[Survey of the use of long-lasting expanding gases in ophthalmology in Japan].
To survey the use of long-lasting expanding gases in ophthalmology in Japan. A questionnaire was sent to 1,236 teaching hospitals approved by the Japanese Ophthalmological Society requesting information regarding indications, methods, efficacy and complications related to the use of long-lasting expanding gases administered from January through December 2005. Four-hundred and fifty-nine hospitals responded to the survey (response rate 37.1%). A total of 174,221 ophthalmic surgeries were performed during the survey period, with long-lasting expanding gases used in 19,816 of cases (11.4%). The surgical procedure was vitrectomy in 89.6% of cases in which gas was administered. The most frequent indication for gas use was rhegmatogenous retinal detachment, for which SF6 was the preferred gas. Industrial use gas was utilized in 76.1% of cases, while 22.4% of cases received medical use gas. Increase in intraocular pressure was the most common complication of intraocular gas tamponade (3121 cases, 15.7%), followed by cataract formation. Ninety-eight percent of ophthalmologists responding supported the use of long-lasting expanding gases with vitrectomy, 85% with scleral buckling procedures, and 84% with surgery to remove subretinal hemorrhage. The consensus was that substantial deterioration of surgical results would occur if long-lasting expanding gases could not be used. Long-lasting expanding gases are being widely administered in ophthalmology in Japan, and appear to have good efficacy for a variety of indications. Several complications related to the use of these gases were reported, however the rates of complications were low.


A microtiter plate-based quantitative method to monitor the growth rate of dermatophytes and test antifungal activity.
Dermatophytosis is one of the most common superficial fungal infections, which is mainly caused by filamentous fungi such as Trichophyton species. A challenging aspect in dermatophyte research is the lack of a straightforward method to measure the rate of growth, in particular when growing dermatophytes in small volumes such as in microtitre plates. However, one characteristic of dermatophytes is their ability to produce compounds such as ammonia that make the growth medium more alkaline. The objective of this study was to test whether the change in pH in a liquid medium, colourimetrically established using the indicator phenol red, was linearly and directly proportional to the growth rate for Trichophyton rubrum and Trichophyton interdigitale. The changes in the colour determined by the phenol-red based assay showed a good correlation with the amount of fungal biomass over an incubation period of 24-120 h. The functionality of the phenol red assay was also validated in experiments on the growth of T. rubrum in the presence of antifungals. The changes in colour showed a clear dose-response relationship compounds and enabled determination of the minimum inhibitory concentration. The phenol red assay is thus a simple and straightforward assay to monitor the rate of growth of Trichophyton spp. and test antifungal activity.


[Perception of the meaning of the caretaker's function for a group of nurses and caretakers: convergences and divergences].
This study review the of role the caretaker at the pediatric unit while the child is in hospital. The opinions of caretaker and nurses were surveyed as for the role that the participating family member would have during their stay along with the child in hospital. Data were gathered between April and June 1997 in units allowing for children to stay together with caretaker, at state hospitals. The interviews with the groups were separated by meas of the stafement analysis, based on the studies by COSTA (1992), and FRIEDMAN (1986), which allowed us to determine six categories: Security & Protection, Caretaking, Recovery, Knowledge, Supervision and Guidance, which in turn allowed us to study, although in a modest fashion, the agreements and disagreements regarding how our interviews perceive the role of the caretaker.


SMAD signaling drives heart and muscle dysfunction in a Drosophila model of muscular dystrophy.
Loss-of-function mutations in the genes encoding dystrophin and the associated membrane proteins, the sarcoglycans, produce muscular dystrophy and cardiomyopathy. The dystrophin complex provides stability to the plasma membrane of striated muscle during muscle contraction. Increased SMAD signaling due to activation of the transforming growth factor-β (TGFβ) pathway has been described in muscular dystrophy; however, it is not known whether this canonical TGFβ signaling is pathogenic in the muscle itself. Drosophila deleted for the γ/δ-sarcoglycan gene (Sgcd) develop progressive muscle and heart dysfunction and serve as a model for the human disorder. We used dad-lacZ flies to demonstrate the signature of TGFβ activation in response to exercise-induced injury in Sgcd null flies, finding that those muscle nuclei immediately adjacent to muscle injury demonstrate high-level TGFβ signaling. To determine the pathogenic nature of this signaling, we found that partial reduction of the co-SMAD Medea, homologous to SMAD4, or the r-SMAD, Smox, corrected both heart and muscle dysfunction in Sgcd mutants. Reduction in the r-SMAD, MAD, restored muscle function but interestingly not heart function in Sgcd mutants, consistent with a role for activin but not bone morphogenic protein signaling in cardiac dysfunction. Mammalian sarcoglycan null muscle was also found to exhibit exercise-induced SMAD signaling. These data demonstrate that hyperactivation of SMAD signaling occurs in response to repetitive injury in muscle and heart. Reduction of this pathway is sufficient to restore cardiac and muscle function and is therefore a target for therapeutic reduction.


Agomelatine for the treatment of generalized anxiety disorder.
Agomelatine is a melatonergic antidepressant, approved for the treatment of Major Depressive Disorder (MDD) in Europe and Australia, but not in the United States. This compound seems to be promising in the short-term and maintenance treatment of Generalized Anxiety Disorder (GAD). Areas covered: This paper presents an evaluation of the available data about the clinical efficacy and tolerability of agomelatine in the treatment of GAD. Expert opinion: First-line GAD treatments are limited by high rates of lack of clinical response. Preliminary data would indicate agomelatine as a safe compound, and with a higher rate of clinical response in the short-term and an earlier improvement of symptoms with respect to Selective Serotonine Reuptake Inhibitors (SSRIs) and Selective Serotonin Noradrenaline Reuptake Inhibitors (SNRIs). In addition, agomelatine has not been associated with potential risk of abuse as in case of pregabalin and with long-term metabolic side effects similar to quetiapine. The major limitation of the results presented is that little data has come from long-term or comparative trials. Furthermore, some caution should be reserved in case of liver impairment (e.g. in subjects with alcohol abuse).


Modeling Public Sentiments About JUUL Flavors on Twitter Through Machine Learning.
The availability of a variety of e-cigarettes flavors is one of the frequently cited reasons for their adoption. An active stream of discussion about flavoring can be observed online. Analyzing these real-time conversations offers nuanced insights into key factors related to the adoption of flavors, subsequently supporting public health interventions. Google's BERT, a state-of-the-art deep learning method was employed to model the first sentiment corpus on JUUL flavors. BERT, which is pre-trained with the complete English Wikipedia was fine-tuned by integrating a classification model, with human labeled Tweets, as training data. A collection of 30 075 Tweets about JUUL flavors was classified into positive and negative sentiments. Finally, using topic models, we identify and grouped thematic areas into positive and negative Tweets. With an average of 89% cross-validation precision for classifying Tweets, the fine-tuned BERT model classified 24 114 Tweets as positive and 5961 Tweets as negative. Through the topic modeling approach 10 thematic topics were identified from the predicted positive and negative sentiments expressed in the Tweets. JUUL flavors, notably mango, mint, and cucumber, provoke overwhelmingly positive sentiments indicating a strong likeness due to favorable taste and odor. Negative discourse about JUUL flavors revolve around addictiveness, high nicotine content, and youth targeted marketing. Limiting the content related to flavors and positive perceptions on social media is necessary to minimize exposure to youth. The novel methodology used in this study may be adopted to monitor e-cigarette discourse periodically, as well as other critical public health phenomena online.


Riots in Beirut: Description of the Impact of a New Type of Mass Casualty Event on the Emergency System in Lebanon.
In the summer of 2015, Beirut experienced a garbage crisis that led to rioting. Riot control measures resulted in multiple casualties. This study examines injury patterns of riot victims presenting to the emergency department of a tertiary care center in a developing country. A retrospective study was conducted in the emergency department of the American University of Beirut Medical Center between August 22 and August 30, 2015. Patients seen in the emergency department with riot injuries were included. Patient characteristics, injuries, and resources utilized in the emergency department were analyzed. Ninety-five patients were identified. Most patients presented to the emergency department within a short time period. The mean age of the patients was 28.0 ± 8.7 years. Most (90.5%) of the patients were males and 92.6% were protestors. Emergency medical services were utilized by 41.0% of patients. Laceration was the most common presenting complaint (28.5%), and blunt trauma was the most common type of injury (50.5%). The head/face/neck was the most common injured body region (55.8%). Most patients did not require blood tests or procedures (91.6% and 61.0%, respectively), and 91.2% of patients were treated in the emergency department and discharged. One patient required intensive care unit admission and another was dead on arrival. Most patients had mild injuries on presentation. The emergency department experienced a high influx of patients. Complications and deaths can occur from seemingly nonlethal weapons used during riots and warrant effective prehospital and hospital disaster planning.


Degradation of beta-amyloid by proteolytic antibody light chains.
Deposition of beta-amyloid (Abeta) is considered an important early event in the pathogenesis of Alzheimer's disease (AD). Clearance of Abeta thus represents a potential therapeutic approach. Antibody-mediated clearance of Abeta by vaccination inhibited and cleared Abeta deposition in animal models; however, inflammatory side effects were observed in humans. An alternative potentially noninflammatory approach to facilitate clearance is to proteolytically cleave Abeta. We screened 12 proteolytic recombinant antibody fragments for potential alpha-secretase activity, a naturally occurring enzyme that cleaves between the Lys16 and Leu17 residues of the amyloid precursor protein (APP). We utilized the synthetic alpha-secretase substrate, benzyloxycarbonyl-l-lysine o-nitrophenyl ester (Z-lys-o-Np) as a preliminary screen for alpha-secretase activity. Two antibody light chain fragments that hydrolyzed Z-lys-o-Np were identified. Abeta hydrolysis was studied using mass spectrometry to identify the cleavage patterns of the antibodies. The recombinant antibody light chain antibody fragment, c23.5, showed alpha-secretase-like activity, producing the 1-16 and 17-40 amino acid fragments of Abeta. The second light chain antibody fragment, hk14, demonstrated carboxypeptidase-like activity, cleaving sequentially from the carboxyl terminal of Abeta. These antibody light chains provide a novel route toward engineering efficient therapeutic antibodies capable of cleaving Abeta in vivo.


Effects of ketamine on sensory perception: evidence for a role of N-methyl-D-aspartate receptors.
The chiral forms of ketamine were applied as probes for N-methyl-D-aspartate receptor-mediated neurotransmission in humans. Both enantiomers, in clinically relevant concentrations, displaced [3H]dizocilpine (MK 801) from specific binding sites (phencyclidine sites) in membrane fractions of brain homogenates. (S)-Ketamine was at least 4 times as potent as (R)-ketamine in this respect. In healthy volunteers, the most obvious effect of subanesthetic doses of both enantiomers was altered sensory perception. (S)-Ketamine was 4 times as potent as (R)-ketamine in reducing pain perception and in causing auditory and visual disturbances. Both enantiomers caused proprioceptive disturbances (feelings of detachment from the body) and slightly reduced the ability to recall objects seen after administration of the drugs. The ability to recall objects seen immediately before drug exposure was unaffected. The results are in accordance with the hypothesis that inhibition of sensory perception by ketamine in subanesthetic concentrations is due to N-methyl-D-aspartate receptor blockade. It is suggested that N-methyl-D-aspartate receptor-mediated transmission is involved in the processing of sensory information in the human brain.


Unravelling spatiotemporal tree-ring signals in Mediterranean oaks: a variance-covariance modelling approach of carbon and oxygen isotope ratios.
Identifying how physiological responses are structured across environmental gradients is critical to understanding in what manner ecological factors determine tree performance. Here, we investigated the spatiotemporal patterns of signal strength of carbon isotope discrimination (Δ(13)C) and oxygen isotope composition (δ(18)O) for three deciduous oaks (Quercus faginea (Lam.), Q. humilis Mill. and Q. petraea (Matt.) Liebl.) and one evergreen oak (Q. ilex L.) co-occurring in Mediterranean forests along an aridity gradient. We hypothesized that contrasting strategies in response to drought would lead to differential climate sensitivities between functional groups. Such differential sensitivities could result in a contrasting imprint on stable isotopes, depending on whether the spatial or temporal organization of tree-ring signals was analysed. To test these hypotheses, we proposed a mixed modelling framework to group isotopic records into potentially homogeneous subsets according to taxonomic or geographical criteria. To this end, carbon and oxygen isotopes were modelled through different variance-covariance structures for the variability among years (at the temporal level) or sites (at the spatial level). Signal-strength parameters were estimated from the outcome of selected models. We found striking differences between deciduous and evergreen oaks in the organization of their temporal and spatial signals. Therefore, the relationships with climate were examined independently for each functional group. While Q. ilex exhibited a large spatial dependence of isotopic signals on the temperature regime, deciduous oaks showed a greater dependence on precipitation, confirming their higher susceptibility to drought. Such contrasting responses to drought among oak types were also observed at the temporal level (interannual variability), with stronger associations with growing-season water availability in deciduous oaks. Thus, our results indicate that Mediterranean deciduous and evergreen oaks constitute two clearly differentiated functional groups in terms of their carbon and water economies, despite co-existing in a wide range of environments. In contrast, deciduous oaks form a rather homogeneous group in terms of climate sensitivity.


Baboon carboxylesterases 1 and 2: sequences, structures and phylogenetic relationships with human and other primate carboxylesterases.
Carboxylesterase (CES) is predominantly responsible for the detoxification of a wide range of drugs and narcotics, and catalyze several reactions in cholesterol and fatty acid metabolism. Studies of the genetic and biochemical properties of primate CES may contribute to an improved understanding of human disease, including atherosclerosis, obesity and drug addiction, for which non-human primates serve as useful animal models. We cloned and sequenced baboon CES1 and CES2 and used in vitro and in silico methods to predict protein secondary and tertiary structures, and examined evolutionary relationships for these enzymes with other primate and mouse CES orthologs. We found that baboon CES1 and CES2 proteins retained extensive similarity with human CES1 and CES2, shared key structural features reported for human CES1, and showed family specific sequences consistent with their multimeric and monomeric subunit structures respectively.


Use of bevacizumab as a single agent or in adjunct with traditional chemotherapy regimens in children with unresectable or progressive low-grade glioma.
In pediatric low-grade gliomas not amenable to complete resection, various chemotherapy regimens are the mainstream of treatment. An excellent overall survival of these patients makes justification of the intensification of chemotherapy difficult and calls for the development of new strategies. Bevacizumab, a humanized monoclonal antibody directed against Vascular endothelial growth factor (VEGF), has been successfully used in combination with irinotecan in a number of adult and pediatric studies and reports. Fifteen patients at median age of 7 years old (range 3 months to 15 years) were treated with bevacizumab in combination with conventional low-toxicity chemotherapy. The majority had chiasmatic/hypothalamic and midline tumors, seven had confirmed BRAF pathway alterations including neurofibromatosis type 1 (2). Fourteen patients had more than one progression and three had radiotherapy. No deaths were documented, PFS at 11 and 15 months was 71.5% ± 13.9% and 44.7% ± 17.6% respectively. At the end of follow-up 40% of patients has radiologically stable disease, three patients progressed shortly after completion of bevacizumab and two showed mixed response with progression of cystic component. Rapid visual improvement was seen in 6/8 patients, resolution of endocrine symptoms in 2/4 and motor function improvement in 4/6. No relation between histology or BRAF status and treatment response was observed. Treatment-limiting toxicities included grade 4 proteinuria (2) and hypertension (2) managed with cessation (1) and pausing of therapy plus antihypertensives (1). In conclusion, bevacizumab is well tolerated and appears most effective for rapid tumor control to preserve vision and improve morbidity.


Dephosphorylation activates the purified plant plasma membrane H+-ATPase--possible function of phosphothreonine residues in a mechanism not involving the regulatory C-terminal domain of the enzyme.
The plasma membrane H+-ATPase was purified from tobacco cells (line BY-2). After solubilization by lysophosphatidylcholine followed by separation on a glycerol gradient, a fraction with a high specific activity of 9 micromol ATP x min(-1) x mg protein(-1) was obtained, in which the H+-ATPase polypeptide represented at least 80% of the protein. The incubation of this fraction in the presence of alkaline phosphatase increased H+-ATPase activity by 40%, in a manner consistent with dephosphorylation of the enzyme itself. The hydrolytic activity of the solubilized enzyme and its proton translocating activity, after reconstitution into proteoliposomes, were stimulated to the same extent. Alkaline phosphatase treatment was also accompanied by a 92% decrease in the H+-ATPase phosphothreonine content, whereas the phosphoserine residues were almost unaffected. The dephosphorylation induced a slight decrease of the affinity of the enzyme towards ATP. The purified enzyme was not activated by lysophosphatidylcholine addition nor by trypsin-mediated proteolysis, two treatments reported to release the inhibitory control by the C-terminal domain of the H+-ATPase and to increase the affinity of the enzyme towards ATP. Based on these results, the regulatory phosphorylation evoked by alkaline phosphatase most likely differs from the autoinhibitory control of the H+-ATPase by its C-terminal domain.


Direct Atom Imaging by Chemical-Sensitive Holography.
In order to understand the physical and chemical properties of advanced materials, functional molecular adsorbates, and protein structures, a detailed knowledge of the atomic arrangement is essential. Up to now, if subsurface structures are under investigation, only indirect methods revealed reliable results of the atoms' spatial arrangement. An alternative and direct method is three-dimensional imaging by means of holography. Holography was in fact proposed for electron waves, because of the electrons' short wavelength at easily accessible energies. Further, electron waves are ideal structure probes on an atomic length scale, because electrons have a high scattering probability even for light elements. However, holographic reconstructions of electron diffraction patterns have in the past contained severe image artifacts and were limited to at most a few tens of atoms. Here, we present a general reconstruction algorithm that leads to high-quality atomic images showing thousands of atoms. Additionally, we show that different elements can be identified by electron holography for the example of FeS2.


Effects of the sea lice chemotherapeutant, emamectin benzoate, on metabolism and behaviour of the sea-pen Pennatula phosphorea.
Chemotherapeutants used to control infestations by sea lice can be released into the marine environment surrounding aquaculture farms. Among these therapeutic agents, emamectin benzoate is extensively utilized even though its impact on non-target taxa has not been thoroughly examined. In this context, we explored the effects of emamectin benzoate on a common Norwegian habitat-forming species: the phosphorescent sea-pen Pennatula phosphorea. Specifically, we examined P. phosphorea metabolic and responses before, during and after exposure to emamectin benzoate. Results indicate that an 8-day emamectin benzoate exposure (0.8 mg/L) did not induce P. phosphorea mortality or significant behavioural or metabolic modifications. However, we highlighted the presence and persistence of emamectin benzoate in exposed P. phosphorea tissue. These results indicate that emamectin benzoate is unlikely to adversely impact P. phosphorea populations in the environment. However, persistence of emamectin benzoate in tissue constitutes a potential for bioaccumulation with repeated treatments and should be examined in further studies.


Analysis of spontaneous adverse drug reaction (ADR) reports using supplementary information.
Assessment of safety of newly marketed drugs is an important public health issue. Once the drug is in the market, clinicians and/or health professionals are responsible for recognizing and reporting suspected side effects known as adverse drug reaction (ADR). Such reports are collected in a so-called spontaneous reporting (SR) system. The primary purpose of spontaneous ADR reporting is to provide early warnings or suspicions, which have not been recognized prior to marketing of a drug because of limitations of clinical trials. We shall discuss the existing work to analyze the SR database and their drawbacks and also suggest methodologies to tackle these drawbacks by defining a source population and considering the problem of under-reporting, with the help of supplementary data. Unbiased estimate of population odds-ratio has been obtained and the corresponding asymptotic results are derived.


E-7869 (R-flurbiprofen) inhibits progression of prostate cancer in the TRAMP mouse.
E-7869 (R-flurbiprofen) is a single enantiomer of a racemic nonsteroidal anti-inflammatory drug. E-7869 does not inhibit either cyclooxygenase-1 or cyclooxygenase-2. We used the transgenic adenocarcinoma mouse prostate (TRAMP) mouse, a prostate cancer model, to evaluate the effect of this drug on prostate cancer progression. Sixty 12-week-old male TRAMP mice were placed randomly into five groups. The animals were treated by daily oral gavage with vehicle (1% carboxymethylcellulose) or E-7869 for 18-weeks. During the course of the study, two diets were used. Three groups (vehicle, 15-mg/kg, and 20-mg/kg drug treatments) received a Teklad diet containing 2.4% saturated fat [a high saturated fat (HSF) diet], and two groups (vehicle and 20 mg/kg drug treatment) received an AIN-93G diet containing 1.05% saturated fat [a low saturated fat (LSF) diet]. At necropsy, the urogenital system and periaortic lymph nodes were removed and weighed. The prostate lobes, seminal vesicles, lungs, and periaortic lymph nodes were preserved and sectioned for histological evaluation. The lung and periaortic lymph nodes were graded as to the presence (+) or absence (-) of metastasis; the urogenital tissues were graded on a 1-6 scale for degree of neoplasia/carcinoma. For both diets, the urogenital wet weights and lymph node wet weights in the 20-mg/kg treatment groups were significantly lower as compared to vehicle control groups. In addition, treatment with 20 mg/kg E-7869 in the LSF diet group resulted in a significantly lower primary tumor incidence (P < 0.05) and reduced incidence of metastasis. In this treatment group, the reduced incidence of metastasis was not statistically significant because the LSF diet itself resulted in a remarkably lower incidence of metastasis in the vehicle control group (10% LSF versus 40% HSF). Treatment with 20 mg/kg E-7869 on the HSF diet resulted in a significantly lower incidence of metastasis (P < 0.05) and a reduction in the primary tumor incidence. These results suggest that E-7869 is a promising chemopreventive and treatment for human prostate cancer.


"Insignificant" mechanism of injury: not to be taken lightly.
Trauma resources should be spent rationally. The mechanism of trauma is used extensively to triage patients to appropriate levels of care. We examine the hypothesis that patients with "insignificant" mechanism of trauma may have major injuries that require expert trauma care. Over 9 months at a high-volume Level I trauma center, a prospective study was done on patients who sustained ground-level falls (GLF), low-level falls (LLF) from less than 10 feet, or were found down (FD) with no external evidence of significant trauma, and required evaluation by the trauma team. Of 301 patients included, 110 (37%) had GLF, 95 (31%) LLF, and 96 (32%) FD. Our main outcomes measure was significant injuries, defined as visceral or intracranial injuries, long-bone, pelvic, facial, or spinal fractures. One hundred ten patients (37%) had significant injuries, 20 (7%) were admitted to the ICU, 14 (5%) required an operation, and 4 (1%) died. The most common injuries were intracranial and skeletal. Almost all patients were evaluated by CT (95%), but only one-quarter had abnormal findings on it. LLF, age more than 55 years, and the absence of severe intoxication (blood alcohol level of less than 200 mg/dL) were independent risk factors for significant injuries. A statistical prediction model showed that, when all risk factors are present, the probability of significant injuries is 73%; when all risk factors are absent, there is still a 16% chance for significant injuries. Patients with significant injuries had more operations, longer hospital stays, and higher hospitalization costs compared with patients without significant injuries. Low-energy trauma may produce significant injuries, predominantly intracranial and skeletal. Trauma care providers should be cautious about dismissing such patients based on the trivial mechanism of injury. Patients with LLF who are older than 55 years and not severely intoxicated have a high likelihood for significant injuries. Resources should be spent rationally for patients who do not have these characteristics, because the probability of significant injuries among them is low, but not zero.


Activation of cerebral Ras-related C3 botulinum toxin substrate (Rac) 1 promotes post-ischemic stroke functional recovery in aged mice.
Brain functional impairment after stroke is common; however, the molecular mechanisms of post-stroke recovery remain unclear. It is well-recognized that age is the most important independent predictor of poor outcomes after stroke as older patients show poorer functional outcomes following stroke. Mounting evidence suggests that axonal regeneration and angiogenesis, the major forms of brain plasticity responsible for post-stroke recovery, diminished with advanced age. Previous studies suggest that Ras-related C3 botulinum toxin substrate (Rac) 1 enhances stroke recovery as activation of Rac1 improved behavior recovery in a young mice stroke model. Here, we investigated the role of Rac1 signaling in long-term functional recovery and brain plasticity in an aged (male, 18 to 22 months old C57BL/6J) brain after ischemic stroke. We found that as mice aged, Rac1 expression declined in the brain. Delayed overexpression of Rac1, using lentivirus encoding Rac1 injected day 1 after ischemic stroke, promoted cognitive (assessed using novel object recognition test) and sensorimotor (assessed using adhesive removal tests) recovery on days 14-28. This was accompanied by the increase of neurite and proliferative endothelial cells in the peri-infarct zone assessed by immunostaining. In a reverse approach, pharmacological inhibition of Rac1 by intraperitoneal injection of Rac1 inhibitor NSC23766 for 14 successive days after ischemic stroke worsened the outcome with the reduction of neurite and proliferative endothelial cells. Furthermore, Rac1 inhibition reduced the activation of p21-activated kinase 1, the protein level of brain-derived neurotrophic factor, and increased the protein level of glial fibrillary acidic protein in the ischemic brain on day 28 after stroke. Our work provided insight into the mechanisms behind the diminished plasticity after cerebral ischemia in aged brains and identified Rac1 as a potential therapeutic target for improving functional recovery in the older adults after stroke.


The trend of the distribution of ectopic pregnancy sites and the clinical characteristics of caesarean scar pregnancy.
Ectopic pregnancy is a life-threatening occurrence and is an important cause of pregnancy-related mortality. We launched the study to investigate the distribution and its variation trend of the ectopic pregnancy sites and the clinical characteristics of caesarean scar pregnancy, to provide information for further clinical practice. A total of 3915 patients were included in our study to calculate the distribution of the implantation sites of ectopic pregnancies. Then, we performed a χ2 test for trend and calculated the quantity of each type of ectopic pregnancy during 2012-2015 and 2016-2019 to analyse the variation trend. (1) The proportion of each site of ectopic pregnancy was as follows: tubal pregnancy (84.70%), ovarian pregnancy (1.56%), caesarean scar pregnancy (8.63%), abdominal pregnancy (0.61%), cornual pregnancy (2.68%), cervical pregnancy (0.49%), heterotopic pregnancy (0.43%). (2) Through the χ2 test for trend, the ratio of caesarean scar pregnancy to ectopic pregnancy showed an upward trend (P = 0.005). From 2012 to 2015 and 2016-2019, the ratio of caesarean scar pregnancy to ectopic pregnancy increased from 5.74 to 11.81% (P < 0.001). (3) A total of 72.78% (246/338) caesarean scar pregnancy patients had one caesarean delivery, 25.15% (85/338) had two caesarean deliveries, and 2.07% (7/338) had three caesarean deliveries. A total of 80.18% (271/338) had aborted before. The most common clinical manifestations were amenorrhea (98.52%), abdominal pain (25.74%) and vaginal bleeding (67.76%), the most common sign was uterine enlargement (46.75%). As the ratio of caesarean scar pregnancy increases, the caesarean delivery rate should be decreased to decrease the morbidity of caesarean scar pregnancy.


Anesthesia issues in the perioperative management of myasthenia gravis.
Myasthenia gravis (MG) is an autoimmune disease of the neuromuscular junction. Current anesthetic practice may require the use of neuromuscular blocking (NMB) drugs that act at this junction to facilitate control of the airway and allow procedures to be performed on a motionless MG patient. This competes with the goals of rapid emergence and recapture of preoperative muscle strength following anesthesia. In particular, avoiding prolonged periods of postoperative mechanical ventilation is a paramount concern of patients, families, and physicians. Standard anesthetic agents and, if needed, judiciously titrated NMB drugs generally allow safe emergence and immediate extubation for most low-risk MG patients. If necessary, postoperative mechanical ventilation is accomplished with the use of specialized monitoring devices that help monitor awareness and depth of sedation. Currently used intravenous sedatives allow titrated depth of sedation and rapid emergence when extubation is appropriate. Communication to the patient, family, and other caregivers of the goals of the anesthetic plan and of the patient's evolving status are also very important duties of the anesthesiologist.


Results of Tibia and Fibula Osteotomies Performed Concomitant to Total Ankle Replacement.
Neutral ankle alignment along with medial and lateral support are paramount to the success of total ankle replacement (TAR). Fibula, intra-articular medial malleolus, and supramalleolar tibia osteotomies have been described to achieve these goals; however, the literature is scant with outcomes and union rates of these osteotomies performed concomitant to TAR. The purpose of this study was to describe our results. A retrospective review was performed to identify patients who had a concomitant tibia, fibula, or combined tibia and fibula osteotomy at the same time as TAR. Routine radiographs were used to assess osteotomy union rates and changes in alignment. Outcomes questionnaires were evaluated preoperatively and at most recent follow-up. Twenty-six patients comprising 4% of the total TAR cohort were identified with a mean follow-up of 3.9 years. There were 12 combined tibia and fibula osteotomies, 9 isolated tibia osteotomies, and 5 isolated fibula osteotomies. The union rate for these osteotomies was 92%, 100%, and 100%, respectively. Mean coronal alignment improved from 15.2 to 2.1 degrees (P < .001). There was significant improvement in patient-reported outcome scores, including Short Form-36, Short Musculoskeletal Function Assessment, and visual analog scale pain. There was 1 failure in the study. These data demonstrate successful use of tibia, fibula, or combined tibia and fibula osteotomies at the same time as TAR in order to gain neutral ankle alignment. The overall union rate was 96% with significant improvement in alignment, pain, and patient-reported outcomes. We believe concomitant osteotomies can be considered a successful adjunctive procedure to TAR. Level III, retrospective comparative series.


Unusual histological findings after partial pancreaticoduodenectomy including benign multicystic mesothelioma, adenomyoma of the ampulla of Vater, and undifferentiated carcinoma, sarcomatoid variant: a case series.
The standard operation for carcinoma of the pancreatic head is a partial pancreaticoduodenectomy. Unusual histological findings may occasionally occur in the surgical specimen. We present three unusual histologic diagnoses after pancreaticoduodenectomy. In the first case, an 86-year-old Caucasian woman was admitted with abdominal pain and nausea. Preoperative evaluation showed a 3 cm cystic lesion in the head of the pancreas. Pathology revealed a benign multicystic mesothelioma. In the second case, a 45-year-old Caucasian man complained of nausea, vomiting and general malaise for several months. Endoscopic retrograde cholangiopancreatographic examination and a computed tomography scan showed a stenosis of the distal bile duct secondary to a mass in the head of the pancreas and duodenum. Histology showed an adenomyoma of the ampulla. In the third case, a 59-year-old Caucasian man presented with chronic alcoholic pancreatitis. A computed tomography scan revealed a 3.5 cm lesion in the head of the pancreas with cystic and solid components. Pathology showed an undifferentiated carcinoma, sarcomatoid variant. Partial pancreaticoduodenectomy is usually performed for ductal adenocarcinomas, neuroendocrine tumors or chronic pancreatitis. Compared to the majority of the above diagnoses, the three cases in our study are very rare. Benign multicystic mesothelioma is a very rare tumor that originates from the peritoneum. Although it demonstrates a benign clinical behaviour, it frequently recurs after resection. Adenomyoma of the bile duct or ampullary region is a very unusual, benign, localized lesion characterized by adenomyomatous hyperplasia. Undifferentiated carcinoma, sarcomatoid variant, is an aggressive tumor and is characterized by spindle cells. As the lesions were suspicious for carcinoma, partial pancreaticoduodenectomy was justified in all three patients. The histologic diagnosis after partial pancreaticoduodenectomy may differ from the preoperative and intraoperative findings. These cases demonstrate that a definitive diagnosis may only be obtained by a pathologic examination of the surgical specimen.


Incorporating networks in a probabilistic graphical model to find drivers for complex human diseases.
Discovering genetic mechanisms driving complex diseases is a hard problem. Existing methods often lack power to identify the set of responsible genes. Protein-protein interaction networks have been shown to boost power when detecting gene-disease associations. We introduce a Bayesian framework, Conflux, to find disease associated genes from exome sequencing data using networks as a prior. There are two main advantages to using networks within a probabilistic graphical model. First, networks are noisy and incomplete, a substantial impediment to gene discovery. Incorporating networks into the structure of a probabilistic models for gene inference has less impact on the solution than relying on the noisy network structure directly. Second, using a Bayesian framework we can keep track of the uncertainty of each gene being associated with the phenotype rather than returning a fixed list of genes. We first show that using networks clearly improves gene detection compared to individual gene testing. We then show consistently improved performance of Conflux compared to the state-of-the-art diffusion network-based method Hotnet2 and a variety of other network and variant aggregation methods, using randomly generated and literature-reported gene sets. We test Hotnet2 and Conflux on several network configurations to reveal biases and patterns of false positives and false negatives in each case. Our experiments show that our novel Bayesian framework Conflux incorporates many of the advantages of the current state-of-the-art methods, while offering more flexibility and improved power in many gene-disease association scenarios.


Diagnosis of nutrient imbalances with vector analysis in agroforestry systems.
Agricultural intensification has had unintended environmental consequences, including increased nutrient leaching and surface runoff and other agrarian-derived pollutants. Improved diagnosis of on-farm nutrient dynamics will have the advantage of increasing yields and will diminish financial and environmental costs. To achieve this, a management support system that allows for site-specific rapid evaluation of nutrient production imbalances and subsequent management prescriptions is needed for agroecological design. Vector diagnosis, a bivariate model to depict changes in yield and nutritional response simultaneously in a single graph, facilitates identification of nutritional status such as growth dilution, deficiency, sufficiency, luxury uptake, and toxicity. Quantitative data from cocoa agroforestry systems and pigeonpea intercropping trials in Ghana and Tanzania, respectively, were re-evaluated with vector analysis. Relative to monoculture, biomass increase in cocoa ( L.) under shade (35-80%) was accompanied by a 17 to 25% decline in P concentration, the most limiting nutrient on this site. Similarly, increasing biomass with declining P concentrations was noted for pigeonpea [ (L). Millsp.] in response to soil moisture availability under intercropping. Although vector analysis depicted nutrient responses, the current vector model does not consider non-nutrient resource effects on growth, such as ameliorated light and soil moisture, which were particularly active in these systems. We revisit and develop vector analysis into a framework for diagnosing nutrient and non-nutrient interactions in agroforestry systems. Such a diagnostic technique advances management decision-making by increasing nutrient precision and reducing environmental issues associated with agrarian-derived soil contamination.


Recovery of duckweed from time-varying exposure to atrazine.
The purpose of the present study was to evaluate the recovery of duckweed (Lemna gibba L. G3) after being removed from multiple duration exposures to the herbicide atrazine. Consequently, L. gibba were exposed under various scenarios to atrazine at nominal concentrations ranging from 5 to 160 µg/L and durations of 1, 3, 5, 7, 9, and 14 d under static-renewal test conditions. Exposures were followed by a recovery phase in untreated media for either 7 or 14 d. The 3-, 5-, 7-, 9-, and 14-d median effective concentration (EC50) values were >137, >137, 124, >77, and >75 µg/L, respectively, based on mean growth rate. No clear effect trends were apparent between exposure duration and the magnitude of effective concentrations (EC50s or EC10s). No phytocidal effects of chlorosis or necrosis were identified for any treatment scenario. Nearly all L. gibba plants transferred from treatment groups of different exposure scenarios to media without atrazine during the recovery phase had growth rates that demonstrated immediate recovery, indicating effects were phytostatic in nature and reversible. Only the 1- and 5-d exposure scenarios had growth rates indicating marginally prolonged recovery at the higher concentrations (160 µg/L; additionally, at 40 µg/L for the 5-d exposure). Time to recovery, therefore, was found to be largely independent of exposure duration except at the highest concentrations assessed. Based on growth rate by interval, all treatments demonstrated recovery by the final assessment interval (days 5-7), indicating complete recovery in all exposure scenarios by 7 d, consistent with the mode of action of atrazine.


Bent and planar structures of μ-η²:η²-N₂ dinuclear early transition metal complexes.
This work studied the bent and planar structures of M2N2 cores of a series of dinuclear early transition-metal complexes (M = Zr, Hf, Nb, Ta, Mo and W) containing a side-on bridging dinitrogen ligand using DFT method. The calculated results propose three key factors favoring a bent structure: (1) the availability of a single electron in the metal centers which leads to the bonding interaction between two metal atoms, (2) no remarkable steric effect around the metal centers, and (3) the cis conformation of the ligands in the dinitrogen dinuclear complexes. In addition, the bent and planar structures of M2N2 could be transformed into each other if the steric hindrance was slight.


Button battery injury causing an aorto-oesophageal fistula in a 1-year-old child - Sengstaken-Blakemore tube, a life-saving bridge during surgery.
AEF: aorto-oesophageal fistula;BB: button battery;CTA: computed tomography angiography;ER: emergency room;GI: gastro-intestinal;SBT: Sengstaken-Blakemore tube.


[Intravenous magnesium administration in bronchial asthma].
The effect of intravenously infused Mg-aspartate hydrochloride (MgAHCl) was studied in 17 asthmatic inpatients. In 6 patients with initial forced vital capacity (FVC) greater than 90% of normal value, there were no significant changes in the lung volumina after 10 mmol of MgAHCl. In 11 patients with initial FVC less than or equal to 90%, the median FVC increased after MgAHCl by 56 to 61% (p less than 0.01), the forced expiratory volume at 1 sec. (FEV1) by 40 to 44% (p less than 0.02) and the peak expiratory flow (PEF) by 45 to 56% (p less than 0.02). No significant changes of respiratory resistance were observed. The average serum concentration of Mg increased by 0.89 to 1.72 mmol/L and decreased to 1.33 mmol/L 20 minutes after the Mg-infusion. Intravenous infusion of Mg produces a significant improvement of FVC, FEV1 and PEF. With its cardioprotective effect and the reduction of bronchial hyperreactivity, Mg could be a valuable method in the treatment of asthmatic patients.


Synthetic affibody molecules: a novel class of affinity ligands for molecular imaging of HER2-expressing malignant tumors.
The Affibody molecule Z(HER2:342-pep2), site-specifically and homogeneously conjugated with a 1,4,7,10-tetra-azacylododecane-N,N',N'',N'''-tetraacetic acid (DOTA) chelator, was produced in a single chemical process by peptide synthesis. DOTA-Z(HER2:342-pep2) folds spontaneously and binds HER2 with 65 pmol/L affinity. Efficient radiolabeling with >95% incorporation of (111)In was achieved within 30 min at low (room temperature) and high temperatures (up to 90 degrees C). Tumor uptake of (111)In-DOTA-Z(HER2:342-pep2) was specific for HER2-positive xenografts. A high tumor uptake of 23% injected activity per gram tissue, a tumor-to-blood ratio of >7.5, and high-contrast gamma camera images were obtained already 1 h after injection. Pretreatment with Herceptin did not interfere with tumor targeting, whereas degradation of HER2 using the heat shock protein 90 inhibitor 17-allylamino-geldanamycin before administration of (111)In-DOTA-Z(HER2:342-pep2) obliterated the tumor image. The present results show that radiolabeled synthetic DOTA-Z(HER2:342-pep2) has the potential to become a clinically useful radiopharmaceutical for in vivo molecular imaging of HER2-expressing carcinomas.


Immunosuppressive Myeloid Cells' Blockade in the Glioma Microenvironment Enhances the Efficacy of Immune-Stimulatory Gene Therapy.
Survival of glioma (GBM) patients treated with the current standard of care remains dismal. Immunotherapeutic approaches that harness the cytotoxic and memory potential of the host immune system have shown great benefit in other cancers. GBMs have developed multiple strategies, including the accumulation of myeloid-derived suppressor cells (MDSCs) to induce immunosuppression. It is therefore imperative to develop multipronged approaches when aiming to generate a robust anti-tumor immune response. Herein, we tested whether combining MDSC depletion or checkpoint blockade would augment the efficacy of immune-stimulatory herpes simplex type-I thymidine kinase (TK) plus Fms-like tyrosine kinase ligand (Flt3L)-mediated immune stimulatory gene therapy. Our results show that MDSCs constitute >40% of the tumor-infiltrating immune cells. These cells express IL-4Rα, inducible nitric oxide synthase (iNOS), arginase, programmed death ligand 1 (PDL1), and CD80, molecules that are critically involved in antigen-specific T cell suppression. Depletion of MDSCs strongly enhanced the TK/Flt3L gene therapy-induced tumor-specific CD8 T cell response, which lead to increased median survival and percentage of long-term survivors. Also, combining PDL1 or CTLA-4 immune checkpoint blockade greatly improved the efficacy of TK/Flt3L gene therapy. Our results, therefore, indicate that blocking MDSC-mediated immunosuppression holds great promise for increasing the efficacy of gene therapy-mediated immunotherapies for GBM.


Closed-Loop Insulin Delivery for Glycemic Control in Noncritical Care.
In patients with diabetes, hospitalization can complicate the achievement of recommended glycemic targets. There is increasing evidence that a closed-loop delivery system (artificial pancreas) can improve glucose control in patients with type 1 diabetes. We wanted to investigate whether a closed-loop system could also improve glycemic control in patients with type 2 diabetes who were receiving noncritical care. In this randomized, open-label trial conducted on general wards in two tertiary hospitals located in the United Kingdom and Switzerland, we assigned 136 adults with type 2 diabetes who required subcutaneous insulin therapy to receive either closed-loop insulin delivery (70 patients) or conventional subcutaneous insulin therapy, according to local clinical practice (66 patients). The primary end point was the percentage of time that the sensor glucose measurement was within the target range of 100 to 180 mg per deciliter (5.6 to 10.0 mmol per liter) for up to 15 days or until hospital discharge. The mean (±SD) percentage of time that the sensor glucose measurement was in the target range was 65.8±16.8% in the closed-loop group and 41.5±16.9% in the control group, a difference of 24.3±2.9 percentage points (95% confidence interval [CI], 18.6 to 30.0; P<0.001); values above the target range were found in 23.6±16.6% and 49.5±22.8% of the patients, respectively, a difference of 25.9±3.4 percentage points (95% CI, 19.2 to 32.7; P<0.001). The mean glucose level was 154 mg per deciliter (8.5 mmol per liter) in the closed-loop group and 188 mg per deciliter (10.4 mmol per liter) in the control group (P<0.001). There was no significant between-group difference in the duration of hypoglycemia (as defined by a sensor glucose measurement of <54 mg per deciliter; P=0.80) or in the amount of insulin that was delivered (median dose, 44.4 U and 40.2 U, respectively; P=0.50). No episode of severe hypoglycemia or clinically significant hyperglycemia with ketonemia occurred in either trial group. Among inpatients with type 2 diabetes receiving noncritical care, the use of an automated, closed-loop insulin-delivery system resulted in significantly better glycemic control than conventional subcutaneous insulin therapy, without a higher risk of hypoglycemia. (Funded by Diabetes UK and others; ClinicalTrials.gov number, NCT01774565 .).


Brain Perfusion Bridges Virtual-Reality Spatial Behavior to TPH2 Genotype for Head Acceleration Events.
Neuroimaging demonstrates that athletes of collision sports can suffer significant changes to their brain in the absence of concussion, attributable to head acceleration event (HAE) exposure. In a sample of 24 male Division I collegiate football players, we examine the relationships between tryptophan hydroxylase 2 (TPH2), a gene involved in neurovascular function, regional cerebral blood flow (rCBF) measured by arterial spin labeling, and virtual reality (VR) motor performance, both pre-season and across a single football season. For the pre-season, TPH2 T-carriers showed lower rCBF in two left hemisphere foci (fusiform gyrus/thalamus/hippocampus and cerebellum) in association with higher (better performance) VR Reaction Time, a dynamic measure of sensory-motor reactivity and efficiency of visual-spatial processing. For TPH2 CC homozygotes, higher pre-season rCBF in these foci was associated with better performance on VR Reaction Time. A similar relationship was observed across the season, where TPH2 T-carriers showed improved VR Reaction Time associated with decreases in rCBF in the right hippocampus/amygdala, left middle temporal lobe, and left insula/putamen/pallidum. In contrast, TPH2 CC homozygotes showed improved VR Reaction Time associated with increases in rCBF in the same three clusters. These findings show that TPH2 T-carriers have an abnormal relationship between rCBF and the efficiency of visual-spatial processing that is exacerbated after a season of high-impact sports in the absence of diagnosable concussion. Such gene-environment interactions associated with behavioral changes after exposure to repetitive HAEs have been unrecognized with current clinical analytical tools and warrant further investigation. Our results demonstrate the importance of considering neurovascular factors along with traumatic axonal injury to study long-term effects of repetitive HAEs.


Chinese Expert Consensus on Perioperative Medication in Laser Corneal Refractive Surgeries (2019).
Laser corneal refractive surgery has become an important treatment to correct ametropia in recent years. Rational medication in the perioperative period is essential to ensure the success of the surgery and to reduce complications. However, in this area there has been no consistent understanding and unified application guide across the world. Experts in Refractive Surgery Group, Ocular Microcirculation Branch of Chinese Society of Microcirculation who are specialized in keratology and optometry had initiated extensive and rigorous discussions and reached a consensus on appropriate medication before, during and after the refractive surgeries. The consensus covers a broad spectrum of commonly used ophthalmic solutions, provides recommendations of routine and enhanced medication on prevention and management of adverse reactions and complications related to the laser corneal refractive surgeries. We hope the consensus serves as a standard perioperative medication regimen for ophthalmologists, helps to ensure the safety and effectiveness of laser corneal refractive surgeries, and improves the quality and outcome of the refractive surgeries.


Plants, viruses and the environment: Ecology and mutualism.
Since the discovery of Tobacco mosaic virus nearly 120 years ago, most studies on viruses have focused on their roles as pathogens. Virus ecology takes a different look at viruses, from the standpoint of how they affect their hosts׳ interactions with the environment. Using the framework of symbiotic relationships helps put the true nature of viruses into perspective. Plants clearly have a long history of relationships with viruses that have shaped their evolution. In wild plants viruses are common but usually asymptomatic. In experimental studies plant viruses are sometimes mutualists rather than pathogens. Virus ecology is closely tied to the ecology of their vectors, and the behavior of insects, critical for transmission of many plant viruses, is impacted by virus-plant interactions. Virulence is probable not beneficial for most host-virus interactions, hence commensal and mutualistic relationships are almost certainly common, in spite of the paucity of literature on beneficial viruses.


Sgt1p and Skp1p modulate the assembly and turnover of CBF3 complexes required for proper kinetochore function.
Kinetochores are composed of a large number of protein complexes that must be properly assembled on DNA to attach chromosomes to the mitotic spindle and to coordinate their segregation with the advance of the cell cycle. CBF3 is an inner kinetochore complex in the budding yeast Saccharomyces cerevisiae that nucleates the recruitment of all other kinetochore proteins to centromeric DNA. Skp1p and Sgt1p act through the core CBF3 subunit, Ctf13p, and are required for CBF3 to associate with centromeric DNA. To investigate the contribution of Skp1p and Sgt1p to CBF3 function, we have used a combination of in vitro binding assays and a unique protocol for synchronizing the assembly of kinetochores in cells. We have found that the interaction between Skp1p and Sgt1p is critical for the assembly of CBF3 complexes. CBF3 assembly is not restricted during the cell cycle and occurs in discrete steps; Skp1p and Sgt1p contribute to a final, rate-limiting step in assembly, the binding of the core CBF3 subunit Ctf13p to Ndc10p. The assembly of CBF3 is opposed by its turnover and disruption of this balance compromises kinetochore function without affecting kinetochore formation on centromeric DNA.


[Cultivation of the clothes lice adapted to feeding on rabbits].
A race of clothes lice adapted to feeding on rabbits is kept at a laboratory longer than 50 years. For this period, more than 850 insect generations undergoing no change in a number of biological tests and morphological indices have been obtained. They have retained a high susceptibility to Provacheck rickettsia infection. All infected lice die, partially with the signs of hemolytic imbibition. Their rickettsial accumulation is as high as 10(5.0) ID50 per insect for albino rats.


Brevifoliol and its Analogs: A New Class of Anti-tubercular Agents.
Brevifoliol is an abeo-taxane isolated from the Taxus wallichiana needles; eighteen semisynthetic esters derivatives of brevifoliol were prepared by Steglich esterification and screened for their anti-tubercular potential against Mycobacterium tuberculosis H37Ra avirulent strain. The 3- [chloro (7)] and 3, 5-[dinitro (8)] benzoic acid ester derivatives were most active (MIC 25 ug/ml) against the pathogen. Further, in silico docking studies of the active derivative 7 with mycobacterium enzyme inhA (enoyl-ACP reductase) gave the LibDock score of 152.68 and binding energy of -208.62 and formed three hydrogen bonds with SER94, MET98, and SER94. Similarly, when derivative 8 docked with inhA, it gave the LibDock score of 113.55 and binding energy of -175.46 and formed a single hydrogen bond with GLN100 and Pi-interaction with PHE97. On the other hand, the known standard drug isoniazid (INH) gave the LibDock score of 61.63, binding energy of -81.25 and formed one hydrogen bond with ASP148. These molecular docking results and the way of binding pattern indicated that compounds 7 and 8 bound well within the binding pocket of inhA and showed a higher binding affinity than the known drug isoniazid. Additionally, both the derivatives (7 and 8) showed no cytotoxicity, with CC50 195.10 and 111.36, respectively towards the mouse bone marrow-derived macrophages.


Impact of a Multimodal Approach in Prevention of Surgical Site Infection in Hepatic Transplant Recipients.
In liver transplant (LT) recipients, surgical site infection (SSI) represents an important cause of morbidity and mortality. This study measures the impact of a multimodal approach to the incidence of surgical site infection in LT recipients. All of the LT recipients in our department were registered on the national database in solid organ transplant. A study was performed in two analytical-interventional phases. Phase 1 took place between July 14, 2009, and February 20, 2014. Phase 2 took place between February 21, 2014, and July 15, 2015. The multimodal change implemented during phase 1 was that 0.5% alcoholic chlorhexidine and ether were applied to the surgical field; surgical prophylaxis was primarily with ampicillin/sulbactam plus cefazolin. In phase 2, 2% alcoholic chlorhexidine alone was applied to the surgical field. The prior standard prophylaxis was changed to piperacillin tazobactam administered during surgery as a continuous infusion of 13.5 g over 8 hours with a pre-incision loading dose of 4.5 g. The loading dose of piperacillin tazobactam was combined with a single dose of gentamicin of 5 mg/kg. One hundred eight patients have received transplants since the start of the program: 82 patients during phase one and 26 patients during phase two. During phase 1, 13 cases of SSI were recorded, representing a rate of 15.85 per 100 transplants. Sixteen micro-organisms were isolated during phase 1, of which 12 corresponded to gram-negative bacilli. With regard to resistance profiles, 13 showed multidrug resistant and extensively drug resistant profiles. During phase 2, no cases of SSI were recorded (relative risk = 0.158 [95% confidence interval 0.0873-0.255], P = .0352]. A multimodal approach allowed for the reduction of the incidence of SSI in LTs and offered a protective strategy.


Invited review: Use of butyrate to promote gastrointestinal tract development in calves.
Promotion of microbial butyrate production in the reticulorumen is a widely used method for enhancing forestomach development in calves. Additional acceleration of gastrointestinal tract (GIT) development, both the forestomach and lower parts of the GIT (e.g., abomasum, intestine, and also pancreas), can be obtained by dietary butyrate supplementation. For this purpose, different sources (e.g., butyrate salts or butyrins), forms (e.g., protected or unprotected), methods (e.g., in liquid feed or solid feed), and periods (e.g., before or after weaning) of butyrate administration can be used. The aim of this paper was to summarize the knowledge in the field of butyrate supplementation in feeds for newborn calves in practical situations, and to suggest directions of future studies. It has been repeatedly shown that supplementation of unprotected salts of butyrate (primarily sodium salt) in milk replacer (MR) stimulates the rumen, small intestine, and pancreas development in calves, with a supplementation level equating to 0.3% of dry matter being sufficient to exert the desired effect on both GIT development and growth performance. On the other hand, the effect of unprotected butyrins and protected forms of butyrate supplementation in MR has not been extensively investigated, and few studies have documented the effect of butyrate addition into whole milk (WM), with those available focusing mainly on the growth performance of animals. Protected butyrate supplementation at a low level (0.3% of protected product in DM) in solid feed was shown to have a potential to enhance GIT development and performance of calves fed MR during the preweaning period. Justification of this form of butyrate supplementation in solid feed when calves are fed WM or after weaning needs to be documented. After weaning, inclusion of unprotected butyrate salts in solid feed was shown to increase solid feed intake, but the effect on GIT development and function has not been determined in detail, and optimal levels of supplementation are also difficult to recommend based on available reports. Future studies should focus on comparing different sources (e.g., salts vs. esters), forms (e.g., protected vs. unprotected), and doses of supplemental butyrate in liquid feeds and solid feeds and their effect not only on the development of rumen, abomasum, and small intestine but also the omasum and large intestine. Furthermore, the most effective source, form, and dose of supplemental butyrate in solid feed depending on the liquid feed program (e.g., MR or WM), stage of rearing (e.g., pre- or postweaning), and solid composition (e.g., lack or presence of forage in the diet) need to be determined.


Reaction mechanism of nucleoside 2'-deoxyribosyltransferases: free-energy landscape supports an oxocarbenium ion as the reaction intermediate.
Insight into the catalytic mechanism of Lactobacillus leichmannii nucleoside 2'-deoxyribosyltransferase (LlNDT) has been gained by calculating a quantum mechanics-molecular mechanics (QM/MM) free-energy landscape of the reaction within the enzyme active site. Our results support an oxocarbenium species as the reaction intermediate and thus an SN1 reaction mechanism in this family of bacterial enzymes. Our mechanistic proposal is validated by comparing experimental kinetic data on the impact of the single amino acid replacements Tyr7, Glu98 and Met125 with Ala, Asp and Ala/norLeu, respectively, and accounts for the specificity shown by this enzyme on a non-natural substrate. This work broadens our understanding of enzymatic C-N bond cleavage and C-N bond formation.


Enhancement of rat colon carcinogenesis by wheat bran consumption during the stage of 1,2-dimethylhydrazine administration.
The effect on intestinal carcinogenesis of feeding a 20% wheat bran dietary supplement, either during and/or after the stage of carcinogen administration with 1,2-dimethylhydrazine, was examined in 48 male Sprague-Dawley rats fed defined diets for 31 weeks. Nutrient intake and body weight gain were equivalent in all groups of animals. In the rats fed bran during carcinogen administration, tumor yield was significantly greater. Benign and malignant tumors increased by 3.4-fold (p less than 0.005), adenomas by 3.5-fold (p less than 0.025), and adenocarcinomas by 3.25-fold (p less than 0.05) over the yield found in the group fed a fiber-free diet. Consumption of wheat bran, after completion of carcinogen exposure, reduced the yield of benign adenomas by 71.4% when compared with the group fed the fiber-free diet (p less than 0.025). Those rats fed a wheat bran supplement during carcinogen administration and then switched to a fiber-free diet afterwards had the highest tumor yield, 4.5 times as many benign and malignant tumors as in those rats consistently fed the fiber-free diet (p less than 0.05) and at least 6 times as many adenomas as any of the other dietary groups (p less than 0.05). These results demonstrate that dietary wheat bran, a fiber which produces a hyperproliferative response in the colon, significantly increases colon carcinogenesis when fed to rats during the stage of carcinogen administration. This effect appears to be further enhanced when the wheat bran is totally removed from the diet following the stage of carcinogen administration. These data indicate that the hyperproliferative effects of wheat bran appear to outweigh any preventive actions that bran may have on colon carcinogenesis by altering the bulk of intestinal contents and their transit time through the bowel.


Defining Lyfe in the Universe: From Three Privileged Functions to Four Pillars.
Motivated by the need to paint a more general picture of what life is-and could be-with respect to the rest of the phenomena of the universe, we propose a new vocabulary for astrobiological research. Lyfe is defined as any system that fulfills all four processes of the living state, namely: dissipation, autocatalysis, homeostasis, and learning. Life is defined as the instance of lyfe that we are familiar with on Earth, one that uses a specific organometallic molecular toolbox to record information about its environment and achieve dynamical order by dissipating certain planetary disequilibria. This new classification system allows the astrobiological community to more clearly define the questions that propel their research-e.g., whether they are developing a historical narrative to explain the origin of life (on Earth), or a universal narrative for the emergence of lyfe, or whether they are seeking signs of life specifically, or lyfe at large across the universe. While the concept of "life as we don't know it" is not new, the four pillars of lyfe offer a novel perspective on the living state that is indifferent to the particular components that might produce it.


In vivo formed metabolites of polyphenols and their biological efficacy.
It is well known that plant-derived polyphenols are biologically relevant for human health both for their direct antioxidant activity and for their effects in the modulation of intracellular signals. Experts in this field have become aware of the need to carefully evaluate the effectiveness of these compounds in vivo, because of their absorption and metabolism kinetics once ingested. Indeed, it has been established that phenolic compounds are exposed to extensive metabolism in the human body, and their bioavailability is poor with respect to their metabolites. Thus, considering the biological activity of parent compounds, instead of that of their metabolites, is the major concern in relation to the studies on these molecules, especially in vitro. Recently, the main metabolites of polyphenols have become the subject of manifold research studies, which have revealed their beneficial effects particularly as antioxidant, anti-inflammatory and anticancer agents. They have also been investigated for their role in the prevention of cardiovascular and neurodegenerative diseases. The goal of this review is to emphasize the importance of the main in vivo formed metabolites of polyphenols for their potential benefits in relation to human health, showing the most significant outcomes of in vivo and in vitro studies carried out in the last few decades.


Use of Robotic Platforms as a Tool to Support STEM and Physical Education in Developed Countries: A Descriptive Analysis.
The lack of interest of children at school is one of the biggest problems that Mexican education faces. Two important factors causing this lack of interest are the predominant methodology used in Mexican schools and the technology as a barrier for attention. The methodology that institutions have followed has become an issue because of its very traditional approach, with the professor giving all the theoretical material to the students while they listen and memorize the contents, and, if we add the issue of the growing access to technological devices for students, children carrying a phone are more likely to be distracted. This study aims to integrate technology through assistive robots as a beneficial tool for educators, in order to improve the attention span of students by making the learning process in multiple areas of the Mexican curriculum more dynamic, therefore obtaining better results. To prove this, four different approaches were implemented; three in elementary schools and one in higher education: the LEGO® robotic kit and the NAO robot for STEM (science, technology, engineering, and mathematics) teaching, the NAO robot for physical education (PE), and the PhantomX Hexapod, respectively. Each of these technological approaches was applied by considering both control and experimental groups, in order to compare the data and provide conclusions. Finally, this study proves that the attention span is indeed improved as a result of implementing robotic platforms during the teaching process, allowing the children to become more motivated during their PE class and become more proactive and retain more information during their STEM classes.


Liver NF-κB-Inducing Kinase Promotes Liver Steatosis and Glucose Counterregulation in Male Mice With Obesity.
Obesity is associated with chronic inflammation and liver steatoses. Numerous proinflammatory cytokines have been reported to regulate liver glucose and lipid metabolism, thus contributing to the pathogenesis of liver steatosis and/or metabolic dysfunction. Nuclear factor-κB-inducing kinase (NIK) is stimulated by many cytokines and mediates activation of the noncanonical nuclear factor-κB pathway. We previously reported that liver NIK is aberrantly activated in obesity; inactivation of NIK by overexpressing dominant negative NIK(KA) suppresses hepatic glucose production. In the present study, we generated conditional NIK knockout mice using the Cre/loxp system. Mice with hepatocyte-specific or hematopoietic lineage-specific deletion of NIK were normal with either normal chow diet or high-fat diet (HFD) conditions. In contrast, deletion of NIK in the liver, including both hepatocytes and immune cells, protected against HFD-induced liver steatosis and attenuated hepatic glucose production. Mechanistically, deletion of liver NIK suppressed liver inflammation and lipogenic programs, thus contributing to protection against liver steatosis. Liver NIK also downregulated cyclic nucleotide phosphodiesterases, thereby augmenting the cyclic adenosine monophosphate/protein kinase A pathway and glucagon-stimulated hepatic glucose production. Together, our data suggest that NIK pathways in both hepatocytes and immune cells act in concert to promote liver steatosis and glucose production in the setting of obesity.


Halloysite nanoclay supported adsorptive removal of oxytetracycline antibiotic from aqueous media.
Halloysite nanoclay was utilized to retain aqueous oxytetracycline (OTC) which is extensively used in the veterinary industry. The micro-structure and functionality of the nanoclay were characterized through spectroscopic techniques before and after adsorption. The OTC removal experiments were performed at different pH conditions (pH 3.0-9.0), ionic strengths (0.001, 0.01, 0.1 M NaNO3) and contact time (up to 32 h) at an initial 25 mg/L OTC concentration with 1.0 g/L halloysite. Oxytetracycline adsorption was pH dependent, and the best pH was observed in the range of pH 3.5-5.5 at a 0.001 M ionic strength. At pH 3.5, the maximum OTC adsorption amount was 21 mg/g which translated to 68% removal of the initial OTC loading. Positively charged inner lumen and negatively charged outer lumen of the tubular halloysite structure led to form inner-sphere complexes with the anionic and cationic forms of OTC, respectively. A rapid adsorption of OTC was observed in the kinetic study where 62% OTC was adsorbed in 90 min.. Pseudo-second order equation obeyed by the kinetic data indicated that the adsorption was governed by chemisorption, whereas Hill isotherm equation was the most fitted with a maximum adsorption capacity of 52.4 mg/g indicating a cooperative adsorption phenomenon.


The relationship between cholesterol and survival in patients with chronic heart failure.
We sought to describe the relationship between cholesterol and survival in patients with chronic heart failure (CHF). Increasing lipoprotein levels are a cardiovascular risk factor. In patients with CHF, the prognostic value of endogenous lipoproteins is not fully clarified. A group of 114 patients with CHF recruited to a metabolic study was followed for a minimum of 12 months (derivation study). The results were applied to a second group of 303 unselected patients with CHF (validation study). The relationship between endogenous lipoproteins and survival was explored. In the derivation study, survival at 12 months was 78% (95% confidence interval [CI] 70% to 86%) and 56% (95% CI 51% to 62%) at 36 months. Increasing total serum cholesterol was a predictor of survival (hazard ratio 0.64, 95% CI 0.48 to 0.86), independent of the etiology of CHF, age, left ventricular ejection fraction, and exercise capacity. Receiver-operating characteristic curves demonstrated a best cut-off value of </=5.2 mmol/l (200.8 mg/dl) as being the best predictor of mortality at 12 months (sensitivity 80.0%, specificity 62.9%). In the validation population, one-year survival was 88% (95% CI 84 to 91%) and three-year survival was 68% (95% CI 63 to 73%). The chance of survival increased 25% for each mmol/l increment in total cholesterol. Survival rates above and below the cut-off value for cholesterol in patients with ischemic heart disease (n = 181) were 92% (95% CI 89 to 94) versus 75% (95% CI 64 to 85%) at one year and 72% (95% CI 67 to 76%) versus 50% (95% CI 43 to 56%) at three years. In patients with CHF, lower serum total cholesterol is independently associated with a worse prognosis.


Genetic compatibility between Anopheles lesteri from Korea and Anopheles paraliae from Thailand.
To assess differentiation and relationships between Anopheles lesteri and Anopheles paraliae we established three and five iso-female lines of An. lesteri from Korea and An. paraliae from Thailand, respectively. These isolines were used to investigate the genetic relationships between the two taxa by crossing experiments and by comparing DNA sequences of ribosomal DNA second internal transcribed spacer (ITS2) and mitochondrial DNA cytochrome c oxidase subunit I (COI) and subunit II (COII). Results of reciprocal and F1-hybrid crosses between An. lesteri and An. paraliae indicated that they were compatible genetically producing viable progenies and complete synaptic salivary gland polytene chromosomes without inversion loops in all chromosome arms. The pairwise genetic distances of ITS2, COI and COII between these morphological species were 0.040, 0.007-0.017 and 0.008-0.011, respectively. The specific species status of An. paraliae in Thailand and/or other parts of the continent are discussed.


An interplay of genetic and environmental factors in familial hepatitis and myasthenia gravis.
A family is described in which there occurred two cases of the lupoid type of active chronic hepatitis with cirrhosis, one of chronic persistent hepatitis, and one of myasthenia gravis. The two cases of lupoid hepatitis were in the proposita, a schoolgirl aged 16 years, and her great-aunt aged 69 years whom she had never met. The case of myasthenia gravis was that of the father. The whole family, except the great-aunt, had been exposed to an epidemic of infectious hepatitis five years previously, and the girl and her brother had contracted this disease. The schoolgirl later developed active chronic hepatitis while her brother had chronic persistent hepatitis without immunological concomitants. APART FROM COINCIDENCE, SOME COMBINATION OF THREE PROCESSES WAS REQUIRED TO ACCOUNT FOR THE ILLNESSES IN THIS FAMILY: a genetic predisposition to chronic liver disease in particular, a genetic predisposition to autoimmune reactions in general, and a ;triggering' effect of infection with the hepatitis virus.


cDNA cloning and expression of a human platelet-derived growth factor (PDGF) receptor specific for B-chain-containing PDGF molecules.
The structure of the human receptor for platelet-derived growth factor (PDGF) has been deduced through cDNA cloning. A 5.45-kilobase-pair cDNA clone predicts a 1,106-amino-acid polypeptide, including the cleavable signal sequence. The overall amino acid sequence similarity with the murine PDGF receptor is 85%. After transcription of the cDNA and translation in vitro, a PDGF receptor antiserum was used to immunoprecipitate a product of predicted size, which also could be phosphorylated in vitro. Stable introduction of the cDNA into Chinese hamster ovary (CHO) cells led to the expression of a 190-kilodalton component, which was immunoprecipitated by the PDGF receptor antiserum; this most probably represents the mature PDGF receptor. Binding assays with different 125I-labeled dimeric forms of PDGF A and B chains showed that the PDGF receptor expressed in CHO cells bound PDGF-BB and, to a lesser extent, PDGF-AB, but not PDGF-AA.


Deposition of sidestream cigarette smoke in the human respiratory tract.
Measurement of deposition of sidestream cigarette smoke in the human respiratory tract is important for assessing the health effects of sidestream cigarette smoke. We measured the deposition fraction of sidestream cigarette smoke in 5 normal adult male volunteers using sidestream smoke at a concentration similar to that encountered indoors with smokers present. The mean deposition was 11%. These data indicate that the deposition fraction of sidestream smoke is similar to other previously studied aerosols in the same size range and is much less than mainstream smoke.


Surgery for ulcerative colitis in geriatric patients is safe with similar risk to younger patients.
A prior study indicated that postoperative mortality and complications were higher in geriatrics with inflammatory bowel disease (IBD). We sought to assess the rates of surgical complications and mortality in patients aged ≥65 years after colectomy for ulcerative colitis (UC). This is a single center retrospective study at a tertiary care center. We reviewed all hospital discharges with ICD-9 code 556.X between January 2002 and January 2014. Patients were included if they underwent a colectomy for UC. All records were manually reviewed for demographics, complications and mortality within 90 days postoperatively. A total of 259 patients underwent surgery for UC during the study period and 34 patients were ≥65 years old (range 65-82) at the time of their surgery. There was no difference in overall length of stay (10.5 days vs. 9.6 days; P = 0.645) or complication rates (44% vs. 47%; P = 0.854) in the ≥65 cohort compared with the under 65 cohort. Mortality was higher in the geriatric cohort but this included only two deaths within 90 days, one of which was unrelated to the surgery, compared with one death related to surgery within 90 days in the younger cohort. Readmissions occurred in 24% of both cohorts within 90 days. Geriatric patients undergoing surgery for UC are not at increased risk of surgery-related morbidity or mortality compared with a younger cohort.


Prohibitin regulates mTOR pathway via interaction with FKBP8.
The ability of tumor cells to sustain continuous proliferation is one of the major characteristics of cancer. The activation of oncogenes and the mutation or inactivation of tumor suppressor genes ensure the rapid proliferation of tumor cells. The PI3K-Akt-mTOR axis is one of the most frequently modified signaling pathways whose activation sustains cancer growth. Unsurprisingly, it is also one of the most commonly attempted targets for cancer therapy. FK506 binding protein 8 (FKBP8) is an intrinsic inhibitor of mTOR kinase that also exerts an anti-apoptotic function. We aimed to explain these contradictory aspects of FKBP8 in cancer by identifying a "switch" type regulator. We identified through immunoprecipitation-mass spectrometry-based proteomic analysis that the mitochondrial protein prohibitin 1 (PHB1) specifically interacts with FKBP8. Furthermore, the downregulation of PHB1 inhibited the proliferation of ovarian cancer cells and the mTOR signaling pathway, whereas the FKBP8 level in the mitochondria was substantially reduced. Moreover, concomitant with these changes, the interaction between FKBP8 and mTOR substantially increased in the absence of PHB1. Collectively, our finding highlights PHB1 as a potential regulator of FKBP8 because of its subcellular localization and mTOR regulating role.


Identification of type I and type II serine/threonine kinase receptors for growth/differentiation factor-5.
Growth/differentiation factor-5 (GDF-5) is a member of the bone morphogenetic protein (BMP) family, which plays an important role in bone development in vivo. Mutations in the GDF-5 gene result in brachypodism in mice and Hunter-Thompson type chondrodysplasia in human. BMPs transduce their effects through binding to two different types of serine/threonine kinase receptors, type I and type II. However, binding abilities appear to be different among the members of the BMP family. BMP-4 binds to two different type I receptors, BMP receptors type IA (BMPR-IA) and type IB (BMPR-IB), and a type II receptor, BMP receptor type II (BMPR-II). In addition to these receptors, osteogenic protein-1 (OP-1, also known as BMP-7) binds to activin type I receptor (ActR-I) as well as activin type II receptors (ActR-II and ActR-IIB). Here we investigate the binding and signaling properties of GDF-5 through type I and type II receptors. GDF-5 induced alkaline phosphatase activity in a rat osteoprogenitor-like cell line, ROB-C26. 125I-GDF-5 bound to BMPR-IB and BMPR-II but not to BMPR-IA in ROB-C26 cells and other nontransfected cell lines. Analysis using COS-1 cells transfected with the receptor cDNAs revealed that GDF-5 bound to BMPR-IB but not to the other type I receptors when expressed alone. When COS-1 cells were transfected with type II receptor cDNAs, GDF-5 bound to ActR-II, ActR-IIB, and BMPR-II but not to transforming growth factor-beta type II receptor. In the presence of type II receptors, GDF-5 bound to different sets of type I receptors, but the binding was most efficient to BMPR-IB compared with the other type I receptors. Moreover, a transcriptional activation signal was efficiently transduced by BMPR-IB in the presence of BMPR-II or ActR-II after stimulation by GDF-5. These results suggest that BMPR-IB mediates certain signals for GDF-5 after forming the heteromeric complex with BMPR-II or ActR-II.


Increased Postoperative Use of Computed Tomography Following Emergency Surgery for Ileocaecal Crohn Disease.
Multiple imaging modalities are often required for the relapsing nature of Crohn disease (CD). Computed tomography (CT) offers a rapid acquisition of images and shows high specificity and sensitivity. However, CT imaging exposes to a higher dose of ionizing radiation than other abdominal imaging modalities. The aim of this study was to compare the use of preoperative and postoperative CT scan in patients undergoing emergency and elective surgery for CD. All patients undergoing emergency and elective surgery for ileocaecal CD January 2014 to December 2018 were included in this prospective observational study. The study objective was to evaluate the frequency of use of CT scan perioperatively with the number and findings of preoperative and postoperative CT being the primary outcomes. The secondary outcomes were operating time, length of hospital stay, reoperations, and rehospitalization. A total of 75 patients were included, 33 in the emergency group (43%) and 44 in the elective group (57%). There was a higher use of preoperative CT scan in the emergency surgery group, with 14 patients (42%) having a CT scan before surgery compared with 2 (5%) in the elective group (P=0.14). Thirteen patients (39.4%) had a postoperative CT scan in the emergency surgery group, compared with 10 patients (23.8%) in the elective surgery group. Patients undergoing emergency surgery for CD are at increased risk of exposure to ionizing radiations due to high perioperative use of CT scan.


Role of the histone deacetylase complex in acute promyelocytic leukaemia.
Non-liganded retinoic acid receptors (RARs) repress transcription of target genes by recruiting the histone deacetylase complex through a class of silencing mediators termed SMRT or N-CoR. Mutant forms of RARalpha, created by chromosomal translocations with either the PML (for promyelocytic leukaemia) or the PLZF (for promyelocytic leukaemia zinc finger) locus, are oncogenic and result in human acute promyelocytic leukaemia (APL). PML-RARalpha APL patients achieve complete remission following treatments with pharmacological doses of retinoic acids (RA); in contrast, PLZF-RARalpha patients respond very poorly, if at all. Here we report that the association of these two chimaeric receptors with the histone deacetylase (HDAC) complex helps to determine both the development of APL and the ability of patients to respond to retinoids. Consistent with these observations, inhibitors of histone deacetylase dramatically potentiate retinoid-induced differentiation of RA-sensitive, and restore retinoid responses of RA-resistant, APL cell lines. Our findings suggest that oncogenic RARs mediate leukaemogenesis through aberrant chromatin acetylation, and that pharmacological manipulation of nuclear receptor co-factors may be a useful approach in the treatment of human disease.


MS4A3 promotes differentiation in chronic myeloid leukemia by enhancing common β-chain cytokine receptor endocytosis.
The chronic phase of chronic myeloid leukemia (CP-CML) is characterized by the excessive production of maturating myeloid cells. As CML stem/progenitor cells (LSPCs) are poised to cycle and differentiate, LSPCs must balance conservation and differentiation to avoid exhaustion, similar to normal hematopoiesis under stress. Since BCR-ABL1 tyrosine kinase inhibitors (TKIs) eliminate differentiating cells but spare BCR-ABL1-independent LSPCs, understanding the mechanisms that regulate LSPC differentiation may inform strategies to eliminate LSPCs. Upon performing a meta-analysis of published CML transcriptomes, we discovered that low expression of the MS4A3 transmembrane protein is a universal characteristic of LSPC quiescence, BCR-ABL1 independence, and transformation to blast phase (BP). Several mechanisms are involved in suppressing MS4A3, including aberrant methylation and a MECOM-C/EBPε axis. Contrary to previous reports, we find that MS4A3 does not function as a G1/S phase inhibitor but promotes endocytosis of common β-chain (βc) cytokine receptors upon GM-CSF/IL-3 stimulation, enhancing downstream signaling and cellular differentiation. This suggests that LSPCs downregulate MS4A3 to evade βc cytokine-induced differentiation and maintain a more primitive, TKI-insensitive state. Accordingly, knockdown (KD) or deletion of MS4A3/Ms4a3 promotes TKI resistance and survival of CML cells ex vivo and enhances leukemogenesis in vivo, while targeted delivery of exogenous MS4A3 protein promotes differentiation. These data support a model in which MS4A3 governs response to differentiating myeloid cytokines, providing a unifying mechanism for the differentiation block characteristic of CML quiescence and BP-CML. Promoting MS4A3 reexpression or delivery of ectopic MS4A3 may help eliminate LSPCs in vivo.


Level I Nodal Positivity as a Factor for Involvement of the Submandibular Gland in Oral Cavity Carcinoma: A Case Series Report.
Introduction The routine practice of neck dissection in the surgical management of oral carcinoma has evolved into a more functionally conservative approach. Over time, the rationale for removal of the submandibular gland has been questioned. Routine extirpation of the submandibular gland can aggravate the xerostomia experienced by many patients, significantly affecting their quality of life. Objective The objective of the present study was to determine the incidence of submandibular gland metastases in oral cavity carcinoma and to identify possible factors that may affect their involvement. Methods A total of 149 cases of oral carcinoma presenting at a private tertiary care hospital in Karachi, Pakistan, over the course of 1 year were reviewed retrospectively. Results Histopathological data showed that the submandibular gland was involved in 7 (4.7%) cases. Involvement of level I lymph nodes was found in all of the cases. Direct extension of primary tumor was noted in two cases when the primary tumor was in the floor of the mouth. Conclusion The results suggest that preservation of the submandibular gland during neck dissection for oral carcinoma can be practiced safely when there is no evidence of direct extension of the primary tumor toward the submandibular gland or when there is no clinical or radiological evidence of neck disease in level I. Presence of pathological lymph nodes in level I requires caution when contemplating preservation of the submandibular gland.


Lifetime costs of invasive meningococcal disease: A Markov model approach.
Invasive meningococcal disease (IMD) is an uncommon but life-threatening infectious disease associated with high sequelae rates in young children and an increased risk of mortality in adolescents and young adults. Funding decisions to reject inclusion of new meningococcal serogroup B vaccines on national immunisation schedules have been criticised by IMD patients, their families, paediatricians and charity organisations. We aim to estimate the lifetime costs of IMD with the best available evidence to inform cost-effectiveness analyses. A Markov model was developed taking healthcare system and societal perspectives. A range of data including age-specific mortality rates, and probabilities of IMD-related sequelae were derived from a systematic review and meta-analysis. All currencies were inflated to year 2017 prices by using consumer price indexes in local countries and converted to US dollars by applying purchasing power parities conversion rates. Expert panels were used to inform the model development process including key structural choices and model validations. The estimated lifetime societal cost is US$319,896.74 per IMD case including the direct healthcare cost of US$65,035.49. Using a discount rate of 5%, the costs are US$54,278.51 and US$13,968.40 respectively. Chronic renal failure and limb amputation result in the highest direct healthcare costs per patient. Patients aged < 5 years incur the higher healthcare expenditure compared with other age groups. The costing results are sensitive to the discount rate, disease incidence, acute admission costs, and sequelae rates and costs of brain injuries and epilepsy. IMD can result in substantial costs to the healthcare system and society. Understanding the costs of care can assist decision-making bodies in evaluating cost-effectiveness of new vaccine programs.


Evaluation of commercial oral replacement formulas in healthy neonatal calves.
Effects of 5 commercial oral replacement formulas on hematologic and plasma biochemical values, body weight, and prevalence of diarrhea were studied in healthy neonatal calves. Products were fed according to manufacturers' recommendations beginning at 3 to 7 days of age for 3 days. Whole milk, diluted 1:1 with commercial formulas, was fed for 3 days thereafter. There were no consistently significant (P greater than 0.05) effects of commercial product feeding with time or by treatment, as compared with those in whole milk-fed controls, on the hematologic or biochemical values of PCV, leukocyte count, platelet count, or plasma K, Cl, glucose, and lactic acid concentrations. Plasma Na concentrations decreased significantly (P less than 0.05) with age in all groups. After 2 weeks, milk-fed calves had gained 2.09 +/- 0.96 kg, and calves fed all but 2 hypertonic energy-dense products 1 and 5 had significant (P less than 0.05) weight losses (up to 2.95 +/- 1.34 kg). Transition to a diet of whole milk and commercial product at one half each of their standard doses resulted in a significant (P less than 0.05) occurrence of diarrhea. Seemingly, such formulas should not be fed to healthy calves on a long term basis. The product with the lowest osmolal and caloric content was associated with the greatest weight loss.


Analysis of TGFBR1*6A variant in individuals evaluated for Marfan syndrome.
Marfan syndrome (MFS) and Loeys-Dietz syndrome (LDS) are genetic disorders that affect connective tissue as a result of dysregulated TGF-β signaling. MFS is most frequently caused by mutations in FBN1 whereas Loeys-Dietz syndrome results from mutations in TGFBR1 or TGFBR2. There is substantial inter- and intra-familial phenotypic variability among these disorders, suggesting the presence of genetic modifiers. Previously, a polymorphism in the TGFβR1 protein termed the TFGBR1*6A allele was found to be overrepresented in patients with MFS and was identified as a low penetrance allele with suggestion as a possible modifier. To further investigate the importance of this variant, a retrospective review of genetic and phenotypic findings was conducted for 335 patients evaluated for suspicion of MFS or related disorders. In patients with a diagnosis of MFS, the presence of the TFGBR1*6A allele was not associated with phenotypic differences. Similarly, careful phenotyping of patients who carried the TFGBR1*6A allele but did not have MFS did not identify an altered frequency of specific connective tissue features. In this small cohort, the results did not reach significance to identify the TFGBR1*6A allele as a major modifier for aortic dilation, ectopia lentis, or systemic features associated with MFS or other connective tissue disorders. © 2016 Wiley Periodicals, Inc.


Karydakis flap repair for sacrococcygeal pilonidal sinus disease: how important is technique?
Numerous operative and conservative treatments have been described in the published work for the management of sacrococcygeal pilonidal sinus; yet there remains considerable debate over its ideal treatment. This report is an audit of our results using the Karydakis flap repair in the management of this condition. We analysed prospective data on 70 patients who had had a Karydakis procedure. The length of follow up ranged from 1 to 79 months (median 36 months). Seventy-one operations were carried out in 70 patients. This included 12 patients (17%) who had previously undergone between one and four procedures (median 2) for recurrent disease. Superficial wound breakdown occurred in 27 patients (38%) and complete wound breakdown occurred in six patients (8.4%). These wounds were allowed to heal by secondary intent. The median time to complete healing for superficial and complete wound breakdown was 80 and 84 days, respectively. Disease recurrence occurred in three patients (4.2%) -- two of whom had recurrent disease at the time of this presentation. Of the three patients who had a recurrence after our surgery, two had a superficial breakdown and one had a complete wound breakdown. Sacrococcygeal pilonidal disease has a low recurrence rate when treated by the Karydakis operation involving flattening of the midline cleft. This procedure avoids the need for more complicated flap repairs.


A Key role for cyclic AMP-responsive element binding protein in hypoxia-mediated activation of the angiogenesis factor CCN1 (CYR61) in Tumor cells.
Hypoxia is a prominent feature of solid tumors known to contribute to malignant progression and therapeutic resistance. Cancer cells adapt to hypoxia using various pathways, allowing tumors to thrive in a low oxygen state. Induction of new blood vessel formation via the secretion of proangiogenic factors is one of the main adaptive responses engaged by tumor cells under hypoxic conditions. Hypoxia-inducible factor 1 (HIF-1) is a transcription factor that plays a pivotal role in mediating such responses. In addition, several other transcription factors have also been implicated in hypoxic gene regulation, either independently or in cooperation with HIF-1. In this work, we show that the expression of the angiogenesis-related, immediate early gene CCN1 (formerly known as CYR61), considered to be involved in tumor growth and invasiveness, is enhanced upon hypoxia stress primarily in a protein kinase A and cyclic AMP-responsive element binding protein (CREB) and CRE-dependent manner in various cell lines. The hypoxia-mediated activation of the CCN1 promoter is independent of HIF-1 and HIF-2, as shown by small interfering RNA knockdown. We identify the cis element in the mouse CCN1 promoter responsible for CREB binding to be one of two partial CRE sites present in the promoter. Moreover, we report for the first time that CREB-mediated CCN1 transcription is enhanced in hypoxic regions of tumors in vivo. Identifying and characterizing the molecular mechanisms that govern the response of tumors to hypoxia may be instrumental to identify the tumors that will respond favorably to inhibition of angiogenesis and thus lead to the development of treatments that could complement hypoxia-inducing treatment modalities.


Effects of nicorandil on electromechanical activity of frog atrial muscle.
The effects of the antianginal drug nicorandil on electrical and mechanical activity of bullfrog atria were examined. The application of nicorandil at concentrations from 0.3 to 10 mM caused a negative inotropic effect without any appreciable change in the resting membrane potential. The amplitude of action potentials was attenuated. In the voltage clamp experiments, the slow inward current was slightly inhibited, but the background inward current and delayed outward current were not affected in the presence of nicorandil. The inward rectifying properties of time-independent outward current were slightly inhibited by 10 mM nicorandil. Nicorandil inhibited the caffeine-induced contractures elicited in the depolarized preparation, but had no effect on the contracture mediated through the Na-Ca exchange mechanism. These results suggest that the negative inotropic action of nicorandil is caused by inhibition of Ca influx and intracellular mobilization of Ca. Nicorandil had little effect on the potassium conductance in this preparation.