher cortical activation during emotion regulation training compared to control trials in the bilateral inferior frontal gyrus (IFG) and dorsolateral prefrontal cortex (DLPFC). Furthermore, cortical oxygenation decreased from session to session in the bilateral DLPFC. The relevance of the results for the psychotherapeutic treatment of MDD as well as further necessary investigations are discussed.


Volumetric tumor tracking from a single cone-beam X-ray projection image enabled by deep learning.
Radiotherapy serves as a pivotal treatment modality for malignant tumors. However, the accuracy of radiotherapy is significantly compromised due to respiratory-induced fluctuations in the size, shape, and position of the tumor. To address this challenge, we introduce a deep learning-anchored, volumetric tumor tracking methodology that employs single-angle X-ray projection images. This process involves aligning the intraoperative two-dimensional (2D) X-ray images with the pre-treatment three-dimensional (3D) planning Computed Tomography (CT) scans, enabling the extraction of the 3D tumor position and segmentation. Prior to therapy, a bespoke patient-specific tumor tracking model is formulated, leveraging a hybrid data augmentation, style correction, and registration network to create a mapping from single-angle 2D X-ray images to the corresponding 3D tumors. During the treatment phase, real-time X-ray images are fed into the trained model, producing the respective 3D tumor positioning. Rigorous validation conducted on actual patient lung data and lung phantoms attests to the high localization precision of our method at lowered radiation doses, thus heralding promising strides towards enhancing the precision of radiotherapy.


MAPK regulation of gene expression in the central nervous system.
Long-term potentiation (LTP), a cellular model for long-term memory, is generally acknowledged to consist of both a short-term phase that is characterized by a dependence on autonomous protein kinase activity, and a long-term phase that is characterized by a dependence on changes in gene expression and new protein synthesis. Similarly, long-term memory exhibits a dependence on gene expression and altered protein synthesis. Recent evidence indicates that the mitogen-activated protein kinase (MAPK) cascade plays a role in both LTP and long-term memory. The MAPK cascade has heretofore largely been studied in the context of cell division and proliferation and as such, mechanisms for the regulation of gene expression by the MAPK cascade have received considerable attention. Given the possible role of altered gene expression in the late phase of LTP and in long-term memory, we evaluated the capacity of the MAPK ERK (extracellular signal-regulated kinase) to regulate phosphorylation of the transcription factor cAMP response element binding protein (CREB) in hippocampal area CA1. Our studies indicate a critical role for the MAPK cascade in the regulation of CREB phosphorylation in the hippocampus.


Use of elemental diets in surgical cases.
Over the past five years elemental diets have assumed an important role in the pre- and postoperative nutrition of patients on the Surgical Service at the St. Vincent's Hospital and Medical Center of New York City. The purpose of this paper is to give the history of this development and the results of our experience with the elemental diet.


Long-term outcome in 87 patients with low-grade soft-tissue sarcoma.
To describe the long-term clinical outcome of patients with low-grade soft-tissue sarcoma and identify factors that may predict or determine their prognosis. Retrospective chart review with multivariate analysis. Large research hospital and referral center. All patients treated between 1975 and 1990 at the National Cancer Institute (Bethesda, Md) who had a confirmed diagnosis of low-grade soft-tissue sarcoma. Surgery and radiation therapy. Local recurrence and overall survival. For patients with nonretroperitoneal lesions, overall survival was excellent, with a history of recurrence, a positive surgical margin, and an absence of adjuvant radiation therapy significantly associated with increased risks of local recurrence. Patients with retroperitoneal lesions not only had an increased risk of local recurrence, but significantly poorer overall survival. Low-grade soft-tissue sarcomas are associated with excellent overall survival, especially those confined to nonretroperitoneal sites. The risk of local recurrence after resection with negative margins and/or adjuvant radiation therapy is very low and most recurrences can be controlled with further therapy.


[The activation of phagocytosis by recombinant human tumor necrosis factor-beta].
The functional activity of phagocytic cells of various types was studied in white non-inbred mice by administering recombinant human tumor necrosis beta (rhTNF-beta). It was shown that rhTNF-beta increased phagocytic activity of the peritoneal exudate, spleen and liver macrophages as well as blood polynuclears. Stimulation of neutrophils was demonstrated in earlier times after administration of the preparation as compared to macrophages (3 h and 24 h, respectively). The duration of the macrophage activation effect and its expression depended on the dose of the preparation and were the most notable when rhTNF-beta was administered in doses of 10(3)-10(5) U/20 g. The addition of reopolyglucin, the polysaccharide filler, didn't remove a stimulatory effect of rhTNF-beta on macrophages, but influenced its dynamics. Multiple administration of the preparation didn't cause the phagocytosis stimulation effect.


Quantitative changes in phenolic content during physiological development of the olive (Olea europaea) cultivar Hardy's Mammoth.
This investigation was designed to characterize phenolic metabolism of the olive cultivar, Hardy's Mammoth, by examining its constitutive tissues. The phenolic profiles of pulp, seed, stone, and new and old season leaves were monitored over two fruiting seasons, to investigate possible relationships between tissues and phenol content and to determine the impact of alternate fruit bearing. No major qualitative differences in phenolic composition were found between the various tissues; however, distinct differences between the tissues with respect to quantifiable phenols were established. Relationships between 2-(3,4-dihydroxyphenyl)ethyl (3E,4E)-4-formyl-3-(2-oxoethyl)hex-4-enoate ester, oleuropein, and hydroxytyrosol in pulp and leaf were identified and found to be related to alternate bearing. Concentrations of 5-caffeoylquinic acid in old season leaves differed dramatically between seasons, confirming earlier studies.


Does informing people who inject drugs of their hepatitis C status influence their injecting behaviour? Analysis of the Networks II study.
People who inject drugs (PWID) are at risk of hepatitis C virus (HCV). It is plausible that PWID who receive a diagnosis of HCV will reduce their injecting risk out of concern for their injecting partners, although evidence for this is currently limited. The aim of this study was to investigate whether informing PWID of their HCV diagnosis was associated with a change in injecting behaviour. Prospective, longitudinal study of PWID recruited from street drug markets across Melbourne, Australia. Interviews and HCV testing were conducted at 3-monthly intervals. The association between receiving a diagnosis of HCV and (i) injecting frequency and (ii) injecting equipment borrowing, was examined using generalized estimating equations (GEE) analysis. Thirty-five individuals received a diagnosis of HCV during the study period. Receiving a diagnosis of HCV was associated with a decrease of 0.35 injections per month (p=0.046) but there was no change in injecting equipment borrowing (p=0.750). A small reduction in injecting frequency was observed in PWID who received a diagnosis of HCV. This finding should be investigated further in larger studies examining a wider range of injecting risk behaviours.


The genetics of a small autosomal region of Drosophila melanogaster containing the structural gene for alcohol dehydrogenase. VI. Induced revertants of scutoid.
Twenty-six induced revertants of Scutoid (Sco), a dominant mutation of Drosophila melanogaster, have been characterized genetically. Sco is an unusual mutation, involving two small reciprocal transpositions within the region 35A4 to 35C5 of chromosome arm 2L. One of these transpositions juxtaposes the noc and l(2)br28 loci. We suggested previously that the Sco phenotype results from the "fusion" of noc and l(2)br28. In support of this idea we now show that 23 of 26 revertants of Sco are noc-, indeed the majority are either chromosome aberrations broken between noc and l(2)br28 or deletions of these loci from the mutant chromosome. However, some revertants of Sco are rather more complex, and their properties suggest an interaction between the pu-noc and l(2)br28-l(2)br37 regions of chromosome arm 2L and also demonstrate the genetic complexity of the el-noc region.


Levonadifloxacin, a Novel Benzoquinolizine Fluoroquinolone, Modulates Lipopolysaccharide-Induced Inflammatory Responses in Human Whole-Blood Assay and Murine Acute Lung Injury Model.
Fluoroquinolones are reported to possess immunomodulatory activity; hence, a novel benzoquinolizine fluoroquinolone, levonadifloxacin, was evaluated in lipopolysaccharide-stimulated human whole-blood (HWB) and mouse acute lung injury (ALI) models. Levonadifloxacin significantly mitigated the inflammatory responses in an HWB assay through inhibition of proinflammatory cytokines and in the ALI model by lowering lung total white blood cell count, myeloperoxidase, and cytokine levels. The immunomodulatory effect of levonadifloxacin, along with promising antibacterial activity, is expected to provide clinical benefits in the treatment of infections.


Prevalence and Intensity of Cornudiscoides Agarwali (Monogenoidea) on the Gills of Day's Mystus (Mystus Bleekeri) in Relation to Some Ecological and Biological Factors from Arunachal Pradesh, India.
This work investigated the relationship of host size, seasons, and water quality parameters with the prevalence and intensity of Cornudiscoides agarwali on Mystus bleekeri collected from the Dikrong River in Arunachal Pradesh, India from February 2016 to January 2017. A total of 2760 specimens of C. agarwali were recovered from 114 individuals of M. bleekeri. The levels of mean intensity, but not the prevalence, of infection of C. agarwali were positively correlated with fish host size, peaking in the largest size class (45.20 ± 5.69 parasites/fi sh). The prevalence values had a statistically significant seasonal trend, reaching highest (100 %) during the pre-monsoon season, followed by 91.8% during the post-monsoon period and 87.5 % during the monsoon season. The levels of mean intensity of infection were also dependent on the seasons, reaching significantly higher levels during the pre-monsoon season (42.75 ± 4.18 parasites/fi sh). All water quality parameters measured were within the safety value recommended for freshwater aquaculture. Cornudiscoides agarwali maintained its prevalence above 87.5 % throughout the annual cycle, which means it was able to reproduce year-round in a non-polluted river. This could be an indication of monogenoidean community and population dynamics thriving best under optimum water quality parameters. Also, this article draws the attention of parasitologists and ichthyologists to a taxonomic problem of the misidentification of Mystus spp., and therefore, possibly of their parasitic monogenoids.


A familiar stranger: CD34 expression and putative functions in SVF cells of adipose tissue.
Human adipose tissue obtained by liposuction is easily accessible and an abundant potential source of autologous cells for regenerative medicine applications. After digestion of the tissue and removal of differentiated adipocytes, the so-called stromal vascular fraction (SVF) of adipose, a mix of various cell types, is obtained. SVF contains mesenchymal fibroblastic cells, able to adhere to culture plastic and to generate large colonies in vitro, that closely resemble bone marrow-derived colony forming units-fibroblastic, and whose expanded progeny, adipose mesenchymal stem/stromal cells (ASC), show strong similarities with bone marrow mesenchymal stem cells. The sialomucin CD34, which is well known as a hematopoietic stem cell marker, is also expressed by ASC in native adipose tissue but its expression is gradually lost upon standard ASC expansion in vitro. Surprisingly little is known about the functional role of CD34 in the biology and tissue forming capacity of SVF cells and ASC. The present editorial provides a short introduction to the CD34 family of sialomucins and reviews the data from the literature concerning expression and function of these proteins in SVF cells and their in vitro expanded progeny.


Endovascular repair of abdominal aortic aneurysm using a pararenal fenestrated stent-graft.
To report an unusual case of endovascular abdominal aortic aneurysm (AAA) exclusion in which a fenestrated stent-graft was used to seal a proximal Type I endoleak. An 84-year-old man with a 6.0-cm AAA underwent an aortomonoiliac aneurysm exclusion procedure that was complicated by a proximal endoleak. Because the patient had no right kidney, an additional stent-graft was designed to cover the right renal artery stump while preserving left renal perfusion through a fenestration in the graft material. This approach was successful in obliterating the endoleak around the proximal attachment site, but flow through the lumbar arteries remained. The use of a fenestrated stent-graft is feasible, but the type of fenestration in this case has limited applicability owing to the rarity of patients with suitable anatomy.


A new species of Phyzelaphryne Heyer, 1977 (Anura: Eleutherodactylidae) from the Japurá River basin, with a discussion of the diversity and distribution of the genus.
We describe and name the second species of Phyzelaphryne (Brachycephaloidea, Eleutherodactylidae), from northwestern Brazilian Amazonia. Phyzelaphryne nimio sp. nov. is distinguished from its only congener, Phyzelaphryne miriamae, by its smaller body size and the anatomy of the carpal and metacarpal regions, with relatively larger (sometimes fused) supernumerary carpal and metacarpal tubercles. Molecular phylogenetic analyses based on fragments of the mitochondrial genes 16S rRNA and COI suggest that the currently known distribution of the species is restricted to its type locality and other areas within Estação Ecológica Juami-Japurá, state of Amazonas, Brazil. Based on molecular, morphological and bioacoustic evidence, we assigned other specimens recently collected in Parque Nacional do Jaú, state of Amazonas, Brazil, to P. miriamae, extending the species' known geographic distribution north of the Amazon River.


[Hepato-pulmonary syndrome and porto-pulmonary hypertension. Nosologic features and etiopathogenic considerations].
The liver controls pulmonary vascular tone by releasing vasoactive substances. In severe liver failure, the imbalance between vasodilator and vasoconstrictive mediators may lead to alteration of the respiratory function, called as hepatopulmonary syndrome (HPS, when a significant decrease of the vascular pulmonary resistance occurs, with development of intrapulmonary vascular dilatations) and portopulmonarv hypertension (PPH, when the vasoconstrictive prevalence, with an increase of the pulmonary vascular resistances). The clinical symptoms consist of various degree of dyspnea and hypoxemia. An overt "cor pulmonale" syndrome with right-side heart failure may be present in the most severe forms of PPH. The alteration of pulmonary vascularization may be diagnosed by means of pulmonary angiography, contrast-enhanced echocardiography and perfusion lung nuclear scanning of the lungs. Both clinical syndromes respond poorly to medical treatment, the unique therapeutical possibilities being represented by orthotopic liver transplantation (or combined heart-lung-liver or lung-liver transplantation in patients with severe PPH).


Response to first line chemotherapy regimen is associated with efficacy of nivolumab in non-small-cell lung cancer.
Nivolumab, an anti PD-1 checkpoint inhibitor has demonstrated efficacy in metastatic non-small-cell lung cancer (NSCLC) patients after failure to standard chemotherapy. Standard chemotherapy agents could promote antitumor immune response. We thus examined whether the response to first line chemotherapy could impact on nivolumab benefit. One hundred and 15 patients with NSCLC were included in this retrospective study from 4 different French centers. Forty-three squamous cell carcinomas (SCC), and 72 non-SCC received nivolumab between 2015 and 2016 (3 mg/kg IV Q2W). Response to first-line chemotherapy and to nivolumab was retrospectively assessed on CT-scan by central review. The association between RECIST response to first-line chemotherapy and nivolumab efficacy were determined using Fisher's exact test and Cox proportional hazard model. Respectively 46 (40%), 44 (38%) and 25 (22%) patients experienced partial response (PR), stable disease (SD), or progressive disease (PD) in response to first-line platinum- based chemotherapy. Twenty 5 (21%), 34 (30%), 56 (49%) respectively experienced PR, SD and PD in response to nivolumab. 60% (54/90) of patients who experienced clinical benefit (PR + SD) after first-line chemotherapy also had clinical benefit after nivolumab, while only 20% (5/25) of patients with initial PD subsequently experienced clinical benefit with nivolumab (Fisher's exact test, P = 0.001). The type of first-line doublet chemotherapy did not influence the response rate to nivolumab. Univariate and multivariate analyses showed that patients with clinical benefit from first-line chemotherapy had higher second-line PFS (P = 0.003) (median PFS on nivolumab of 5, 3.3 and 1.9 months for patients with PR, SD and PD in response to first-line therapy, respectively). Similar results were obtained for OS. Thus this study suggests that the efficacy of first-line chemotherapy may be a valuable surrogate marker of the benefit of nivolumab in terms of PFS and OS.


Generalized pairwise comparison methods to analyze (non)prioritized composite endpoints.
In the analysis of composite endpoints in a clinical trial, time to first event analysis techniques such as the logrank test and Cox proportional hazard test do not take into account the multiplicity, importance, and the severity of events in the composite endpoint. Several generalized pairwise comparison analysis methods have been described recently that do allow to take these aspects into account. These methods have the additional benefit that all types of outcomes can be included, such as longitudinal quantitative outcomes, to evaluate the full treatment effect. Four of the generalized pairwise comparison methods, ie, the Finkelstein-Schoenfeld, the Buyse, unmatched Pocock, and adapted O'Brien test, are summarized. They are compared to each other and to the logrank test by means of simulations while specifically evaluating the effect of correlation between components of the composite endpoint on the power to detect a treatment difference. These simulations show that prioritized generalized pairwise comparison methods perform very similarly, are sensitive to the priority rank of the components in the composite endpoint, and do not measure the true treatment effect from the second priority-ranked component onward. The nonprioritized pairwise comparison test does not suffer from these limitations and correlation affects only its variance.


Pair-distribution function of active Brownian spheres in three spatial dimensions: simulation results and analytical representation.
The pair-distribution function, which provides information about correlations in a system of interacting particles, is one of the key objects of theoretical soft matter physics. In particular, it allows for microscopic insights into the phase behavior of active particles. While this function is by now well studied for two-dimensional active matter systems, the more complex and more realistic case of three-dimensional systems is not well understood by now. In this work, we analyze the full pair-distribution function of spherical active Brownian particles interacting via a Weeks-Chandler-Andersen potential in three spatial dimensions using Brownian dynamics simulations. Besides extracting the structure of the pair-distribution function from the simulations, we obtain an analytical representation for this function, parametrized by activity and concentration, which takes into account the symmetries of a homogeneous stationary state. Our results are useful as input to quantitative models of active Brownian particles and advance our understanding of the microstructure in dense active fluids.


Skeletomuscular adaptations of head and legs of Melissotarsus ants for tunnelling through living wood.
While thousands of ant species are arboreal, very few are able to chew and tunnel through living wood. Ants of the genus Melissotarsus (subfamily Myrmicinae) inhabit tunnel systems excavated under the bark of living trees, where they keep large numbers of symbiotic armoured scale insects (family Diaspididae). Construction of these tunnels by chewing through healthy wood requires tremendous power, but the adaptations that give Melissotarsus these abilities are unclear. Here, we investigate the morphology of the musculoskeletal system of Melissotarsus using histology, scanning electron microscopy, X-ray spectrometry, X-ray microcomputed tomography (micro-CT), and 3D modelling. Both the head and legs of Melissotarsus workers contain novel skeletomuscular adaptations to increase their ability to tunnel through living wood. The head is greatly enlarged dorsoventrally, with large mandibular closer muscles occupying most of the dorsal half of the head cavity, while ventrally-located opener muscles are also exceptionally large. This differs from the strong closing: opening asymmetry typical of most mandibulated animals, where closing the mandibles requires more force than opening. Furthermore, the mandibles are short and cone-shaped with a wide articulatory base that concentrates the force generated by the muscles towards the tips. The increased distance between the axis of mandibular rotation and the points of muscle insertion provides a mechanical advantage that amplifies the force from the closer and opener muscles. We suggest that the uncommonly strong opening action is required to move away crushed plant tissues during tunnelling and allow a steady forward motion. X-ray spectrometry showed that the tip of the mandibles is reinforced with zinc. Workers in this genus have aberrant legs, including mid- and hindlegs with hypertrophied coxae and stout basitarsi equipped with peg-like setae, and midleg femura pointed upward and close to the body. This unusual design famously prevents them from standing and walking on a normal two-dimensional surface. We reinterpret these unique traits as modifications to brace the body during tunnelling rather than locomotion per se. Melissotarsus represents an extraordinary case study of how the adaptation to - and indeed engineering of - a novel ecological niche can lead to the evolutionary redesign of core biomechanical systems.


What Are the Human Resources Required to Control a Foot-and-Mouth Disease Outbreak in Austria?
Contingency planning allows veterinary authorities to prepare a rapid response in the event of a disease outbreak. A recently published foot-and-mouth disease (FMD) simulation study indicated concerns whether capacity was sufficient to control a potential FMD epidemic in Austria. The objectives of the study presented here were to estimate the human resources required to implement FMD control measures and to identify areas of the operational activities that could potentially delay successful control of the disease. The stochastic spatial simulation model EuFMDiS (The European Foot-and-Mouth Disease Spread Model) was used to simulate a potential FMD outbreak and its economic impact, including different control scenarios based on variations of culling, vaccination, and pre-emptive depopulation. In this context, the utilization of human resources was assessed based on the associated EuFMDiS output regarding the performance of operational activities. The assessments show that the number of personnel needed in an outbreak with a stamping-out policy would reach the peak at the end of the second week of control with a median of 540 (257-926) individuals, out of which 31% would be veterinarians. Approximately 58% of these human resources would be attributable to surveillance, followed by staff for cleaning and disinfection activities. Our analysis demonstrates that, of the operational activities, surveillance personnel were the largest factor influencing the magnitude of the outbreak. The aim of the assessment presented here is to assist veterinary authorities in the contingency planning of required human resources to respond effectively to an outbreak of animal diseases such as FMD.


Candidate codes in the gustatory system of caterpillars.
Larvae of tobacco hornworms offer unique opportunities to relate the electrophysiological output of identified chemosensory neurons to specific behavioral responses. Larvae can discriminate among three preferred plants with only eight functioning gustatory receptors. They can be induced to prefer any one of the plants, and these preferences can be reversed. All eight neurons respond to each plant sap. Two fire too infrequently to permit detailed analysis. Analyses of the remaining six show that all electrophysiological responses consist of phasic and tonic components. Only the "salt best" cell fires during the phasic period. Temporal analysis of the spike train during this period shows that tomato and tobacco could be distinguished from Jerusalem cherry but not from each other by a rate code. Measurements of behavioral response times together with the nonspecificity of this with respect of food plants, unacceptable plants, and sodium chloride eliminate a phasic period rate code as a probable mechanism for complex discrimination. Events occurring in the tonic period, when all cells are firing, suggest a major role for this period. Analyses of variance in the interval frequencies of the large and medium spikes suggest that a variance code could allow discrimination among the three plants as long as both cells were firing at the same time. Evidence has been found for temporal patterning in the tonic response of the "salt best" cell to Jerusalem cherry but is absent elsewhere. The most likely basis for coding the difference between each of the three plants is across-fiber patterning in which the relative rates of firing and the variances of all the sensory neurons in the tonic phase are critical.


[Leishmania (Viannia) braziliensis in naturally infected dogs].
Eight dogs from Maricá Municipality (RJ), with suggestive lesion of American tegumentary leishmaniasis were studied by parasitological and serological methods. Leishmania spp was found in six dogs by in vitro cultivation. Specific antibodies were detected in six dogs by ELISA and in two by indirect immunofluorescence. Five canine isolates were found to belong to the same zymodeme as Leishmania (Viannia) braziliensis. The authors suggest that clinically suspect dogs should be followed-up in an attempt to confirm the diagnostic of canine tegumentary leishmaniasis.


Increment of synapsin I immunoreactivity in the hippocampus of the rat kindling model of epilepsy.
Synapsin is a vesicle-associated protein that is thought to be involved in synaptogenesis and neurotransmitter release. In this study, we investigated the repeated amygdala kindling-induced changes in levels of synapsin I, a marker of enhanced synaptic activity, using immunohistochemistry. Eight hours after the last seizure, synapsin I immunoreactivity (IR) was increased bilaterally in the polymorphic zone of the dentate gyrus, the hilus and the stratum lucidum in area CA3 of the hippocampus. However, 4 weeks after the last kindled seizures, synapsin I IR was not significantly changed in any of the brain regions studied. Therefore, the increased levels of synapsin I protein observed in these brain regions early after the last seizure may reflect the plastic changes that occur in the specific neural networks of the hippocampus directly after kindling-induced seizure activity.


Multichannel image compression by bijection mappings onto zero-trees.
A new approach to multichannel image compression is introduced where the intra- and cross-band correlations are jointly exploited in a surprisingly simple yet very effective manner. The key component of the algorithm is a bijection mapping of the original multichannel image into a virtual two-dimensional (2-D) scalar image. By optimally mapping the multichannel image set into a 2-D array and by subsequently applying a scalar image coding algorithm, the spatial correlation and the spectral correlation of the multichannel data set are jointly exploited. Based on the statistical characteristics of the multichannel data, the bijection mapping can be optimized to minimize the distortion introduced by the compression algorithm. The optimization reduces to the maximization of a function of the second-order statistics of the multichannel data. At high compression rates, the new algorithm outperforms traditional compression algorithms whenever the cross-band correlation is high and it yields comparable performance at low compression rates.


Otitis media with perforation of the tympanic membrane: a longitudinal experimental study.
Despite the high incidence and prevalence of otitis media, its pathogenesis is not thoroughly understood. In an effort to provide a better understanding of this disease, experimental animal models have been developed which corroborate the changes observed in humans. In this study a new factor was added: tympanic membrane perforation 1 week after Eustachian tube obstruction. Twelve cats were divided in 4 even groups, and sacrificed at 1 and 2 weeks, 1 and 3 months after perforation, and their temporal bones were studied. Findings revealed an early massive reaction of the mucoperiosteum with granulation and polypoidal tissue formation which filled a considerable portion of the middle ear cavity. Polypoidal changes involved the stapediovestibular joint, possibly explaining the cases of stapes fixation found at tympanomastoidectomy procedures for chronic otitis media. Cholesterol granulomas with the classic characteristics as described in humans were observed in all animals at 3 month periods. These were preceded by clefts in the effusions, at 1 month, containing red blood cells. These clefts were considered as probable precursors of cholesterol granuloma formation. The association of endolymphatic hydrops, round window membrane changes, and otitis media without purulent labyrinthitis was observed; however, it was felt that the paucity of animals precluded any definite conclusions.


Ross procedure for everyone.
Aortic valve replacement using a pulmonary homograft is a complex procedure which provides very good functional results in most patients. Negligible valve-related morbidity, freedom from anticoagulation, and the ability to accommodate growth make it a valid therapeutic modality in infants and children. Due to the excellent quality of life which it provides, the procedure is increasingly being performed in adults. However, it has become apparent that pulmonary homograft insufficiency may be a relatively common problem. Dilatation of the pulmonary autograft is the most common complication after a Ross procedure affecting nearly one-third of patients. It was suggested that dilatation of the pulmonary autograft occurs because of a geometric mismatch between the aortic and pulmonary roots. Despite there been no morphological or physiological data, the authors believed that spatial geometry may influence the dilatation of the neo-aortic root. Herein, I analyse the actual literature stressing long-term results and predictive factors for neo-aorta failure following the Ross procedure. According to my previous morphological investigations I made a proposition of how the Ross procedure may be modified in order to include it for everyone as an aortic valve substitute.


Relapsing fever spirochetes contain chromosomal genes with unique direct tandemly repeated sequences.
Genome sequencing of the relapsing fever spirochetes Borrelia hermsii and Borrelia turicatae identified three open reading frames (ORFs) on the chromosomes that contained internal, tandemly repeated amino acid sequences that were absent in the Lyme disease spirochete Borrelia burgdorferi. The predicted amino acid sequences of these genes (BH0209, BH0512, and BH0553) have hydrophobic N termini, indicating that these proteins may be secreted. B. hermsii transcribed the three ORFs in vitro, and the BH0512- and BH0553-encoded proteins (PBH-512 and PBH-553) were produced in vitro and in experimentally infected mice. PBH-512 and PBH-553 were on the spirochete's outer surface, and antiserum to these proteins reduced the adherence of B. hermsii to red blood cells. PCR analyses of 28 isolates of B. hermsii and 8 isolates of B. turicatae demonstrated polymorphism in each gene correlated with the number of repeats. Serum samples from relapsing fever patients reacted with recombinant PBH-512 and PBH-553, suggesting that these proteins are produced during human infection. These polymorphic proteins may be involved in the pathogenicity of these relapsing fever spirochetes and provide a mechanism for antigenic heterogeneity within their populations.


Strongly Correlated States of Light and Repulsive Photons in Chiral Chains of Three-Level Quantum Emitters.
We study the correlated transport of photons through a chain of three-level emitters that are coupled chirally to a photonic mode of a waveguide. It is found that this system can transfer a weak classical input into a strongly correlated state of light in a unitary manner. Our analysis reveals two-photon scattering eigenstates, that are akin to Fano resonances or shape resonances in particle collisions and facilitate the emergence of antibunched light with long-range correlations upon crossing a critical length of the chain. By operating close to conditions of electromagnetically induced transparency of the three-level medium, a high degree of antibunching and photon transmission can be maintained in the presence of moderate losses. These features suggest a promising mechanism for single-photon generation and may open the door to exploring correlated quantum many-body states of light with repulsively interacting photons.


Transdiagnostic inflexible learning dynamics explain deficits in depression and schizophrenia.
Deficits in reward learning are core symptoms across many mental disorders. Recent work suggests that such learning impairments arise by a diminished ability to use reward history to guide behaviour, but the neuro-computational mechanisms through which these impairments emerge remain unclear. Moreover, limited work has taken a transdiagnostic approach to investigate whether the psychological and neural mechanisms that give rise to learning deficits are shared across forms of psychopathology. To provide insight into this issue, we explored probabilistic reward learning in patients diagnosed with major depressive disorder (n = 33) or schizophrenia (n = 24) and 33 matched healthy controls by combining computational modelling and single-trial EEG regression. In our task, participants had to integrate the reward history of a stimulus to decide whether it is worthwhile to gamble on it. Adaptive learning in this task is achieved through dynamic learning rates that are maximal on the first encounters with a given stimulus and decay with increasing stimulus repetitions. Hence, over the course of learning, choice preferences would ideally stabilize and be less susceptible to misleading information. We show evidence of reduced learning dynamics, whereby both patient groups demonstrated hypersensitive learning (i.e. less decaying learning rates), rendering their choices more susceptible to misleading feedback. Moreover, there was a schizophrenia-specific approach bias and a depression-specific heightened sensitivity to disconfirmational feedback (factual losses and counterfactual wins). The inflexible learning in both patient groups was accompanied by altered neural processing, including no tracking of expected values in either patient group. Taken together, our results thus provide evidence that reduced trial-by-trial learning dynamics reflect a convergent deficit across depression and schizophrenia. Moreover, we identified disorder distinct learning deficits.


Localized mutagenesis of any specific small region of the bacterial chromosome.
A method, which we call localized mutagenesis, is described for the isolation of temperature-sensitive and other types of mutations in any specific small region (about 1%) of the bacterial chromosome. The principle of this method is to mutate the transducing DNA rather than the bacterial DNA. One can select for the introduction of this mutated DNA into any particular region of the bacterial chromosome by transducing an auxotrophic marker in that region to prototrophy, thereby introducing new mutations in the neighborhood. We have used this method to isolate many different temperature-sensitive mutations in genes of unknown function in particular regions of the chromosome. Since the method is very simple, it can be used to saturate any region of the map with mutations in essential genes, or for various types of genetic manipulations. Although we have used hydroxylamine-mutagenized phage P22 and Salmonella typhimurium, the method should be applicable to other mutagens and bacteria and transducing phage.


Structuring and validating a cost-effectiveness model of primary asthma prevention amongst children.
Given the rising number of asthma cases and the increasing costs of health care, prevention may be the best cure. Decisions regarding the implementation of prevention programmes in general and choosing between unifaceted and multifaceted strategies in particular are urgently needed. Existing trials on the primary prevention of asthma are, however, insufficient on their own to inform the decision of stakeholders regarding the cost-effectiveness of such prevention strategies. Decision analytic modelling synthesises available data for the cost-effectiveness evaluation of strategies in an explicit manner. Published reports on model development should provide the detail and transparency required to increase the acceptability of cost-effectiveness modelling. But, detail on the explicit steps and the involvement of experts in structuring a model is often unevenly reported. In this paper, we describe a procedure to structure and validate a model for the primary prevention of asthma in children. An expert panel was convened for round-table discussions to frame the cost-effectiveness research question and to select and structure a model. The model's structural validity, which indicates how well a model reflects the reality, was determined through descriptive and parallel validation. Descriptive validation was performed with the experts. Parallel validation qualitatively compared similarity between other published models with different decision problems. The multidisciplinary input of experts helped to develop a decision-tree structure which compares the current situation with screening and prevention. The prevention was further divided between multifaceted and unifaceted approaches to analyse the differences. The clinical outcome was diagnosis of asthma. No similar model was found in the literature discussing the same decision problem. Structural validity in terms of descriptive validity was achieved with the experts and was supported by parallel validation. A decision-tree model developed with experts in round-table discussions benefits from a systematic and transparent approach and the multidisciplinary contributions of the experts. Parallel validation provides a feasible alternative to validating novel models. The process of structuring and validating a model presented in this paper could be a useful guide to increase transparency, credibility, and acceptability of (future, novel) models when experts are involved.


Atypical mitogen-activated protein kinase phosphatase implicated in regulating transition from pre-S-Phase asexual intraerythrocytic development of Plasmodium falciparum.
Intraerythrocytic development of the human malaria parasite Plasmodium falciparum appears as a continuous flow through growth and proliferation. To develop a greater understanding of the critical regulatory events, we utilized piggyBac insertional mutagenesis to randomly disrupt genes. Screening a collection of piggyBac mutants for slow growth, we isolated the attenuated parasite C9, which carried a single insertion disrupting the open reading frame (ORF) of PF3D7_1305500. This gene encodes a protein structurally similar to a mitogen-activated protein kinase (MAPK) phosphatase, except for two notable characteristics that alter the signature motif of the dual-specificity phosphatase domain, suggesting that it may be a low-activity phosphatase or pseudophosphatase. C9 parasites demonstrated a significantly lower growth rate with delayed entry into the S/M phase of the cell cycle, which follows the stage of maximum PF3D7_1305500 expression in intact parasites. Genetic complementation with the full-length PF3D7_1305500 rescued the wild-type phenotype of C9, validating the importance of the putative protein phosphatase PF3D7_1305500 as a regulator of pre-S-phase cell cycle progression in P. falciparum.


Control of somatic embryogenesis and embryo development by AP2 transcription factors.
Members of the AP2 family of transcription factors, such as BABY BOOM (BBM), play important roles in cell proliferation and embryogenesis in Arabidopsis thaliana (AtBBM) and Brassica napus (BnBBM) but how this occurs is not understood. We have isolated three AP2 genes (GmBBM1, GmAIL5, GmPLT2) from somatic embryo cultures of soybean, Glycine max (L.) Merr, and discovered GmBBM1 to be homologous to AtBBM and BnBBM. GmAIL5 and GmPLT2 were homologous to Arabidopsis AINTEGUMENTA-like5 (AIL5) and PLETHORA2 (PLT2), respectively. Constitutive expression of GmBBM1 in Arabidopsis induced somatic embryos on vegetative organs and other pleiotropic effects on post-germinative vegetative organ development. Sequence comparisons of BBM orthologues revealed the presence of ten sequence motifs outside of the AP2 DNA-binding domains. One of the motifs, bbm-1, was specific to the BBM-like genes. Deletion and domain swap analyses revealed that bbm-1 was important for somatic embryogenesis and acted cooperatively with at least one other motif, euANT2, in the regulation of somatic embryogenesis and embryo development in transgenic Arabidopsis. The results provide new insights into the mechanisms by which BBM governs embryogenesis.


Sodium content in processed foods in Argentina: compliance with the national law.
Despite the body of evidence that documents the unfavorable effects of excessive sodium consumption on blood pressure and cardiovascular health, public health efforts to decrease sodium consumption have been limited to a few countries. Argentina is the first country in Latin America to regulate sodium content of processed foods by means of a national law. The objective of this cross-sectional quantitative study is to provide a baseline comparison against the reduction targets set by the national law before its entry into force. Data were collected in February 2014 in a leading supermarket chain located in Buenos Aires. Nutrient data from package labels were analysed for 1,320 products within 14 food groups during the study period. To compare sodium concentration levels with the established maximum levels we matched the collected food groups with the food groups included in the law resulting in a total of 292 products. Data analysis was conducted using SPSS version 20 software. Food groups with the highest median sodium content were sauces and spreads (866.7 mg/100 g), meat and meat products (750 mg/100 g) and snack foods (644 mg/100 g). Categories with the highest sodium content were appetizers (1,415 mg/100 g), sausages (1,050 mg/100 g) and ready-made meals (940.7 mg/100 g). We also found large variability within products from the same food categories. Products included in the national law correspond to 22.1% (n=292) of the surveyed foods. From the 18 food groups, 15 showed median sodium values below the established targets. Products exceeding the established maximum levels correspond to 15.1% (n=44) of the products included in the analysis. This study is the first analysis of food labels to determine sodium concentrations of processed foods in Argentina and to provide a baseline against the national law standards. Upon the completion of this analysis, maximum levels have been achieved by most of the food groups included in the law. Thus, the introduction of further reductions for the existing maximum levels and the establishment of sodium targets for all relevant product categories not included in the law should be considered as the next steps in the process.


Novel Immunoglobulin Domain Proteins Provide Insights into Evolution and Pathogenesis of SARS-CoV-2-Related Viruses.
A novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was recently identified as the causative agent for the coronavirus disease 2019 (COVID-19) outbreak that has generated a global health crisis. We use a combination of genomic analysis and sensitive profile-based sequence and structure analysis to understand the potential pathogenesis determinants of this virus. As a result, we identify several fast-evolving genomic regions that might be at the interface of virus-host interactions, corresponding to the receptor binding domain of the Spike protein, the three tandem Macro fold domains in ORF1a, and the uncharacterized protein ORF8. Further, we show that ORF8 and several other proteins from alpha- and beta-CoVs belong to novel families of immunoglobulin (Ig) proteins. Among them, ORF8 is distinguished by being rapidly evolving, possessing a unique insert, and having a hypervariable position among SARS-CoV-2 genomes in its predicted ligand-binding groove. We also uncover numerous Ig domain proteins from several unrelated metazoan viruses, which are distinct in sequence and structure but share comparable architectures to those of the CoV Ig domain proteins. Hence, we propose that SARS-CoV-2 ORF8 and other previously unidentified CoV Ig domain proteins fall under the umbrella of a widespread strategy of deployment of Ig domain proteins in animal viruses as pathogenicity factors that modulate host immunity. The rapid evolution of the ORF8 Ig domain proteins points to a potential evolutionary arms race between viruses and hosts, likely arising from immune pressure, and suggests a role in transmission between distinct host species.IMPORTANCE The ongoing COVID-19 pandemic strongly emphasizes the need for a more complete understanding of the biology and pathogenesis of its causative agent SARS-CoV-2. Despite intense scrutiny, several proteins encoded by the genomes of SARS-CoV-2 and other SARS-like coronaviruses remain enigmatic. Moreover, the high infectivity and severity of SARS-CoV-2 in certain individuals make wet-lab studies currently challenging. In this study, we used a series of computational strategies to identify several fast-evolving regions of SARS-CoV-2 proteins which are potentially under host immune pressure. Most notably, the hitherto-uncharacterized protein encoded by ORF8 is one of them. Using sensitive sequence and structural analysis methods, we show that ORF8 and several other proteins from alpha- and beta-coronavirus comprise novel families of immunoglobulin domain proteins, which might function as potential immune modulators to delay or attenuate the host immune response against the viruses.


Test Agreement among Biochemical Methods, Matrix-Assisted Laser Desorption Ionization-Time of Flight Mass Spectrometry, and 16S rRNA Sequencing for Identification of Microorganisms Isolated from Bovine Milk.
The objective of this prospective study was a blinded comparison of three methods for the identification of bacteria isolated on Columbia blood agar from milk samples of dairy cows. Basic biochemical testing, matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS), and 16S rRNA partial genome sequence analysis were compared for bacterial identification to the genus or species level. Milk samples submitted from a commercial dairy farm from recently calved cows or clinical mastitis cases were cultured, and 181 isolates were identified by biochemical testing, MALDI-TOF MS, and 16S rRNA sequence analysis (179 isolates; 2 isolates could not be recovered from storage). For Staphylococcus aureus and Escherichia coli, agreement was determined at the species level. For other microbes, agreement was determined at the genus level or at the group level for streptococcus-like organisms. The positive agreement among all 3 diagnostic methods was 94%, with 95% to 98% between each pair of methods. The overall (including negative agreement) agreement among all 3 methods ranged from 97% to 100%. MALDI-TOF MS is becoming more commonplace for the genus- and/or species-level identification of bacteria isolated from milk samples and, in some laboratories, has replaced conventional biochemical methods. The results of the present study suggest that when identifying pathogens at the genus or group level, conventional culture followed up with either secondary biochemical testing or MALDI-TOF MS is of practical value. For purposes of milk quality and udder health monitoring or research, any of the 3 methods is a valuable tool for genus-level identification of bacteria isolated from dairy cow milk.


Overexpression of the auxin binding protein1 modulates PIN-dependent auxin transport in tobacco cells.
Auxin binding protein 1 (ABP1) is a putative auxin receptor and its function is indispensable for plant growth and development. ABP1 has been shown to be involved in auxin-dependent regulation of cell division and expansion, in plasma-membrane-related processes such as changes in transmembrane potential, and in the regulation of clathrin-dependent endocytosis. However, the ABP1-regulated downstream pathway remains elusive. Using auxin transport assays and quantitative analysis of cellular morphology we show that ABP1 regulates auxin efflux from tobacco BY-2 cells. The overexpression of ABP1can counterbalance increased auxin efflux and auxin starvation phenotypes caused by the overexpression of PIN auxin efflux carrier. Relevant mechanism involves the ABP1-controlled vesicle trafficking processes, including positive regulation of endocytosis of PIN auxin efflux carriers, as indicated by fluorescence recovery after photobleaching (FRAP) and pharmacological manipulations. The findings indicate the involvement of ABP1 in control of rate of auxin transport across plasma membrane emphasizing the role of ABP1 in regulation of PIN activity at the plasma membrane, and highlighting the relevance of ABP1 for the formation of developmentally important, PIN-dependent auxin gradients.


Early Life Socioeconomic Disparities in Children's Sleep: The Mediating Role of the Current Home Environment.
Despite identified concurrent socioeconomic disparities in children's sleep, little research has examined pathways explaining such associations. This study examined the quality of the home environment as a direct predictor of sleep and potential mediator of associations between early life socioeconomic status and objective and subjective indicators of sleep in middle childhood. A socioeconomically and ethnically diverse sample of 381 twin children (50% female; 46.6% lower middle class or living at or below the poverty line; 26% Hispanic/Latino) were assessed at 12 months for SES and eight years using gold-standard home environment interviews and actigraphy-measured sleep. Multilevel mediation path models indicated that lower early SES and lower quality concurrent home environments were associated with shorter sleep durations, longer sleep latencies, and greater sleep timing variability. The home environment significantly mediated associations with sleep duration and sleep timing variability. The findings illustrate an important target in the prevention of poor childhood and adolescent sleep.


Group visits for Hmong adults with type 2 diabetes mellitus: a pre-post analysis.
Hmong refugees with type 2 diabetes mellitus (DM2) have poor glycemic control. For Hmong adults with DM2, group visits were instituted at a community health center and evaluated for their influence on diabetes management. Pre- and postintervention measures of physical health, mental health, and behavior were collected on 39 participants (64% participation rate). Baseline characteristics and clinical outcomes of 39 group visit participants were compared with 22 Hmong DM2 adults who refused to participate and 216 nonparticipating Hmong DM2 adults from a local diabetes registry. Baseline characteristics were similar among the three groups. Although participants received good medical services and their mental health improved (p < 0.05), clinical outcomes did not significantly improve. Although group visits are feasible for providing medical services for Hmong adults with DM2, clinical outcomes remain outside of recommended targets. Addressing mental health in this population may be necessary before people can institute behavioral changes that improve diabetes management.


Retrospective cohort study of wrong-patient imaging order errors: how many reach the patient?
Studying near-miss errors is essential to preventing errors from reaching patients. When an error is committed, it may be intercepted (near-miss) or it will reach the patient; estimates of the proportion that reach the patient vary widely. To better understand this relationship, we conducted a retrospective cohort study using two objective measures to identify wrong-patient imaging order errors involving radiation, estimating the proportion of errors that are intercepted and those that reach the patient. This study was conducted at a large integrated healthcare system using data from 1 January to 31 December 2019. The study used two outcome measures of wrong-patient orders: (1) wrong-patient orders that led to misadministration of radiation reported to the New York Patient Occurrence Reporting and Tracking System (NYPORTS) (misadministration events); and (2) wrong-patient orders identified by the Wrong-Patient Retract-and-Reorder (RAR) measure, a measure identifying orders placed for a patient, retracted and rapidly reordered by the same clinician on a different patient (near-miss events). All imaging orders that involved radiation were extracted retrospectively from the healthcare system data warehouse. Among 293 039 total eligible orders, 151 were wrong-patient orders (3 misadministration events, 148 near-miss events), for an overall rate of 51.5 per 100 000 imaging orders involving radiation placed on the wrong patient. Of all wrong-patient imaging order errors, 2% reached the patient, translating to 50 near-miss events for every 1 error that reached the patient. This proportion provides a more accurate and reliable estimate and reinforces the utility of systematic measure of near-miss errors as an outcome for preventative interventions.


Comparison Between 18F-Dopa and 18F-Fet PET/CT in Patients with Suspicious Recurrent High Grade Glioma: A Literature Review and Our Experience.
The aims of the present study were to: 1- critically assess the utility of L-3,4- dihydroxy-6-18Ffluoro-phenyl-alanine (18F-DOPA) and O-(2-18F-fluoroethyl)-L-tyrosine (18F-FET) Positron Emission Tomography (PET)/Computed Tomography (CT) in patients with high grade glioma (HGG) and 2- describe the results of 18F-DOPA and 18F-FET PET/CT in a case series of patients with recurrent HGG. We searched for studies using the following databases: PubMed, Web of Science and Scopus. The search terms were: glioma OR brain neoplasm and DOPA OR DOPA PET OR DOPA PET/CT and FET OR FET PET OR FET PET/CT. From a mono-institutional database, we retrospectively analyzed the 18F-DOPA and 18F-FET PET/CT of 29 patients (age: 56 ± 12 years) with suspicious for recurrent HGG. All patients underwent 18F-DOPA or 18F-FET PET/CT for a multidisciplinary decision. The final definition of recurrence was made by magnetic resonance imaging (MRI) and/or multidisciplinary decision, mainly based on the clinical data. Fifty-one articles were found, of which 49 were discarded, therefore 2 studies were finally selected. In both the studies, 18F-DOPA and 18F-FET as exchangeable in clinical practice particularly for HGG patients. From our institutional experience, in 29 patients, we found that sensitivity, specificity and accuracy of 18F-DOPA PET/CT in HGG were 100% (95% confidence interval- 95%CI - 81-100%), 63% (95%CI: 39-82%) and 62% (95%CI: 39-81%), respectively. 18F-FET PET/CT was true positive in 4 and true negative in 4 patients. Sensitivity, specificity and accuracy for 18F-FET PET/CT in HGG were 100%. 18F-DOPA and 18F-FET PET/CT have a similar diagnostic accuracy in patients with recurrent HGG. However, 18F-DOPA PET/CT could be affected by inflammation conditions (false positive) that can alter the final results. Large comparative trials are warranted in order to better understand the utility of 18F-DOPA or 18F-FET PET/CT in patients with HGG.


Diagnosis and treatment of Hymenoptera venom allergy: S2k Guideline of the German Society of Allergology and Clinical Immunology (DGAKI) in collaboration with the Arbeitsgemeinschaft für Berufs- und Umweltdermatologie e.V. (ABD), the Medical Association of German Allergologists (AeDA), the German Society of Dermatology (DDG), the German Society of Oto-Rhino-Laryngology, Head and Neck Surgery (DGHNOKC), the German Society of Pediatrics and Adolescent Medicine (DGKJ), the Society for Pediatric Allergy and Environmental Medicine (GPA), German Respiratory Society (DGP), and the Austrian Society for Allergy and Immunology (ÖGAI).
Hymenoptera venom (HV) is injected into the skin during a sting by Hymenoptera such as bees or wasps. Some components of HV are potential allergens and can cause large local and/or systemic allergic reactions (SAR) in sensitized individuals. During their lifetime, ~ 3% of the general population will develop SAR following a Hymenoptera sting. This guideline presents the diagnostic and therapeutic approach to SAR following Hymenoptera stings. Symptomatic therapy is usually required after a severe local reaction, but specific diagnosis or allergen immunotherapy (AIT) with HV (VIT) is not necessary. When taking a patient's medical history after SAR, clinicians should discuss possible risk factors for more frequent stings and more severe anaphylactic reactions. The most important risk factors for more severe SAR are mast cell disease and, especially in children, uncontrolled asthma. Therefore, if the SAR extends beyond the skin (according to the Ring and Messmer classification: grade > I), the baseline serum tryptase concentration shall be measured and the skin shall be examined for possible mastocytosis. The medical history should also include questions specific to asthma symptoms. To demonstrate sensitization to HV, allergists shall determine concentrations of specific IgE antibodies (sIgE) to bee and/or vespid venoms, their constituents and other venoms as appropriate. If the results are negative less than 2 weeks after the sting, the tests shall be repeated (at least 4 - 6 weeks after the sting). If only sIgE to the total venom extracts have been determined, if there is double sensitization, or if the results are implausible, allergists shall determine sIgE to the different venom components. Skin testing may be omitted if in-vitro methods have provided a definitive diagnosis. If neither laboratory diagnosis nor skin testing has led to conclusive results, additional cellular testing can be performed. Therapy for HV allergy includes prophylaxis of reexposure, patient self treatment measures (including use of rescue medication) in the event of re-stings, and VIT. Following a grade I SAR and in the absence of other risk factors for repeated sting exposure or more severe anaphylaxis, it is not necessary to prescribe an adrenaline auto-injector (AAI) or to administer VIT. Under certain conditions, VIT can be administered even in the presence of previous grade I anaphylaxis, e.g., if there are additional risk factors or if quality of life would be reduced without VIT. Physicians should be aware of the contraindications to VIT, although they can be overridden in justified individual cases after weighing benefits and risks. The use of β-blockers and ACE inhibitors is not a contraindication to VIT. Patients should be informed about possible interactions. For VIT, the venom extract shall be used that, according to the patient's history and the results of the allergy diagnostics, was the trigger of the disease. If, in the case of double sensitization and an unclear history regarding the trigger, it is not possible to determine the culprit venom even with additional diagnostic procedures, VIT shall be performed with both venom extracts. The standard maintenance dose of VIT is 100 µg HV. In adult patients with bee venom allergy and an increased risk of sting exposure or particularly severe anaphylaxis, a maintenance dose of 200 µg can be considered from the start of VIT. Administration of a non-sedating H1-blocking antihistamine can be considered to reduce side effects. The maintenance dose should be given at 4-weekly intervals during the first year and, following the manufacturer's instructions, every 5 - 6 weeks from the second year, depending on the preparation used; if a depot preparation is used, the interval can be extended to 8 weeks from the third year onwards. If significant recurrent systemic reactions occur during VIT, clinicians shall identify and as possible eliminate co-factors that promote these reactions. If this is not possible or if there are no such co-factors, if prophylactic administration of an H1-blocking antihistamine is not effective, and if a higher dose of VIT has not led to tolerability of VIT, physicians should should consider additional treatment with an anti IgE antibody such as omalizumab as off lable use. For practical reasons, only a small number of patients are able to undergo sting challenge tests to check the success of the therapy, which requires in-hospital monitoring and emergency standby. To perform such a provocation test, patients must have tolerated VIT at the planned maintenance dose. In the event of treatment failure while on treatment with an ACE inhibitor, physicians should consider discontinuing the ACE inhibitor. In the absence of tolerance induction, physicians shall increase the maintenance dose (200 µg to a maximum of 400 µg in adults, maximum of 200 µg HV in children). If increasing the maintenance dose does not provide adequate protection and there are risk factors for a severe anaphylactic reaction, physicians should consider a co-medication based on an anti-IgE antibody (omalizumab; off-label use) during the insect flight season. In patients without specific risk factors, VIT can be discontinued after 3 - 5 years if maintenance therapy has been tolerated without recurrent anaphylactic events. Prolonged or permanent VIT can be considered in patients with mastocytosis, a history of cardiovascular or respiratory arrest due to Hymenoptera sting (severity grade IV), or other specific constellations associated with an increased individual risk of recurrent and/or severe SAR (e.g., hereditary α-tryptasemia). In cases of strongly increased, unavoidable insect exposure, adults may receive VIT until the end of intense contact. The prescription of an AAI can be omitted in patients with a history of SAR grade I and II when the maintenance dose of VIT has been reached and tolerated, provided that there are no additional risk factors. The same holds true once the VIT has been terminated after the regular treatment period. Patients with a history of SAR grade ≥ III reaction, or grade II reaction combined with additional factors that increase the risk of non response or repeated severe sting reactions, should carry an emergency kit, including an AAI, during VIT and after regular termination of the VIT.


Viruses and tumor cell microenvironment: A brief summary.
An infectious etiology for a number of cancers has been entertained for over 100 years and modern studies have confirmed that a number of viruses are linked to cancer induction. While a large number of viruses have been demonstrated in a number of types of cancers, most such findings have been dismissed in the past as opportunistic infections, especially with persistent viruses with high rates of infectivity of the world's populations. More recent studies have clearly shown that while not definitely causing these cancers, these viruses appear capable of affecting the biology of these tumors in such a way as to make them more aggressive and more resistant to conventional treatments. The term oncomodulatory viruses have been used to describe this phenomenon. A number of recent studies have shown a growing number of ways; these oncomodulatory viruses can alter the pathology of these tumors by affecting cell signaling, cell metabolism, apoptosis mechanisms, cell-cell communication, inflammation, antitumor immunity suppression, and angiogenesis. We are also learning that much of the behavior of tumors depends on cancer stem cells and stromal cells within the tumor microenvironment, which participate in extensive, dynamic crosstalk known to affect tumor behavior. Cancer stem cells have been found to be particularly susceptible to infection by human cytomegaloviruses. In a number of studies, it has been shown that while only a select number of cells are actually infected with the virus, numerous viral proteins are released into the cancer and stromal cells in the microenvironment and these viral proteins are known to affect tumor behavior and aggressiveness.


Benign breast tumours in an African population.
A detailed prospective clinical study of 238 women presenting with benign breast swellings in the South Eastern equatorial rainforest of Nigeria clearly shows that 94% of lesions were due to two disorders, fibroadenomas and bacterial infections, and that they affected mostly young women in the peak of their reproductive life. Fibroadenoma which accounted for disease in no less than 69% of the women was multiple in 8%, bilateral in 11%, and was considered giant in size in 5% of the cases; by contrast, fibroadenosis was rare, accounting for swellings in only eight patients. Bacterial infections, chronic pyogenic mastitis and tuberculosis together caused breast swellings in 25% of the women studied. In tropical Africa, multiple chronic discharging sinuses suggest tuberculosis of the breast.


Implementing the Precautionary Principle: incorporating science, technology, fairness, and accountability in environmental, health, and safety decisions.
The Precautionary Principle is in sharp political focus today because: 1) the nature of scientific uncertainty is changing, and 2) there is increasing pressure to base governmental action on more "rational" schemes, such as cost-benefit analysis and quantitative risk assessment, the former being an embodiment of "rational choice theory" promoted by the Chicago School of Law and Economics. The Precautionary Principle has been criticized as being both too vague and too arbitrary to form a basis for rational decision making. The assumption underlying this criticism is that any scheme not based on cost-benefit analysis and risk assessment is both irrational and without secure foundation in either science or economics. This paper contests that view and makes explicit the rational tenets of the Precautionary Principle within an analytical framework as rigorous as uncertainties permit, and one that mirrors democratic values embodied in regulatory, compensatory, and common law. Unlike other formulations that reject risk assessment, this paper argues that risk assessment can be used within the formalism of tradeoff analysis--a more appropriate alternative to traditional cost-benefit analysis and one that satisfies the need for well-grounded public policy decision making. This paper will argue that the precautionary approach is the most appropriate basis for policy, even when large uncertainties do not exist, especially where the fairness of the distributions of costs and benefits of hazardous activities and products are a concern. Furthermore, it will offer an approach to making decisions within an analytic framework, based on equity and justice, to replace the economic paradigm of utilitarian cost-benefit analysis.


Which targets in clinical practice guidelines are associated with improved survival in a large dialysis organization?
Professional organizations have developed practice guidelines in the hope of improving clinical outcomes. The National Kidney Foundation's Kidney Disease Outcomes Quality Initiative (KDOQI) has set targets for dialysis dosage (single-pool Kt/V), hematocrit, serum albumin, calcium, phosphorus, parathyroid hormone, and BP for hemodialysis (HD) patients. Several guidelines are largely based on results from observational studies. In contrast to other parameters, BP values within the KDOQI guidelines have been associated with increased mortality. Therefore, it was postulated that having multiple parameters that satisfy the current guidelines, except those for BP, is associated with improved survival among HD patients. A retrospective analysis was conducted of incident HD patients who were treated at facilities operated by Dialysis Clinic Inc., a not-for-profit dialysis provider, between January 1, 1998, and December 31, 2004 (n = 13,792). Cox proportional hazards models were used to assess the association between satisfying guidelines and mortality. Values within guidelines for single-pool Kt/V, hematocrit, serum albumin, calcium, phosphorus, and parathyroid hormone were associated with decreased mortality (P < or = 0.0001). The largest survival benefit was found for serum albumin (hazard ratio [HR] 0.27; 95% confidence interval [CI] 0.24 to 0.31). Satisfying these six guidelines simultaneously was associated with an 89% reduction in mortality (HR 0.11; 95% CI 0.06 to 0.19]). Conversely, BP values satisfying the guideline were associated with increased mortality (HR 1.90; 95% CI 1.73 to 2.10). Because this target was largely extrapolated from the general population, a randomized, controlled trial is needed to identify the optimal BP for HD patients.


[Immune status and proinflammatury cytokines in pregnant women with acute cytomegalovirus infection].
A total of 64 pregnant women aged 16-40 years with acute cytomegalovirus (CMV) infection were examined. CMV infection was diagnosed by the detection of anti- CMV IgM (by the enzyme immunoassay) or DNA by PCR in the blood. The immunophenotype of lymphocytes CD3+, CD4+, CD8+, CD16+, CD19+, IgG, IgM, IgA and the spontaneous production of TNFalpha and IL-8 in the blood were studied. In pregnant women with CMV infection the presence of the immunosuppression of cell-mediated immunity reactions, the hyperproduction of Fc-receptors of natural killers, B lymphocytes (CD19+), the hyperglobulinemia of serum IgM and IgG, as well as the increased synthesis of proinflammatory cytokines--TNFalpha and IL-8--were established.


Evidence for multiple bone resorption-stimulating factors produced by normal human keratinocytes in culture.
Conditioned medium from cultured normal human foreskin keratinocytes enhanced the release of calcium from neonatal mouse calvaria in organ culture. Unfractionated keratinocyte-conditioned medium (KCM) stimulated bone resorption in a dose-dependent manner, but it did not increase the concentration of prostaglandin E2 (PGE2) in the bone culture medium until a maximal dose of KCM for resorption was used. Furthermore, inhibitors of PGE2 synthesis, indomethacin, ibuprofen, and piroxicam, did not inhibit KCM-induced calcium release. High concentrations of KCM increased cAMP production by calvaria in the presence of isobutylmethylxanthine, but the increase was small compared with that produced by a dose of bovine PTH that caused a similar level of bone resorption. The bone resorption-stimulating activity of KCM was not lost after incubation at 56 C for 60 min, but it was lost after heating at 100 C for 10 min. Fractionation of KCM by gel filtration chromatography revealed two distinct peaks of bone resorption-stimulating activity. One peak, KCMI, caused a significant increase in bone resorption at 2 micrograms protein/ml. KCMI did not increase medium PGE2, and inhibition of PGE2 synthesis in bone had no effect on KCMI-induced bone resorption. KCMI failed to increase cAMP production by human osteosarcoma SaOS-2 cells. Another peak, KCMII, caused a dose-dependent increase in bone resorption, and a significant increase in medium calcium was noted at a 20-fold lower concentration (0.1 microgram protein/ml) than with KCMI. In contrast to KCMI, the increase in bone resorption stimulated by KCMII was accompanied by a parallel increase in the production of PGE2, and inhibition of PGE2 synthesis completely inhibited the bone resorption-stimulating activity of KCMII. KCMII also caused an increase in cAMP production by SaOS-2 cells. We conclude that KCM contains at least two distinct bone resorption-stimulating factors, one of which acts via a PG-mediated mechanism and the other by a PG-independent pathway.


A family of genes clustered at the Triplo-lethal locus of Drosophila melanogaster has an unusual evolutionary history and significant synteny with Anopheles gambiae.
Within the unique Triplo-lethal region (Tpl) of the Drosophila melanogaster genome we have found a cluster of 20 genes encoding a novel family of proteins. This family is also present in the Anopheles gambiae genome and displays remarkable synteny and sequence conservation with the Drosophila cluster. The family is also present in the sequenced genome of D. pseudoobscura, and homologs have been found in Aedes aegypti mosquitoes and in four other insect orders, but it is not present in the sequenced genome of any noninsect species. Phylogenetic analysis suggests that the cluster evolved prior to the divergence of Drosophila and Anopheles (250 MYA) and has been highly conserved since. The ratio of synonymous to nonsynonymous substitutions and the high codon bias suggest that there has been selection on this family both for expression level and function. We hypothesize that this gene family is Tpl, name it the Osiris family, and consider possible functions. We also predict that this family of proteins, due to the unique dosage sensitivity and the lack of homologs in noninsect species, would be a good target for genetic engineering or novel insecticides.


Adaptability of sulfur-disproportionating bacteria for mine water remediation under the pressures of heavy metal ions and high sulfate content.
Biological sulfide production processes mediated by sulfate/sulfur reduction have gained attention for metal removal from industrial wastewater (e.g., mine water (MW) and metallurgical wastewater) via forming insoluble metal sulfides. However, these processes often necessitate the addition of external organic compounds as electron donors, which poses a constraint on the broad application of this technology. A recent proof of concept study reported that microbial sulfur disproportionation (SD) produced sulfide with no demand for organics, which could achieve more cost-benefit MW treatment against the above-mentioned processes. However, the resistance of SD bioprocess to different metals and high sulfate content in MW remains mysterious, which may substantially affect the practical applicability of such process. In this study, the sulfur-disproportionating bacteria (SDB)-dominated consortium was enriched from a previously established SD-driven bioreactor, in which Dissulfurimicrobium sp. with a relative abundance of 39.9 % was the predominated SDB. When exposed to the real pretreated acidic MW after the pretreatment process of pH amelioration, the sulfur-disproportionating activity remained active, and metals were effectively removed from the MW. Metal tolerance assays further demonstrated that the consortium had a good tolerance to different metal ions (i.e., Pb2+, Cu2+, Ni2+, Mn2+, Zn2+), especially for Mn2+ with a concentration of approximately 20 mg/L. It suggested the robustness of Dissulfurimicrobium sp. likely due to the presence of genes encoding for the enzymes associated with metal(loid) resistance/uptake. Additionally, although high sulfate content resulted in a slight inhibition on the sulfur-disproportionating activity, the consortium still achieved sulfide production rates of 27.3 mg S/g VSS-d on average under an environmentally relevant sulfate level (i.e., 1100 mg S/L), which is comparable to those reported in sulfate reduction. Taken together, these findings imply that SDB could ensure sustainable MW treatment in a more cost-effective and organic-free way.