Comparative study of two complementary proliferation markers in 200 breast carcinomas: Ki67 and mitotic index.
The evaluation of the proliferation in the mammary carcinomas provides useful prognostic and predictive information for subsequent management. The purely morphological evaluation of proliferative activity was represented by the evaluation of mitotic index. New analytical methods were gradually developed and performed. Among these methods, evaluation of Ki67 by immunohistochemistry is particularly interesting. Its expression is significantly increased in the cell cycle. To correlate the mitotic index as a classic method of assessing cell proliferation and Ki 67 proliferation index detected by immunohistochemistry to identify the most reliable proliferative marker. We studied 200 patients with invasive ductal carcinoma breast over a period of 12 months of 2014. We identified in each case the SBR grade, Ki67 proliferation index and the mitotic index. Correlation between the two parameters was identified using the Spearman test. A result is considered significant when p < 0.01. The distribution of these markers by SBR gradewas studied using the ANOVA method. Ki67 is significantly correlated to the mitotic index. Although these two methods are dependent, Ki67 is the most sensitive and bonded to SBR grade. Determination of Ki67 provides interesting information that could replace the mitotic account. It provides reliable and reproducible data that can be incorporated into a prognostic score. Ki67 is a more efficient marker mitotic index, reflecting the cell proliferation.


Studies on the mechanisms of action of progesterone antagonists.
Antigestagens of RU-38.486-type were investigated in different pregnancy models reflecting either "endometrial" or "myometrial" effects. All antigestagens were found effective inhibitors of nidation in guinea pigs. This was evidence for a role of embryonic progesterone in the earliest events of nidation. No comparable inhibition could be obtained by ovariectomy. A more complex pharmacology was found around day 43 p.c. when the abortion was brought about by expulsion. RU-38.486 had marginal activity only. Antigestagens with reduced anti-glucocorticoid activity tended to induce abortions more effectively and faster. Some antigestagen-prostaglandin combinations were found of extreme abortifacient activity. Surprisingly it seemed that anti-glucocorticoid properties in addition to (or rather than) antigestagenic activities bring about this synergism with prostaglandin. The employed guinea pig model for pregnancy termination thus characterized two types of antigestagens: ideal ones for monotherapy or combined use with prostaglandin, respectively. Antigestagens induced a highly sensitive myometrium to prostaglandin-stimulation (Sulprostone) and a marked softening and dilatation of the cervix. Antigestagens perfectly prime the genital tract for oxytocic stimuli, they do not overcome the arrested uterine prostaglandin-secretion of the pregnant uterus at the same time.


Potentiation by the hypoxic cytotoxin SR 4233 of cell killing produced by fractionated irradiation of mouse tumors.
The new bioreductive drug 3-amino-1,2,4-benzotriazine 1,4-dioxide (SR 4233) shows a high selective cytotoxicity for hypoxic cells, both in vitro and in tumors in vivo. In the present experiments, we have tested the hypothesis that this selective killing of hypoxic cells might be exploited by taking advantage of the fluctuating hypoxia in tumors by use of a multidose regimen of SR 4233 with multiple small doses of X-rays. We have tested four different transplantable mouse tumors using a standard fractionated protocol of 8 x 2.5 Gy in 4 days, using a well tolerated dose of SR 4233 given with each radiation dose. All of the tumors showed a substantial enhancement of cell killing by SR 4233 over that produced by radiation alone with dose-modifying factors of 1.5 to 3.0 for the different tumors. In all four tumors, the enhancement of cell killing was greater than that produced by a large dose of the hypoxic cell sensitizer SR 2508 given before each irradiation, thereby demonstrating the superiority of the approach of using a hypoxic cytotoxic agent rather than a radiosensitizer in fractionated radiation protocols. The data suggest that SR 4233 has considerable promise as an adjunct to standard radiotherapy.


Mineralcorticoid receptors along the nephron: [3H]aldosterone binding in rabbit tubules.
To identify the site of mineralocorticoid action along the nephron, we measured the specific binding of [3H]aldosterone to nephron segments microdissected from aldosterone-deficient rabbits. Specific binding was defined as the difference between binding measured in the absence or in the presence of 2,000-fold excess of unlabeled hormone (in 10(-18) mol X cm tubule length-1 +/- SE). High specific binding capacity was found in the branched collecting tubule (108 +/- 4), the cortical collecting tubule (119 +/- 9), and the outer medullary collecting tubule (115 +/- 16), whereas specific binding was negligible in the proximal convoluted tubule (8 +/- 9), pars recta (2 +/- 6), medullary thick ascending limb (4 +/- 6), cortical thick ascending limb (6 +/- 2), and distal convoluted tubule (6 +/- 6). In cortical collecting tubules, Scatchard analysis of the specific [3H]aldosterone binding indicated a dissociation constant (KD) of 2.2 X 10(-9) M and a maximum number of binding sites of 157 X 10(-18) mol X cm tubule length-1. The steroid specificity was assessed from the competition of various steroids for [3H]aldosterone binding sites. Receptors from the cortical collecting tubule revealed the following sequence of affinities: aldosterone greater than DOCA greater than spironolactone greater than dexamethasone greater than 5 alpha-dihydrotestosterone = progesterone = 17 beta-estradiol, indicating that the binding sites in the collecting tubule are mineralocorticoid receptors. These results demonstrate significant [3H]aldosterone binding to receptors of high affinity and mineralocorticoid specificity only in the collecting tubule and suggest that this nephron segment is the target site of mineralocorticoid action in the rabbit kidney.


Development of a new gaze stabilization test.
The gaze stabilization test (GST) is used not only in examining gaze stability required by daily life activities, but also in identifying unilateral or bilateral vestibular deficits. However, a computerized GST (CGST) is an expensive assessment, which cannot be commonly used in most clinics. Validation of low-cost and low-technical clinical tests is required to decrease health care costs. The purpose of this study was to measure the accuracy of a new GST (NGST) in a cohort of healthy young adults with no history of vestibular or balance disorders, as well as the test-retest reliability when re-assessed 5-7 days. Subjects identified a visual target while actively and passively performing head movements in the yaw plane at an initial screening velocity of 130 degs/sec. The main outcome was a strong positive correlation in both active and passive NGST head movement amplitude degree and head movement velocity. Passive head movements had good accuracy (85%) to identify healthy individuals with no history of vestibular or balance disorders. In addition, the NGST has good test-retest reliability in head movement amplitude degree (r=0.795) and head movement velocity (r=0.797) of passive NGST within two testing sessions.


Pharmacist intervention to enhance postoperative fluid prescribing practice in an Iraqi hospital through implementation of NICE guideline.
The objectives of this study were to evaluate the current practice of postoperative fluid prescribing and assess the effectiveness of pharmacist-led intervention in the implementation of the National Institute of Health and Care Excellence (NICE) fluid therapy guideline in an Iraqi hospital. The prospective interventional study was conducted at AL-Hilla Teaching Hospital, Babylon, Iraq between November 2017 and July 2018. The study included two phases: The pre-intervention phase with 84 patients and the post-intervention phase with 112 patients. A pharmacist provided training and educational sessions for the hospital physicians and pharmacists about the NICE guideline of fluid therapy. The researcher calculated the amount of given post-operative fluids and compared to the NICE guideline and also measured the patients' body weight, serum Na, K and creatinine pre-and post-operatively. The pre-intervention phase showed no correlation between the amounts of prescribed fluids and body weight which caused increases in patients' body weight. In pre-intervention phase, 6% of patients experienced hyponatremia, 19% had hypernatremia and 7.1% had hypokalemia. In the post-intervention phase, abnormal level of electrolytes and patient weight gain decreased significantly. Additionally, the intervention led to a strong correlation between body weight and amount of prescribed fluids in addition to lowering the incidence of electrolyte disturbances. A high proportion of patients in the pre-intervention phase experienced fluid overload, weight gain and electrolyte disturbances when fluid therapy was not prescribed in accordance with the NICE guidelines. The pharmacist-led intervention increased the surgeon awareness of the proper use of the NICE guideline which decreased the incidence of fluid-related complications and the inconsistency of fluid prescribing. Pharmacists can play a critical role to enhance post-operative fluid prescribing and minimize fluid-induced complications.


Optical-rotatory-dispersion studies of compounds related to cholesterol in liposomes and the membranes of erythrocyte 'ghosts'.
1. Steroid molecules containing the alpha,beta-unsaturated oxo group in various positions were incorporated with egg phosphatidylcholine into liposomes and into human erythrocyte membranes. 2. The liposomes formed contained 0.3-0.94mol of steroid/mol of phospholipid and the steroids replaced 19-76% of the erythrocyte membrane sterol. 3. The optical rotatory dispersion (o.r.d.) spectra of the steroids in these structures were compared with those obtained in solvents of different polarity. 4. The o.r.d. spectra of cholesta-4,6-dien-3-one and 3-hydroxycholest-3-en-2-one in liposomes resembled those obtained with polar solvents such as ethanol or triethyl phosphate-water (1:1, v/v). 5. The o.r.d. spectra of 3-hydroxycholest-7-en-6-one and 3-hydroxycholest-5-en-7-one in liposomes resembled those obtained with moderately polar solvents such as dioxan. 6. The o.r.d. spectrum of 3-hydroxycholest-8(14)-en-15-one in liposomes resembled those obtained with non-polar solvents such as cyclohexane. 7. 3-Hydroxycholest-3-en-2-one did not exchange with erythrocyte membrane cholesterol, but the other steroids did do so and the o.r.d. spectra of the membranes containing them closely resembled those obtained with liposomes. 8. From the results, the position of sterol molecules with respect to the phospholipid molecules in liposomes and membranes of human erythrocyte ;ghosts' can be deduced.


A single centre retrospective study of systemic reactions to subcutaneous immunotherapy.
Subcutaneous immunotherapy (SCIT) is the standard approach for treating patients with sensitizations to aeroallergens. However, immunotherapy can trigger severe systemic reactions if delivered inappropriately or to high risk patients. We sought to characterize and quantify SCIT systemic reactions requiring epinephrine administration during a 6-year period in a Canadian setting following the recommendations for components and dosages published in the 2010 Canadian Society of Allergy and Clinical Immunology (CSACI) Immunotherapy Manual. A single centre retrospective chart review was performed for all patients with systemic reactions to subcutaneous immunotherapy requiring intramuscular epinephrine injection between January 2011 and October 2017. Each systemic reaction requiring epinephrine was reviewed for baseline patient characteristics, details of the reaction, and reaction severity. Research ethics approval was obtained through McMaster University. 28 of 380 patients experienced a systemic reaction requiring epinephrine administration, with an incidence rate of 1 per 1,047 injection visits (0.095%). 26 of the 28 reactions occurred within the mandatory 30-minute observation period post allergen immunotherapy. Of the 28 patients that experienced a systemic reaction to SCIT, 11 patients had asthma and 5 patients had a history of possible food allergy. All of the systemic reactions occurred during injections from vial number 4, and five patients reacted to their first shot of a re-ordered extract. 10 of the 28 patients required more than one intramuscular injection of epinephrine, and 20 of 28 patients were transferred to the hospital by ambulance. This is the first Canadian study to review patients with systemic reactions to subcutaneous immunotherapy. Several best practice methods were employed throughout the study to optimize subcutaneous delivery of immunotherapy extract, and our recorded per injection incidence rate for systemic reactions was comparable or below the rate published in similar studies. The recommendations in the CSACI Immunotherapy Manual provide an approach to standardizing prescriptions for SCIT to maximize immunotherapy efficacy and reduce the risk of systemic reactions, though similar studies in larger multicenter settings are needed to confirm these observations. These observations provide important objective information to clinicians about the potential risks for systemic reactions in patients considering SCIT.


Host specialization of parasitoids and their hyperparasitoids on a pair of syntopic aphid species.
Parasitoids of herbivorous insects have frequently evolved specialized lineages exploiting hosts occurring on different plants. This study investigated whether host specialization is also observed when closely related parasitoids exploit herbivorous hosts sharing the same host plant. The question was addressed in economically relevant aphid parasitoids of the Lysiphlebus fabarum group. They exploit two aphid species (Aphis fabae cirsiiacanthoides and Brachycaudus cardui), co-occurring in mixed colonies (syntopy) on the spear thistle (Cirsium vulgare). Two morphologically distinguishable parasitoid lineages of the genus Lysiphlebus were observed and each showed virtually perfect host specialization on one of the two aphid species in this system. From A. f. cirsiiacanthoides, only females emerged that morphologically belonged to Lysiphlebus cardui, while males and females belonging to L. fabarum hatched from B. cardui. Microsatellite analyses indicated clear genetic differentiation of L. fabarum and L. cardui. L. cardui comprised only two distinct asexual lineages, one of which predominated throughout the area investigated. Population genetic analysis of sexual L. fabarum showed evidence for relatively strong spatial structuring and limited dispersal ability. Hyperparasitoids emerged from a large proportion of aphid mummies. One species, Pachyneuron aphidis, was significantly associated with B. cardui/L. fabarum mummies, indicating that host specialization may even extend to the trophic level above parasitoids.


Photographic comparison of pupillary and corneal diameters when one eye is deviated.
A method is presented for predicting the horizontal pupillary and corneal diameters when one eye is deviated. When the actual diameters are equal, the apparent diameter of the deviated pupil or cornea is equal to the cosine of the angle of deviation multiplied by the pupillary or corneal diameter of the undeviated eye.


Chimerism and cure: hematologic and pathologic correction of murine sickle cell disease.
Bone marrow transplantation (BMT) is the only curative therapy for sickle cell disease (SCD). However, the morbidity and mortality related to pretransplantation myeloablative chemotherapy often outweighs the morbidity of SCD itself, thus severely limiting the number of patients eligible for transplantation. Although nonmyeloablative transplantation is expected to reduce the risk of BMT, it will likely result in mixed-chimerism rather than complete replacement with donor stem cells. Clinical application of nonmyeloablative transplantation thus requires knowledge of the effect of mixed chimerism on SCD pathophysiology. We have, therefore, created a panel of transplanted SCD mice that received transplants displaying an array of red blood cell (RBC) and white blood cell (WBC) chimerism. A significant enrichment of RBC over WBC chimerism occurred in these mice, because of the dramatic survival advantage of donor over sickle RBCs in the peripheral blood. Increasing levels of RBC chimerism provided progressive correction of hematologic and pathologic abnormalities. However, sickle bone marrow and splenic hematopoiesis was not corrected until peripheral blood sickle RBCs were fully replaced with donor RBCs. These results have important and unexpected implications for nonmyeloablative BMT for SCD. As the critical hematopoietic organs were not corrected without full RBC replacement, 100% peripheral blood RBC chimerism becomes the most important benchmark for cure after nonmyeloablative BMT.


[Harms technique of C1-C2 fixation with polyaxial screws and rods].
The Harms technique of stabilizing C1-C2 by fixation with polyaxial screws and rods is a further option for atlantoaxial fixation from the dorsal approach. Harms and Melcher published this method in 2001, but the operation had first been performed by Harms in August 1997. The aim of this study is to evaluate the first results and try to assign the Harms C1-C2 fixation an appropriate standing in the in broad range of options for stabilization of the atlantoaxial complex. Between December 2002 and January 2004 we carried out the Harms fixation of C1-C2 on 22 patients admitted to the Department of Spine Surgery, Motol University Hospital, 2nd Medical Faculty in Prague. Out of these, 18 patients were included in this study, 10 men and 8 women between 23 and 84 years of age (average, 55.4 years) followed-up longer than 6 months. In 14 patients we used the Harms technique as a permanent fixation of C1-C2 in order to achieve atlantoaxial arthrodesis and, in four patients, we applied it only for a period of 4 to 6 months without the use of bone grafts or their substitutions. We employed the permanent fixation to treat the following conditions: fracture of the atlas in three patients, type IIA comminuted fracture of the dens base in three patients, fracture of C2 categorized as "other" in two patients, atlantoaxial vertical instability in one patient with rheumatoid arthritis, malunion of the fractured dens in one patient, and complicated trauma to C1-C2 in four patients. The temporary fixation was used for type III displaced fractures of the dens in two and fixed atlantoaxial rotatory dislocations also in two cases. Only one patient showed signs of Frankel C neurological deficit on admission, the rest were without neurological findings. All screws were inserted under an image intensifier always in lateral projection. First we retracted the greater occipital nerve in a caudal direction towards C2 with a fine raspatory and, using an awl, marked the entry point in the C1 lateral mass; a pilot hole, reaching through the anterior cortical bone, was made with a 2.5 mm drill. It followed a straight or slightly convergent trajectory in an anterior-posterior direction and parallel to the plane of the C1 posterior arch in the sagittal direction. Individual anatomical variations in the atlantoaxial complex of every patient were respected. The hole was tapped through the entire vertebral body, with the exception of osteoporous bone in which only the posterior cortical bone was treated with a screw tap. At this stage profuse bleeding usually arose from dissection around the epidural venous plexus along the C1-C2 joint. This was effectively controlled by a quick insertion of a screw and compression of the venous plexus with the screw head. To control bleeding by bipolar electrocautery is difficult and is always associated with a risk of nerve injury. Screws 3.5 mm thick, with polyaxial heads, were inserted bicortically into the lateral mass of C1. Subsequently, the intervertebral C2-C3 joint was localized and its medial border in the spinal canal was palpated. The entry point for placement of a C2 pedicle screw was marked with an awl at the point of intersection at a distance of 2 mm from the medial border and 5 mm from the caudal border of the C2 articular process. Under an X-ray intensifier in lateral projection, a hole was drilled approximately parallel to the screws inserted in C1, i. e., at an angle of 20 to 30 degrees cranially, up to and through the anterior cortical bone. In the transversal plane, the screws were situated in a convergent direction at an angle of 20 to 25 degrees. After all screws had been inserted, we reduced the antlantoaxial complex in the correct anatomical position by manipulating the patient's head or by directly adjusting the screws. Connecting 3.0-mm rods were then applied and fastened by cap nuts or inner nuts according to the instrumentation used. Operative time ranged from 35 to 155 min, with an average of 81 min. Intra-operative blood loss ranged from 50 to 1500 ml, with an average of 560 ml. The X-ray intensifier was used for a period of 0.4 to 2.6 min, with an average of 0.9 min. A total of 36 screws were inserted in the atlas; their length ranged from 16 to 34 mm (average, 30.6 mm). All screws were positioned correctly in the C1 lateral mass; two screws did not reach up to the anterior cortical bone and one protruded over it, but without causing clinical problems. Thirty-six screws were inserted in the axis. Their length ranged from 28 to 36 mm (average, 31.7) mm). Twenty-seven screws were correctly applied through the isthmus into the C2 anterior cortical bone, three were too short to reach it and five were placed too close to the vertebral artery canal. Of these, two protruded into the artery canal, but without clinical consequences. One screw inserted too medially passed into the spinal canal, but this also was without clinical response. Of the 36 screws inserted in C2, three (8.3 %) were malpositioned. Bony fusion at C1-C2 was the goal of this operation in 14 patients. At 6 weeks post-operatively, it was achieved in two patients, at 12 weeks in 12 patients and at 6 months in all 14 patients. The C1-C2 segment was stable at 12 weeks in all 18 treated patients. Four patients reported restriction of motion in rotation by 10 to 25 % after removal of the instrumentation. Operative time, longer at the beginning than with the Magerl technique, gradually shortened to between 45 and 60 min. Similar trends were seen when intra-operative blood loss and X-ray exposure were evaluated. Using the Harms and Melcher procedure we saved the greater suboccipital nerve. In contrast to these authors, however, we did not resect the atlantoaxial joint. Solid fusion was achieved in all our patients. Of the total of 72 screws inserted, only three (4.2 %) were assessed as malpositioned; however, when related to the 36 screws inserted in C2, this was 8.3 %, which indicates that insertion of screws in C2 was more difficult. We did not observe any clinical consequences in any of these cases. The Harms fixation of C1-C2 is a very effective technique for stabilizing the atlantoaxial complex. It enables us to provide temporary fixation without damage to atlantoaxial joints and to reduce the vertebrae after the screws and rods had been inserted, which is unique. These advantages compensate for a higher cost of the implant.


A Scoping Review of Different Ways of Thinking in Children.
Despite the growing interest in differences in thinking, much less is known about differences in how children think and how they come to think. The aim of this scoping review is to map out the key concepts underpinning the conceptual boundaries of children's (5⁻12 years of age) individual differences in thinking. The scoping review identified eight papers for analysis; all of which were set in an educational context. The findings presented inconclusive results regarding learning and thinking differences related to students' academic achievement. This review has identified two main drawbacks with this research area. Firstly, there is little consensus between the models employed to understand the different ways children think. To further place these findings into context we look at conceptualisations of individual differences, where individuality is considered a process of stable characteristics interacting with more dynamic structures. This analysis highlights the second drawback, previous research has solely focused on exploring thinking characteristics that are not stable and are therefore subject to change depending on the context. The review found that there is little to no research which explores thinking preferences in children that are consistent across contexts and time. Moreover, there was no research identified that explored the impact of differences in thinking outside the educational domain, such as children's wellbeing. Further research is required to identify the more stable characteristics that reflect and capture children's different ways of thinking.


Treatment of primary vaginal malignant melanoma and review of previous literature: A case report.
Primary vaginal malignant melanoma is a rare gynecological malignant tumor with high malignancy and poor prognosis. Because of its insidious incidence, it is generally diagnosed in the late stage, and the 5-year survival rate is only 5% to 25%. Due to the rarity of this disease and the limited number of related cases reported in the literature, there is currently no unified standard for its diagnosis and treatment. Therefore, the treatment of this disease has always been a difficult problem in clinical practice. A 56-year-old woman was admitted to our hospital with discomfort in the lower abdomen. The final diagnosis of this patient was vaginal malignant melanoma (T4N1M0). The patient underwent extensive hysterectomy, bilateral adnexectomy, pelvic lymph node resection, and total vaginectomy. Following the surgery, the patient received adjuvant chemotherapy. The patient was followed up regularly. No recurrence or metastasis has been reported to date. The treatment of primary vaginal malignant melanoma is still dominated by surgery, while radiotherapy and chemotherapy are controversial. Immunotherapy and targeted therapy highlight certain advantages in advanced patients, which still need to be verified by large sample studies, We provide a case of postoperative adjuvant chemotherapy for vaginal malignant melanoma. So far, no signs of disease recurrence have been found. As the price of chemotherapy drugs decreases, it is economically convenient and acceptable for most patients, but its effectiveness needs to be observed in large-scale clinical trials.


The surgical management of asymptomatic primary hyperparathyroidism: proceedings of the Fourth International Workshop.
The surgical management of primary hyperparathyroidism (PHPT) has undergone considerable advances over the past two decades. The purpose of this report is to review these advances. This subgroup was constituted by the Steering Committee of the Fourth International Workshop on the Management of Asymptomatic Primary Hyperparathyroidism to address key questions related to the surgical management of PHPT. Data since the last International Workshop were presented and discussed in detail. The topics included improvements in preoperative imaging, intraoperative adjuncts, refinements in local and regional anesthesia, and rapid intraoperative PTH assays. Questions were developed by the International Task Force on PHPT. A comprehensive literature search for relevant studies was undertaken. After extensive review and discussion, the subgroup agreed on what recommendations should be made to the Expert Panel regarding surgical approaches to parathyroidectomy. 1) All patients with PHPT who meet surgical criteria should be referred to an experienced endocrine surgeon to discuss the risks, benefits, and potential complications of surgery. 2) Patients who do not meet surgical criteria and in whom there are no medical contraindications to surgery may request a visit with an experienced endocrine surgeon. Alternatively, a multidisciplinary endocrine conference with surgeon involvement could be employed to address all relevant issues. 3) Imaging is not a diagnostic procedure; it is a localization procedure to help the surgeon optimize the operative plan. 4) The frequency of hereditary forms of PHPT may be underappreciated and needs to be assessed with increased vigilance. And 5) surgery is likely to benefit patients due to high cure rates, low complication rates, and the likelihood of reversing skeletal manifestations.


Recruitment of Scc2/4 to double-strand breaks depends on γH2A and DNA end resection.
Homologous recombination enables cells to overcome the threat of DNA double-strand breaks (DSBs), allowing for repair without the loss of genetic information. Central to the homologous recombination repair process is the de novo loading of cohesin around a DSB by its loader complex Scc2/4. Although cohesin's DSB accumulation has been explored in numerous studies, the prerequisites for Scc2/4 recruitment during the repair process are still elusive. To address this question, we combine chromatin immunoprecipitation-qPCR with a site-specific DSB in vivo, in Saccharomyces cerevisiae We find that Scc2 DSB recruitment relies on γH2A and Tel1, but as opposed to cohesin, not on Mec1. We further show that the binding of Scc2, which emanates from the break site, depends on and coincides with DNA end resection. Absence of chromatin remodeling at the DSB affects Scc2 binding and DNA end resection to a comparable degree, further indicating the latter to be a major driver for Scc2 recruitment. Our results shed light on the intricate DSB repair cascade leading to the recruitment of Scc2/4 and subsequent loading of cohesin.


[Age limitation to lung transplant recipients. Ethical aspects].
We present a review of bioethical aspects of limiting patients 65 years or older to lung transplantation. Lung transplantation is a therapeutic option in patients with severe advanced respiratory diseases, progressive despite medical treatment to prolong the expected survival. It is an aggressive surgical treatment, and the patient must complete a lifelong immunosuppressive treatment. Given the donor shortage, access to this treatment is regulated by organ transplant societies, which develop patient selection guidelines. One contraindication to transplantation has been the age of 65 years, sustained by the poor results of older patients and following utilitarian bioethics concept. For the time being there is no unified selection criteria to identify older patients susceptible to have a worse outcome after transplantation. Applying a personalist bioethics, we propose to use selection criteria based on frailty scales to identify those frail patients more likely to die after the transplant procedure.


Trends in Formulation Approaches for Sustained Drug Delivery to the Posterior Segment of the Eye.
The eye, an intricate organ comprising physical and physiological barriers, poses a significant challenge for ophthalmic physicians seeking to treat serious ocular diseases affecting the posterior segment, such as age-related macular degeneration (AMD) and diabetic retinopathy (DR). Despite extensive efforts, the delivery of therapeutic drugs to the rear part of the eye remains an unresolved issue. This comprehensive review delves into conventional and innovative formulation strategies for drug delivery to the posterior segment of the eye. By utilizing alternative nanoformulation approaches such as liposomes, nanoparticles, and microneedle patches, researchers and clinicians can overcome the limitations of conventional eye drops and achieve more effective drug delivery to the posterior segment of the eye. These innovative strategies offer improved drug penetration, prolonged residence time, and controlled release, enhancing therapeutic outcomes for ocular diseases. Moreover, this article explores recently approved delivery systems that leverage diverse polymer technologies, such as chitosan and hyaluronic acid, to regulate drug-controlled release over an extended period. By offering a comprehensive understanding of the available formulation strategies, this review aims to empower researchers and clinicians in their pursuit of developing highly effective treatments for posterior-segment ocular diseases.


Development of a method for concentration of rotavirus and its application to recovery of rotaviruses from estuarine waters.
As part of our studies on the ecology of human enteric viruses, an improved method for detection of rotaviruses in water was developed, and their presence in Galveston Bay was monitored. Samples (378 liters) of estuarine water adjusted to pH 3.5 and a final AlCl3 molarity of 0.001 were filtered through 25-cm pleated cartridge-type filters (Filterite Corp., Timonium, Md.) of 3.0- and 0.45-micron porosity. Adsorbed virus was eluted with 1 liter of 10% tryptose phosphate broth, pH 9.5. Primary eluates were reconcentrated to a final volume of 10 to 20 ml by a simple and rapid magnetic iron oxide adsorption and elution procedure. Two percent casein at pH 8.5 effectively eluted rotavirus from iron oxide. A total of 21 of 72 samples of water, suspended solids, fluffy sediments, and compact sediments collected in different seasons in Galveston Bay yielded rotaviruses. Recovery of rotaviruses varied from 119 to 1,000 PFU/378 liters of water, 1,200 PFU/1,000 g of compact sediment, 800 to 3,800 PFU/378 liters of fluffy sediment, and 1,800 to 4,980 PFU from suspended solids derived from 378 liters of water based on immunofluorescent foci counts on cover slip cultures of fetal monkey kidney cells.


Identification of LEM-14 inhibitor of the oncoprotein NSD2.
The NSD family (NSD1, NSD2/MMSET/WHSC1, and NSD3/WHSC1L1) are histone lysine methyltransferases (HMTases) essential for chromatin regulation. The NSDs are oncoproteins, drivers of a number of tumors and are considered important drug-targets but the lack of potent and selective inhibitors hampers further therapeutic development and limits exploration of their biology. In particular, MMSET/NSD2 selective inhibition is being pursued for therapeutic interventions against multiple myeloma (MM) cases, especially in multiple myeloma t(4;14)(p16.3;q32) translocation that is associated with a significantly worse prognosis than other MM subgroups. Multiple myeloma is the second most common hematological malignancy, after non-Hodgkin lymphoma and remains an incurable malignancy. Here we report the discovery of LEM-14, an NSD2 specific inhibitor with an in vitro IC50 of 132 μM and that is inactive against the closely related NSD1 and NSD3. LEM-14-1189, a LEM-14 derivative, differentially inhibits the NSDs with in vitro IC50 of 418 μM (NSD1), IC50 of 111 μM (NSD2) and IC50 of 60 μM (NSD3). We propose LEM-14 and derivative LEM-14-1189 as tools for studying the biology of the NSDs and constitute meaningful steps toward potent NSDs therapeutic inhibitors.


Clusters of premenstrual symptoms in women with PMDD: Appearance, stability and association with impairment.
Although premenstrual dysphoric disorder (PMDD) is assumed to be a homogenous diagnostic entity, it is hallmarked by highly diverse clinical symptoms. In this study, we investigate symptom clusters in women prospectively diagnosed with severe premenstrual syndrome (PMS) or PMDD using factor analysis; analyze the stability of the structures of different symptom patterns and their association with impairment at work, in recreation, and in relationships. A total of 174 prospective symptom diaries were analyzed with principal axis factoring revealing six clusters named affective dysphoria, somatic dysphoria, irritability, breast/body sensitivity, pain, and eating behavior. Cronbach's alpha was good for all clusters (0.83 to 0.91) with the exception of the cluster pain (0.69). Clusters of symptoms appeared to be stable between two consecutive menstrual cycles (except of pain and eating behavior) and between two cycles with a waiting period of eight weeks in between. Multiple regression analyses showed different associations of the clusters with impairment. Somatic dysphoria was the cluster most strongly associated with impairment. The results indicate that in severe PMS/PMDD, different symptom patterns should be considered. As the risk of impairment differs between symptom clusters, individual treatment options should be considered and further investigated in research and treatment.


Alzheimer's disease-related misfolded proteins and dysfunctional organelles on autophagy menu.
Autophagy is a housekeeping process responsible for the bulk degradation of misfolded protein aggregates and damaged organelles through the lysosomal machinery. Given its key role as a cellular quality control mechanism, autophagy is now a focus of intense scrutiny in Alzheimer's disease (AD). The hallmarks of this devastating neurodegenerative disease are the accumulation of misfolded amyloid-β (Aβ) peptide and hyperphosphorylated tau protein and neuronal loss, which are accompanied by mitochondrial dysfunction and endoplasmic reticulum (ER) stress, suggesting that faulty autophagy is a contributing factor to AD pathology. Indeed, the AD brain is characterized by a massive accumulation of autophagic vacuoles within large swellings along dystrophic neurites and defects at different steps of the autophagic-lysosomal pathway. In this sense, this review provides an overview on the role of autophagy on Aβ metabolism, tau processing and clearance, and the contribution of ER-phagy and mitophagy to AD pathology. From a therapeutic perspective, this review also intends to clarify whether, when, and how autophagy can be targeted to efficaciously counteract AD-related symptomatic and neuropathological features.


Requirement for scleraxis in the recruitment of mesenchymal progenitors during embryonic tendon elongation.
The transcription factor scleraxis (Scx) is required for tendon development; however, the function of Scx is not fully understood. Although Scx is expressed by all tendon progenitors and cells, only long tendons are disrupted in the Scx-/- mutant; short tendons appear normal and the ability of muscle to attach to skeleton is not affected. We recently demonstrated that long tendons are formed in two stages: first, by muscle anchoring to skeleton via a short tendon anlage; and second, by rapid elongation of the tendon in parallel with skeletal growth. Through lineage tracing, we extend these observations to all long tendons and show that tendon elongation is fueled by recruitment of new mesenchymal progenitors. Conditional loss of Scx in mesenchymal progenitors did not affect the first stage of anchoring; however, new cells were not recruited during elongation and long tendon formation was impaired. Interestingly, for tenocyte recruitment, Scx expression was required only in the recruited cells and not in the recruiting tendon. The phenotype of Scx mutants can thus be understood as a failure of tendon cell recruitment during tendon elongation.


Microdilution susceptibility testing of amphotericin B, itraconazole, and voriconazole against clinical isolates of Aspergillus and Fusarium species.
We compared the activities of amphotericin B, itraconazole, and voriconazole against clinical Aspergillus (n = 82) and Fusarium (n = 22) isolates by a microdilution method adopted from the National Committee for Clinical Laboratory Standards (NCCLS-M27A). RPMI 1640 (RPMI), RPMI 1640 supplemented to 2% glucose (RPMI-2), and antibiotic medium 3 supplemented to 2% glucose (AM3) were used as test media. MICs were determined after 24, 48, and 72 h. A narrow range of amphotericin B MICs was observed for Aspergillus isolates, with minor variations among species. MICs for Fusarium isolates were higher than those for Aspergillus isolates. MICs of itraconazole were prominently high for two previously defined itraconazole-resistant Aspergillus fumigatus isolates and Fusarium solani. Voriconazole showed good in vitro activity against itraconazole-resistant isolates, but the MICs of voriconazole for F. solani were high. RPMI was the most efficient medium for detection of itraconazole-resistant isolates, followed by RPMI-2. While the significance remains unclear, AM3 lowered the MICs, particularly those of amphotericin B.


Nuclear transport in 3T3 fibroblasts: effects of growth factors, transformation, and cell shape.
Nucleocytoplasmic transport of fluorescent-labeled macromolecules was investigated in transformed and nontransformed 3T3 fibroblasts. Insulin and epidermal growth factor enhanced transport three-fold after 1-2-h incubation with nontransformed adhering fibroblasts; no enhancement of transport was observed for spherical unattached fibroblasts. The concentration of growth factor for maximal enhancement was 3-10 nM. Nuclear transport for Kirsten murine sarcoma virus-transformed BALB/c 3T3 fibroblasts, however, was maximally enhanced before addition of growth factors; addition of insulin or epidermal growth factor causes no additional transport enhancement. Transformation also minimizes cell shape effects on macromolecular nuclear transport. These results provide evidence that protein growth factors and oncogenic transformation may use a similar mechanism for activation of nuclear transport.


[Current possibilities in immunotherapy of cancer].
Recent developments in biotechnology have resulted in a substantial renewal of cancer immunotherapy. In particular, the availability of murine monoclonal antibodies and recombinant biological response modifiers by genetic manipulation has made it possible to re-test abandoned concepts of adoptive humoral and cellular immunotherapy and to reconsider the biomodulation of the patient's immune system. Thus, the utilization of monoclonal antibodies to purge ex vivo autologous marrow from residual tumor cells has reached an advanced stage of clinical investigation in the field of autologous bone marrow transplantation for leukemia or lymphoma. Numerous promising clinical trials are being performed by the injection of monoclonal antibodies directed at tumor-associated antigens, coupled with cytotoxic agents (isotopes, drugs, toxins). In the area of recombinant technology, interferon-alpha has become the drug of choice for a particular form of chronic leukemia (hairy-cell leukemia). Interleukin-2 administered in conjunction with autologous activated lymphocytes has been shown to mediate significant anti-tumor activity in metastatic cancer patients. This review briefly describes recent clinical results obtained in cancer immunotherapy and discusses the potential of these new approaches.


[Morphologic changes in popliteal lymph nodes subjected local irradiation with low energy red laser].
Changes of morphological parameters of relative area of structural components on histological section, submicroscopic peculiarities of cells from regional and contralateral popliteal lymph nodes (LN) of albino rats were found to correlate with the dose of irradiation of low power laser (LPL) (3-30.0 J/cm2). It was proven that 3.0 J/cm2 irradiation stimulates LN. It is essential that local action of LPL causes similar reaction in the contralateral right popliteal LN, which indicates systemic reaction of the immune system to this physical factor.


MDM2 E3 ubiquitin ligase mediates UT-A1 urea transporter ubiquitination and degradation.
UT-A1 is the primary urea transporter in the apical plasma membrane responsible for urea reabsorption in the inner medullary collecting duct. Although the physiological function of UT-A1 has been well established, the molecular mechanisms that regulate its activity are less well understood. Analysis of the UT-A1 amino acid sequence revealed a potential MDM2 E3 ubiquitin ligase-binding motif in the large intracellular loop of UT-A1, suggesting that UT-A1 urea transporter protein may be regulated by the ubiquitin-proteasome pathway. Here, we report that UT-A1 is ubiquitinated and degraded by the proteasome but not the lysosome proteolytic pathway. Inhibition of proteasome activity causes UT-A1 cell surface accumulation and concomitantly increases urea transport activity. UT-A1 interacts directly with MDM2; the binding site is located in the NH2-terminal p53-binding region of MDM2. MDM2 mediates UT-A1 ubiquitination both in vivo and in vitro. Overexpression of MDM2 promotes UT-A1 degradation. The mechanism is likely to be physiologically important as UT-A1 ubiquitination was identified in kidney inner medullary tissue. The ubiquitin-proteasome degradation pathway provides an important novel mechanism for UT-A1 regulation.


Effects of the peripheral layers on the optical properties of spherical fish lenses.
We created a computational optical model of spherical fish lenses that takes into account the effects of the peripheral layers, which differ in cellular composition from the bulk of the lens. A constant refractive index, except for the lens capsule, in the outer about 6% of lens radius made it possible to uniquely infer the refractive index gradient in more central layers from a known or desired longitudinal spherical aberration curve using the inverse Abel transform. Since the zone of constant refractive index is wider than necessary to make the solution unique and for optimal optical performance of the lens, we propose that its width be set by the metabolic needs of the lens.


Optoelectronics and Nanophotonics of Vapor-Liquid-Solid Grown GaSe van der Waals Nanoribbons.
2D/layered semiconductors are of interest for fundamental studies and for applications in optoelectronics and photonics. Work to date focused on extended crystals, produced by exfoliation or growth and investigated by diffraction-limited spectroscopy. Processes such as vapor-liquid-solid (VLS) growth carry potential for mass-producing nanostructured van der Waals semiconductors with exceptionally high crystal quality and optoelectronic/photonic properties at least on par with those of extended flakes. Here, we demonstrate the synthesis, structure, morphology, and optoelectronics/photonics of GaSe van der Waals nanoribbons obtained by Au- and Ag-catalyzed VLS growth. Although all GaSe ribbons are high-quality basal-plane oriented single crystals, those grown at lower temperatures stand out with their remarkably uniform morphology and low edge roughness. Photoluminescence spectroscopy shows intense, narrow light emission at the GaSe bandgap energy. Nanophotonic experiments demonstrate traveling waveguide modes at visible/near-infrared energies and illustrate approaches for locally exciting and probing such photonic modes by cathodoluminescence in transmission electron microscopy.


Feeding behavior analysis of the soybean aphid (Hemiptera: Aphididae) on resistant soybean 'Dowling'.
Soybean aphid, Aphis glycines Matsumura (Hemiptera: Aphididae), is an exotic pest of soybean, Glycine max (L.) Merr., in North America. Plant resistance to the soybean aphid was recently discovered in 'Dowling' soybean in 2005. Dowling exhibits strong antibiotic effects on the soybean aphid by limiting colonization and effectively controlling aphid population development during all soybean growth stages. In addition, aphids feeding on Dowling experienced significantly reduced survival, longevity, and fecundity and increased developmental times. An assessment of soybean aphid feeding behavior was compared on Dowling and the susceptible check 'Glenwood' by using the electrical penetration graph technique. The effects of plant resistance on aphid feeding behavior were analyzed by comparing the amount of time soybean aphid spent feeding on various plant tissues on resistant and susceptible plants. There was no significant difference in the initial time for the aphid to begin probing on resistant and susceptible plants indicating no adverse effect of plant exterior on the soybean aphid attempting to feed. However the time from the beginning of plant penetration by the stylets to the first phloem sieve element phase was significantly different. In aphids that successfully reached phloem on Dowling, the time taken to reach this phase was triple the time of aphids reaching the phloem sieve element on the susceptible line. In addition, the total number of probing events and the duration of nonprobing were not significantly different between Dowling and Glenwood. When comparing feeding between lines, a greater proportion of aphids showed ingestion of xylem when feeding on Dowling, whereas successful feeding on phloem on Dowling was significantly shorter than when feeding on the susceptible line. Therefore, the antibiotic effect of Dowling resistance seems to reside at the level of the phloem sieve element, prohibiting the aphid from successfully exploiting phloem, and as a consequence the aphid abandons the Dowling plant or dies of inadequate nutritional intake.


Bone repair using mineral trioxide aggregate combined to a material carrier, associated or not with calcium hydroxide in bone defects.
Mineral trioxide aggregate (MTA) is a powder aggregate containing mineral oxides with a good biological action and may facilitate the regeneration of the periodontal ligament and formation of bone. Calcium hydroxide demonstrates antibacterial properties, enhances tissue dissolution, and induces bone formation. The objective of this study was to evaluate the MTA in the bone healing process and verify if the calcium hydroxide P.A. can improve and accelerate this process. It was used forty male Wistar rats, which were divided into two groups, considering or not the use of calcium hydroxide P.A. solution before treatment. Thus, each one of these groups was divided in four groups with five animals each, according to the treatment and the defect filled by: animal's coagulum, monoolein gel, MTA in aqueous solution, and MTA combined with monoolein gel. After 10 days, the animals were perfused and the right hemimandibles removed for histological analysis. Statistical analysis of the data showed significant difference between all analyzed groups when it was made comparisons using or not calcium hydroxide P.A. (p<0.0001). There was found statistical difference between the groups that was inserted or not MTA, independently the calcium hydroxide application (p<0.05). Results showed that the MTA used was able to induce bone regeneration and had its action optimized when combined to calcium hydroxide P.A.


The prognostic factors for clinical N1b patients in thyroid papillary carcinoma.
The aim of this study is to determine the prognostic factors which affect both disease-free survival (DFS) and overall survival (OS) in thyroid papillary carcinoma with clinical lateral lymph node metastasis. One hundred and three papillary thyroid carcinomas diagnosed in adult patients received therapeutic lateral neck dissection between December 1989 and June 2010 were analyzed retrospectively. All of the patients were classified as American Thyroid Association (ATA) intermediate risk category. Age, gender, tumor stage and size, multicentricity and bilaterality, vascular invasion and extrathyroidal invasion, ipsilateral/contralateral lymph node involvement, lymph node ratio, extranodal tumor extension, and development of recurrence were the factors which might affect disease-free and OS. Univariate and multivariate analyses were performed. ROC analysis was used to find the cutoff value for lymph node ratio. One hundred and three patients were followed median 101 months. Locoregional or systemic recurrence developed in 20 patients (19.4%) while 7 patients (6.8%) had persistent disease. In multivariate analysis, lymph node ratio (P = 0.003, relative risk [RR] 5.4, 95% confident interval [CI] 1.7-16.5) and contralateral lymph node involvement (P = 0.02, RR 4.9, 95% CI 1.3-18.5) were the independent factors affecting DFS where contralateral lymph node involvement (P = 0.009, RR 44.4, 95% CI 2.5-765.2) was the only factor which affected OS. Lymph node ratio and contralateral metastasis affect DFS while contralateral metastases only affect OS in patients with N1b thyroid papillary carcinoma.


High incidence of discrepancies in new Siemens assay - a comparison of cardiac troponin I assays.
Cardiac troponin (cTn) is the biochemical gold standard for diagnosing myocardial infarction (MI). We compared the Siemens ADVIA Centaur High-Sensitivity (hs-cTnI) assay with the Siemens Ultra assay (cTnI-U). Over 3 months cTnI-U and hs-cTnI were measured simultaneously at Herlev-Gentofte Hospital. Acute myocardial injury was diagnosed using the 4th universal definition. Disputed cases were adjudicated using clinical data. We compared diagnostic accuracy using area under the curve (AUC) of the receiver operating characteristic. Outliers in between-assay differences were defined as a factor-5 difference and ≥1 measurement >40 ng/L. Patients with outlier differences were invited for re-sampling and tested with serial dilution and heterophilic blocking tubes. From the 18th January to the 20th April 2019, 4,369 samples on 2,658 patients were included. cTnI-U measured higher concentrations than hs-cTnI (mean 23%, -52-213%), resulting in a higher frequency of acute myocardial injury, 255 (9.6%) vs. 203 (7.6%), p<0.001. This remained significant after adjudication, 212 vs 197, p<0.001. AUC for the prediction of MI for was 0.963 for cTnI-U and 0.959 for hs-cTnI, p=0.001. Outlier differences were seen in 35 (1.2%) patients, primarily with elevated hs-cTnI (n=33, 94%). On two re-samplings (median 144 and 297 days since inclusion), 16 of 20 (80%) and 11 of 11 had sustained elevation of hs-cTnI. The samples showed no signs of heterophilic antibodies. Using hs-cTnI resulted in a subset of patients with large, discrepant elevations in concentration. These patients still had elevated hs-cTnI 6-10 months post admission but no heterophilic antibodies.


Sagittal Radiographic Parameters of the Spine in Three Physiological Postures Characterized Using a Slot Scanner and Their Potential Implications on Spinal Weight-Bearing Properties.
Prospective radiographic comparative study. To compare and understand the load-bearing properties of each functional spinal unit (FSU) using three commonly assumed, physiological, spinal postures, namely, the flexed (slump sitting), erect (standing) and extended (backward bending) postures. Sagittal spinal alignment is posture-dependent and influences the load-bearing properties of the spine. The routine placement of intervertebral cages "as anterior as possible" to correct deformity may compromise the load-bearing capabilities of the spine, leading to complications. We recruited young patients with nonspecific low back pain for <3 months, who were otherwise healthy. Each patient had EOS images taken in the flexed, erect and extended positions, in random order, as well as magnetic resonance imaging to assess for disk degeneration. Angular and disk height measurements were performed and compared in all three postures using paired t-tests. Changes in disk height relative to the erect posture were caclulated to determine the alignment-specific load-bearing area of each FSU. Eighty-three patients (415 lumbar intervertebral disks) were studied. Significant alignment changes were found between all three postures at L1/2, and only between erect and flexion at the other FSUs. Disk height measurements showed that the neutral axis of the spine, marked by zones where disk heights did not change, varied between postures and was level specific. The load-bearing areas were also found to be more anterior in flexion and more posterior in extension, with the erect spine resembling the extended spine to a greater extent. Load-bearing areas of the lumbar spine are sagittal alignment-specific and level-specific. This may imply that, depending on the surgical realignment strategy, attention should be paid not just to placing an intervertebral cage "as anterior as possible" for generating lordosis, but also on optimizing load-bearing in the lumbar spine.


Practice-Based Longitudinal Study of Multifactorial Risk Assessment for Periodontal Condition and Survival of Remaining Teeth in Patients with Removable Partial Dentures.
This retrospective cohort study examined factors affecting the periodontal condition and survival of remaining teeth 5 years after removable partial denture (RPD) placement using multivariate analyses. Of 231 patients who received RPDs at Tohoku University Hospital, 108 patients who had agreed to undergo a 5-year follow-up were examined. The outcomes of RPD treatment were assigned to one of three categories: successful (n = 58), remake (n = 36), and failure (n = 14). A total of 80 patients in the successful and remake groups were included in this study. The parameters analyzed to evaluate the periodontal condition were probing depth, Miller index of tooth mobility, and bone resorption level. Criterion variables were the outcome of each periodontal condition, deterioration, and tooth loss. Independent variables were sex, age, smoking habit, number of periodic maintenance appointments, location of RPD, number of abutment teeth, denture base material, design, and existence of a denture in the opposite jaw. Bivariate analyses were performed using chi-square test, and multivariate regression analysis was used to assess significance. Sex and frequency of maintenance care were independently associated with deterioration of the periodontal condition. Sex and existence of a denture in the opposite jaw were independently associated with tooth loss. The findings suggest that periodic maintenance care and condition of the opposite jaw are essential for maintaining the condition of the remaining teeth.


Aberrant laminin beta3 isoforms downstream of EWS-ETS fusion genes in Ewing family tumors.
Ewing family tumors (EFTs) are associated with a chromosomal translocation resulting in a fusion of the amino-terminus of EWS with the DNA-binding domain of an ETS transcription factor. Although previous reports suggested that these chimeric proteins would act as aberrant transcription factors, their downstream targets have not been fully elucidated. To identify downstream targets of these EWS-ETS fusion proteins, we introduced EWS-ETS fusion constructs into a human fibrosarcoma cell line, HT-1080, by retroviral transduction. Here we report that the LAMB3 gene encoding the beta3 chain of basement membrane protein laminin-5 is induced to a significantly higher level in cells expressing EWS-ETSs than in cells expressing normal ETSs. Additionally through use of an antisense oligonucleotide for EWS-ERG in the W-ES EFT cell line, laminin beta3 protein was reduced coordinately with EWS-ERG fusion protein expression. Furthermore, we found small mRNAs were preferentially transcribed from the LAMB3 gene in EFT cell lines. Molecular cloning of the entire coding region shows that the alternative transcripts from different promoter(s) located within the intron 14, which encode small proteins, likely are major products of the LAMB3 gene in EFT cells. We show that the small isoforms conferred increased anchorage-independent proliferation to NIH3T3 cells. Together with previous studies showing that laminin-5 is involved in the invasive and malignant phenotype of several tumor types, our data suggest that the oncogenic effect of EWS-ETS may be mediated in part by upregulation of LAMB3 expression.


Quasicontinuous-Variable Quantum Computation with Collective Spins in Multipath Interferometers.
Collective spins of large atomic samples trapped inside optical resonators can carry quantum information that can be processed in a way similar to quantum computation with continuous variables. It is shown here that by combining the resonators in multipath interferometers one can realize coupling between different samples, and that polynomial Hamiltonians can be constructed by repeated spin rotations and twisting induced by dispersive interaction of the atoms with light. Application can be expected in the efficient simulation of quantum systems.


[Hygienic evaluation of women's work in radio-manufacturing industry].
Conditions and character of labour of women working in revolver production are determined by exposure to noise, contact with cooling oils, static field, monotony, hypodynamics, tension of the visual analyser, which leads to the stress of the functional systems of the organism, development of fatigue, decrease in labour productivity, increased morbidity level with temporary loss of capacity for work. A complex of health-improving measures on normalization of occupational factors, rationalization of labour and rest regimen, implementation of which would promote increase in the capacity for work of women engaged in revolver production.


SITS-sensitive Cl- conductance pathway in chick intestinal cells.
The unidirectional influx of 36Cl- into isolated chick epithelial cells is 30% inhibited by 300 microM SITS. Characteristics of the SITS-sensitive flux pathway were examined in terms of sensitivity to changes in membrane potential and intracellular pH. Potential dependence was evaluated using unidirectional influx of [14C]tetraphenylphosphonium ([14C]-TPP+) as a qualitative sensor of diffusion potentials created by experimentally imposed gradients of Cl-. Steady-state distribution of [14C]methylamine ([14C]MA) was used to examine for Cl(-)-dependent changes in intracellular pH. Imposed Na+ gradients, but not Cl- gradients, induce changes in [14C]MA distribution. SITS does not alter the [14C]MA distribution observed in cells with imposed gradients of Na+ and Cl-. Both results suggest that inhibition of Cl(-)-OH- exchange system is not the basis for the SITS effect on Cl- influx. However, if relative permeabilities for ion pairs via conductance pathways are compared, it can be shown that SITS causes a marked reduction of Pcl relative to either PNa or PK. SITS also inhibits electrically induced influx of [14C]TPP+ or [14C] alpha-methylglucoside driven by imposed Cl- gradients. Conversely, electrically driven Cl- influx can be blocked by SITS. These observations are all consistent with a SITS-sensitive Cl- conductance pathway associated with the plasma membrane of chick intestinal cells. No Cl(-)-OH- exchange capability can be detected for chick intestinal cells.


Effect of intraoperative radiation on the tensile strength of small bowel anastomoses.
Increasing interest in the use of preoperative or intraoperative radiation therapy for cancer has led to concerns regarding tissue healing and integrity subsequent to treatment. This is especially so for intestinal anastomoses incorporating irradiated bowel, where poor healing may lead to anastomotic disruption and sepsis. One hundred thirty Sprague-Dawley rats were randomized into five groups as follows: both limbs, one limb, or neither limb of an anastomosis received 2,000 R of radiation intraoperatively. A fourth group had a segment of small bowel irradiated, with no anastomosis; a fifth group had the gut exposed by celiotomy. The control groups and all anastomoses underwent tensile strength measurements on the seventh postoperative day, with findings as follows: no anastomosis, no irradiation, 143.75 g; no anastomosis, irradiated, 114.50 g; anastomosis, no irradiation, 85.273 g; anastomosis, one limb irradiated, 78.100 g; anastomosis, both limbs irradiated, 59.00 g. There was no statistical difference in tensile strength of the anastomosis between when neither limb and when just one limb was irradiated. However, when both limbs were irradiated, the loss of strength was statistically significant (P = 0.002). Irradiation damage scores were assigned using Black et al.'s histologic scoring system. These scores were not significantly different between the irradiated segments. Inflammation and fibrosis scores for the anastomoses were also not significantly different. These results indicate that, in rats, anastomotic healing is impaired only when both limbs of the anastomosed intestine are irradiated. The normal strength of the anastomosis with only one limb irradiated cannot be explained by differences in inflammation, fibrosis, or radiation damage and is caused by an undetermined factor.


Nanocrystal formulations of a poorly soluble drug. 2. Evaluation of nanocrystal liver uptake and distribution after intravenous administration to mice.
A stabilized high drug load intravenous formulation could allow compounds with less optimal pharmacokinetic profiles to be developed. Polyethylene glycol (PEG)-ylation is a frequently used strategy for particle delivery systems to avoid the liver, thereby extending blood circulation time. The present work reports the mouse in vivo distribution after i.v. administration of a series of nanocrystals prepared with the bead milling technique and PEG-ylated with DSPE-PEG2000 and Pluronic F127, with and without polyvinylpyrrolidone K30 (PVP)/Aerosol OT (AOT) as primary stabilizers. While all formulations were cleared significantly faster than expected from nanocrystal dissolution alone, purely DSPE-PEG2000 PEG-ylated particles displayed prolonged circulation time (particles elimination half-life of 9min) compared to DSPE-PEG2000/PVP/AOT formulation (half-life of 3min). The two Pluronic F127 stabilized formulations displayed similar half-lives (9min with and without PVP/AOT, respectively). Whole tissue kinetics shows that clearance of particles could be attributed to accumulation in the liver. A separate in vivo study addressed the liver cell distribution after administration. Dissolved compound accumulated in hepatocytes only, while particles were distributed between liver sinusoidal endothelial cells and Kupffer cells. More DSPE-PEG2000/PVP/AOT stabilized particles accumulated in the liver, preferably in Kupffer cells, compared to Pluronic F127/PVP/AOT stabilized particles. The present study extends the understanding of PEG-ylation and "stealth" behaviour to also include nanocrystals.


Retinal pigment epithelial cell-based gene therapy against hemoglobin toxicity.
To determine if overexpression of the human heme oxygenase (HO-1) protects retinal pigment (RPE) cells from hemoglobin toxicity, a human RPE cell line was infected by an adenoviral vector containing the HO-1 (Ad-HO-1) gene or transfected with a plasmid containing the cytomegalovirus promoter and HO-1 cDNA (pRc/CMV-HO-1) complexed to cationic liposomes. Phase contrast microscopy and acid phosphatase activity were examined to insure homogeneity of the cell line. Mitochondrial cytochrome and microsomal heme content were measured in both transduced and control cells. RPE cells were then challenged with hemoglobin and their viability estimated. We determined that cells transfected with Ad HO-1 overexpressed HO-1 compared to control cells: HO-1 mRNA levels were increased 3-fold within 3 days, decreasing in 7 days. In addition, we permanently transfected RPE cells with HO-1 gene. Transfected cell clones selected for neomycin resistance had elevated levels of HO activity 3-fold higher than control. Transfected cells exposed to hemoglobin had a survival rate of 93%; non-transfected cells had a 65-75% rate of survival. Transfected cells overexpressing HO-1 proved highly viable when challenged with hemoglobin. HO-1 appears to be an important component of the cellular anti-oxidant defense mechanisms against hemoglobin toxicity. However, the choice of transient or permanent expression of HO-1 against hemoglobin toxicity and hemorrhage needs to be further evaluated.


Recent trends in pediatric bacterial meningitis in Japan--a country where Haemophilus influenzae type b and Streptococcus pneumoniae conjugated vaccines have just been introduced.
To investigate the trends in incidence and the characteristics of bacterial meningitis in Japan where Haemophilus influenzae type b (Hib) vaccine and 7-valent pneumococcal conjugated vaccine (PCV7) were introduced in 2008 and 2010, respectively, which was 5-20 years after their introduction in western countries. The nationwide Japanese survey of pediatric and neonatal bacterial meningitis was performed in 2011 and 2012. We analyzed the epidemiological and clinical data, and compared the information obtained in the previous nationwide survey database. We also investigated the risk factors for disease outcome. In the 2011-2012 surveys, 357 patients were evaluated. H. influenzae, Streptococcus pneumoniae, Streptococcus agalactiae and Escherichia coli were the main organisms. The number of patients hospitalized with bacterial meningitis per 1000 admissions decreased from 1.31 in 2009 to 0.43 in 2012 (p < 0.001). The incidence of H. influenzae and S. pneumoniae meningitis also decreased from 0.66 to 0.08 (p < 0.001), and 0.30 to 0.06 (p < 0.001), respectively. Only 0-2 cases with Neisseria meningitidis were reported each year throughout 2001-2012. The median patient age was 10-12 months in 2001-2011, and became lower in 2012 (2 month old) (p < 0.001). The fatality rate for S. agalactiae is the highest (5.9% (11/187)) throughout 2001-2012 among the four organisms. Risk factors for death and sequelae were convulsions at onset, low CSF glucose, S. agalactiae etiology, and persistent positive CSF culture. Hib vaccine and PCV7 decreased the rate of bacterial meningitis. Earlier introduction of these vaccines may have prevented bacterial meningitis among Japanese children.


Voltage-dependent calcium channel in the squid axon.
A voltage-dependent inward calcium current insensitive to tetrodotoxin has been measured in internally perfused or dialyzed squid giant axons. Sodium conductance was blocked by tetrodotoxin, and potassium conductance was irreversibly destroyed by the lack of potassium in the external and internal medium. Chloride conductance was eliminated by replacement of chloride with methylsulfonate. The calcium current was activated at about -40 mV and it peaked at about 0 mV. The peak inward current was 3 microA/cm2 when external Ca was 80 mM and 0.9 microA/cm2 in 8 mM Ca. In 80 mM Ca, the calcium current is turned on in less than 10 msec, and it does not decay appreciably for pulses up to 70 msec in duration. Barium can replace calcium, and cadmium blocks the calcium current.


Proteomic analysis on symbiotic differentiation of mitochondria in soybean nodules.
Symbiotic interactions between legume plants and rhizobia induce specific metabolisms and intracellular organelles in nodules. For surveying symbiotic differentiation of a key organelle, mitochondria, protein constituents of soybean nodule and root mitochondria were compared after two-dimensional (2-D) electrophoresis, and the proteins were characterized in combination with matrix-assisted desorption/ionization time-of-flight mass spectrometry, electrospray ionization mass spectrometry and N-terminal amino acid sequencing. Of the proteins that were detected only in nodule mitochondria, phosphoserine aminotransferase, flavanone 3-hydroxylase, coproporphyrinogen III oxidase, one ribonucleoprotein and three unknown proteins were identified. Seven up-regulated, eight down-regulated and two strongly suppressed protein spots in nodule mitochondria were also assigned protein identities. The physiological roles of these differential expressions were discussed in relation to nodule-specific metabolisms in soybean nodules.


American Society of Clinical Oncology/National Comprehensive Cancer Network Quality Measures.
The National Cancer Policy Board recommended the creation of quality measures and a national reporting system in 1999. Representatives from the American Society of Clinical Oncology (ASCO) and the National Comprehensive Cancer Network (NCCN) collaborated to create metrics suitable for national performance measurement. Content and methodology experts nominated by ASCO and NCCN met to select and refine metrics for breast, colon, and rectal cancer based on National Initiative for Cancer Care Quality and NCCN measures and NCCN and ASCO guidelines. Measures were selected based on their impact on disease free and overall survival, the degree to which opportunities for improvement exist, and the feasibility of data collection. Three breast cancer measures and four colorectal cancer measures were chosen. Measures for breast cancer included adjuvant hormone therapy for hormone receptor-positive tumors, chemotherapy for hormone receptor-negative cancer, and radiation after lumpectomy. Colorectal measures included adjuvant radiation and chemotherapy for rectal cancer, and adjuvant chemotherapy for colon cancer. All but one were recommended as accountability measures and one for quality improvement (removal and examination of 12 or more lymph nodes in colon cancer). Specifications were developed for each measure using tumor registries as the data source. ASCO/NCCN measures can be implemented by health systems, provider groups or payors for improvement or accountability using local tumor registries to furnish data on staging and treatment.


Morphological and functional changes in the preweaning basolateral amygdala induced by early chronic stress associate with anxiety and fear behavior in adult male, but not female rats.
Suboptimal maternal care is a form of chronic early-life stress (ELS) and a risk factor for mental illness and behavioral impairments throughout the life span. The amygdala, particularly the basolateral amygdala (BLA), exhibits exquisite sensitivity to ELS and could promote dysregulation of stress reactivity and anxiety-related disorders. While ELS has profound impacts on the adult or adolescent amygdala, less is known regarding the sensitivity of the preweaning BLA to ELS. We employed a naturalistic rodent model of chronic ELS that limits the amount of bedding/nesting material (LB) available to the mother between postnatal day (PND) 1-9 and examined the morphological and functional effects in the preweaning BLA on PND10 and 18-22. BLA neurons displayed dendritic hypertrophy and increased spine numbers in male, but not female, LB pups already by PND10 and BLA volume tended to increase after LB exposure in preweaning rats, suggesting an accelerated and long-lasting recruitment of the amygdala. Morphological changes seen in male LB pups were paralleled with increased evoked synaptic responses recorded from BLA neurons in vitro, suggesting enhanced excitatory inputs to these neurons. Interestingly, morphological and functional changes in the preweaning BLA were not associated with basal hypercorticosteronemia or enhanced stress responsiveness in LB pups, perhaps due to a differential sensitivity of the neuroendocrine stress axis to the effects of LB exposure. Early changes in the synaptic organization and excitability of the neonatal amygdala might contribute to the increased anxiety-like and fear behavior observed in adulthood, specifically in male offspring.


Placing death and dying: Making place at the end of life.
Over the last decade, policies in both the UK and many other countries have promoted the opportunity for patients at the end of life to be able to choose where to die. Central to this is the expectation that in most instances people would prefer to die at home, where they are more likely to feel most comfortable and less medicalised. In so doing, recording the preferred place of death and reducing the number of hospital deaths have become common measures of the overall quality of end of life care. We argue that as a consequence, what constitutes a desired or appropriate place is routinely defined in a very simple and static 'geographical' way, that is linked to conceptualising death as an unambiguous and discrete event that happens at a precise moment in time in a specific location. In contrast, we draw on 18 months of ethnographic fieldwork with two inner-London palliative care teams to describe the continual work staff do to make places suitable and appropriate for the processes of dying, rather than for a singular event. In this way, instead of 'place of death' merely defined in geographic terms, the palliative care staff attend to the much more dynamic relation between a patient and their location as they approach the end of their life. Central to this is an emphasis on dying as an open-ended process, and correspondingly place as a social space that reflects, and interacts with, living persons. We propose the term 'placing work' to capture these ongoing efforts as a patient's surroundings are continually altered and adjusted over time, and as a way to acknowledge this as a significant feature of the care given.


Ventilator withdrawal: procedures and outcomes. Report of a collaboration between a critical care division and a palliative care service.
To describe an institutional procedure for ventilator withdrawal and to analyze patient responses to terminal extubation, the medical records of 21 patients who underwent withdrawal of mechanical ventilation according to the process followed by an interdisciplinary palliative care team were retrospectively reviewed. The cohort was a convenience sample of sequentially treated patients in a 1048-bed urban university-affiliated medical center. Sixteen of the 21 patients were on medical or surgical floors and five patients were in critical care units. Patients were assessed for discomfort, such as dyspnea, agitation, or anxiety. Sedative and analgesic medications were administered based on clinical parameters. Palliative care clinician observations of patient reports, tachypnea,use of accessory muscles, and signs of discomfort such as agitation or anxiety were recorded for the first 4 hours after extubation. Medication use and length of survival were recorded. Fifty-seven percent were symptomatic during the extubation process and required administration of either a benzodiazepine or opioid medication. The median survival of the 18 patients who died post-extubation was 0.83 hours (interquartile range 0.5-43.8). Bolus doses of opioid or benzodiazepine medications were effective for management of symptoms in about two-thirds of patients. One-third of patients required continuous infusions. Eighteen patients died following extubation in the medical center, and three of these patients were transferred to an inpatient hospice unit. Three patients (14%) survived to discharge from the hospital. The procedure followed provides a foundation for collaboration between palliative care and critical care services to ensure continuity of care across clinical settings/units.


Pulmonary artery involvement in Takayasu arteritis. PET/CT versus CT angiography.
To report a patient with Takayasu arteritis in whom 18F-Fluorodeoxyglucose (FDG) positron emission tomography (PET)/computerised tomography (CT) failed to demonstrate pulmonary artery involvement. A patient with Takayasu arteritis underwent PET/CT and CT angiography before and one year after immunosuppressive treatment. Before treatment, PET/CT showed increased FDG uptake in the aortic arch and epiaortic arteries; pulmonary arteries were not visualised. Follow-up PET/CT one year later demonstrated resolution of abnormal vascular FDG uptake. CT angiography of the chest/abdomen prior to treatment revealed circumferential thickening of the ascending aorta, aortic arch, supra-aortic branches, and left inferior intralobar pulmonary artery with normal lumen diameter (27 mm). After therapy, CT angiography revealed decreased aortic wall thickening with complete resolution of intralobar wall thickening. However, the lumen of the central pulmonary artery was increased (32 mm). PET/CT is very sensitive in depicting active vasculitis, but cannot visualise the pulmonary arteries, presumably because their diameter is below the power of detection of PET/CT. CT angiography or magnetic resonance angiography is required to evaluate pulmonary artery abnormalities.


Protection of trabecular bone in ovariectomized rats by turmeric (Curcuma longa L.) is dependent on extract composition.
Extracts prepared from turmeric (Curcuma longa L., [Zingiberaceae]) containing bioactive phenolic curcuminoids were evaluated for bone-protective effects in a hypogonadal rat model of postmenopausal osteoporosis. Three-month female Sprague-Dawley rats were ovariectomized (OVX) and treated with a chemically complex turmeric fraction (41% curcuminoids by weight) or a curcuminoid-enriched turmeric fraction (94% curcuminoids by weight), both dosed at 60 mg/kg 3x per week, or vehicle alone. Effects of two months of treatment on OVX-induced bone loss were followed prospectively by serial assessment of bone mineral density (BMD) of the distal femur using dual-energy X-ray absorptiometry (DXA), while treatment effects on trabecular bone microarchitecture were assessed at two months by microcomputerized tomography (microCT). Chemically complex turmeric did not prevent bone loss, however, the curcuminoid-enriched turmeric prevented up to 50% of OVX-induced loss of trabecular bone and also preserved the number and connectedness of the strut-like trabeculae. These results suggest that turmeric may have bone-protective effects but that extract composition is a critical factor.


Measurement of Blood Dilution during Lancet-Free Blood Sampling.
In this paper, we report on a fluorescent and colorimetric system for measuring the dilution of capillary blood released by a needle-free jet injector. Jet injection uses a high-speed liquid jet to penetrate tissue, and in the process can release capillary blood that can be collected for performing blood tests. In this way, blood sampling can be performed without the use of a lancet. However, any injectate that mixes with the collected blood dilutes the sample and may significantly impact subsequent analyses. By adding the fluorescent marker indocyanine green to the injected liquid, the fraction of injectate mixed into the collected blood can be measured. The incorporation of colorimetry allows our system to also correct for the impact of hematocrit on fluorescence. The results from this system show that it can determine the dilution of blood that has been diluted by up to 10 %, the upper limit of dilution typically observed in lancet-free blood sampling via jet injection.Clinical Relevance- Blood samples can be collected by jet injection without significant dilution, avoiding the need for lancing.


Shared decision making about blood tests: secondary analysis of video-recorded primary care consultations.
Awareness of the importance of shared decision making (SDM) is widespread; however, little research has focused on discussions surrounding investigations, despite increasing laboratory testing in primary care. To explore the discussion of blood tests in routine primary care consultations. A secondary analysis of 50 video-recorded routine primary care consultations, linked surveys, and records data (all from the One in a Million [OiaM] archive). The consultations were taken by 22 GPs across 12 practices. A coding scheme was developed, using qualitative content analysis, to explore discussion of blood tests in transcripts of recorded consultations. Codes focused on instigating testing, the extent of SDM, and how results were explained. Survey data were used to compare patients' pre-visit expectations with consultation content. Medical records were reviewed to compare tests discussed with those ordered. In 36 out of 50 consultations that discussed ordering blood tests, 11 patients (31%) hinted that they wanted a blood test; however, none asked explicitly. Only four patients (11%) were offered alternative options. In 29 cases (81%) the GP gave some explanation of the indication, but only in six cases (17%) were the limitations of testing explained. Only 10 out of 31 patients (32%) were informed about all blood tests ordered. Of the 23 out of 50 consultations in which results were conveyed, the GP gave no explanation of the results in six cases (26%). Thirteen patients (57%) were only informed of an assessment of the results (for example, 'normal'), rather than the actual results. A lack of information dissemination and SDM exists around ordering tests and conveying results. Promoting SDM could reduce unnecessary testing and improve patient-centred care.


Misread and mistaken: Étienne Lancereaux's enduring legacy in the classification of diabetes mellitus.
Historians of diabetes have long claimed that physicians were aware of two distinct types of diabetes mellitus by the 1880s, and that these were the direct forerunners of type 1, juvenile-onset and type 2, adult-onset diabetes. French physician Étienne Lancereaux (1829-1910), based on autopsy and clinical studies, classified diabetes either as diabète maigre (thin, or more accurately emaciated, diabetes), which he believed to be pancreatic in origin with a poor prognosis, or diabète gras (fat diabetes), which he believed had a much better prognosis and was not pancreatic in origin. Historians citing Lancereaux have claimed that he observed the former to occur in young and the latter in middle-aged and elderly people. We review the papers of Lancereaux to clarify his clinical observations and understanding of diabetes. Lancereaux's description of diabète maigre bores little resemblance to juvenile diabetes and all of his thin patients were middle-aged or older. On the other hand, his diabète gras is akin to type 2 diabetes and he might well deserve credit for its characterization.


Cognitive screening in substance users: Diagnostic accuracies of the Mini-Mental State Examination, Addenbrooke's Cognitive Examination-Revised, and Montreal Cognitive Assessment.
Despite the considerable prevalence of cognitive impairment in substance-using populations, there has been little investigation of the utility of cognitive screening measures within this context. In the present study the accuracy of three cognitive screening measures in this population was examined-the Mini-Mental State Examination (MMSE), the Addenbrooke's Cognitive Examination-Revised (ACE-R), and the Montreal Cognitive Assessment (MoCA). A sample of 30 treatment-seeking substance users and 20 healthy individuals living in the community were administered the screening measures and a neuropsychological battery (NPB). Agreement of classification of cognitive impairment by the screening measures and NPB was examined. Results indicated that the ACE-R and MoCA had good discriminative ability in detection of cognitive impairment, with areas under the receiver-operating characteristic (ROC) curve of .85 (95% confidence interval, CI [.75. .94] and .84 (95% CI [.71, .93]) respectively. The MMSE had fair discriminative ability (.78, 95% CI [.65, .93]). The optimal cut-score for the ACE-R was 93 (impairment = score of 92 or less), at which it correctly classified 89% of individuals as cognitively impaired or intact, while the optimal cut-score for the MoCA was <26 or <27 depending on preference for either specificity or sensitivity. The optimal cut-score for the MMSE was <29; however, this had low sensitivity despite good specificity. These findings suggest that the MoCA and ACE-R are both valid and time-efficient screening tools to detect cognitive impairment in the context of substance use.


Acute kidney injury in critical COVID-19 patients: usefulness of urinary biomarkers and kidney proximal tubulopathy.
Tubular injury is the main cause of acute kidney injury (AKI) in critically ill COVID-19 patients. Proximal tubular dysfunction (PTD) and changes in urinary biomarkers, such as NGAL, TIMP-2, and IGFBP7 product ([TIMP-2]•[IGFBP7]), could precede AKI. We conducted a prospective cohort study from 2020/03/09 to 2020/05/03, which consecutively included all COVID-19 patients who had at least one urinalysis, to assess the incidence of PTD and AKI, and the effectiveness of PTD, NGAL, and [TIMP-2]•[IGFBP7] in AKI and persistent AKI prediction using the area under the receiver operating characteristic curves (AUCs), Kaplan-Meier methodology (log-rank tests), and Cox models. Among the 60 patients admitted to the ICU with proven COVID-19 (median age: 63-year-old (interquartile range: IQR, 55-74), 45 males (75%), median simplified acute physiology score (SAPS) II: 34 (IQR, 22-47) and median BMI: 25.7 kg/m2 (IQR, 23.3-30.8)) analyzed, PTD was diagnosed in 29 patients (48%), AKI in 33 (55%) and persistent AKI in 20 (33%). Urinary NGAL had the highest AUC for AKI prediction: 0.635 (95%CI: 0.491-0.779) and persistent AKI prediction: 0.681 (95%CI: 0.535-0.826), as compared to PTD and [TIMP-2]•[IGFBP7] (AUCs <0.6). AKI was independently associated with higher SAPSII (HR = 1.04, 95%CI: 1.01-1.06, p = 0.005) and BMI (HR = 1.07, 95%CI: 1.00-1.14, p = 0.04) and persistent AKI with higher SAPSII (HR = 1.03, 95%CI: 1.00-1.06, p = 0.048) and nephrotoxic drug use (HR = 3.88, 95%CI: 1.20-12.5, p = 0.02). In conclusion, in critically ill COVID-19 patients, the incidence of PTD and AKI was relatively high. NGAL was the best urinary biomarker for predicting AKI, but only clinical severity was independently associated with its occurrence.


Maternal and Paternal Caffeine Intake and ART Outcomes in Couples Referring to an Italian Fertility Clinic: A Prospective Cohort.
Caffeine intake, a frequent lifestyle exposure, has a number of biological effects. We designed a cohort study to investigate the relation between lifestyle and assisted reproduction technique (ART) outcomes. From September 2014 to December 2016, 339 subfertile couples referring to an Italian fertility clinic and eligible for ART procedures were enrolled in our study. Sociodemographic characteristics, smoking, and usual alcohol and caffeine consumption in the year prior to ART were recorded. The mean age of participants was 36.6 ± 3.6 years in women and 39.4 ± 5.2 years in men. After oocytes retrieval, 293 (86.4%) underwent implantation, 110 (32.4%) achieved clinical pregnancy, and 82 (24.2%) live birth. Maternal age was the main determinant of ART outcome. In a model including women's age and college degree, smoking habits, calorie and alcohol intake for both partners, previous ART cycles, and partner's caffeine intake, we did not observe any association between caffeine intake and ART outcome. Using the first tertile of caffeine intake by women as a reference, the adjusted rate ratio (ARR) for live birth was 1.09 (95% confidence interval (CI) 0.79⁻1.50) in the second and 0.99 (95% CI 0.71⁻1.40) in the third tertiles. In conclusion, a moderate caffeine intake by women and men in the year prior to the ART procedure was not associated with negative ART outcomes.


Exercise-induced energy expenditure: implications for exercise prescription and obesity.
Walking is commonly recommended to help with weight management. We measured total energy expenditure (TEE) and its components to quantify the impact of increasing exercise-induced energy expenditure (ExEE) on other components of TEE. Thirteen obese women underwent an 8-week walking group intervention. TEE was quantified using doubly labeled water, ExEE was quantified using heart rate monitors, daily movement was assessed by accelerometry and resting metabolic rate was measured using indirect calorimetry. Four of the 13 participants achieved the target of 1500kcalwk(-1) of ExEE and all achieved 1000kcalwk(-1). The average ExEE achieved by the group across the 8 weeks was 1434+/-237kcalwk(-1). Vigorous physical activity, as assessed by accelerometry, increased during the intervention by an average of 30min per day. Non-exercise activity thermogenesis (NEAT) decreased, on average, by 175kcald(-1) (-22%) from baseline to the intervention and baseline fitness was correlated with change in NEAT. Potential alterations in non-exercise activity should be considered when exercise is prescribed. The provision of appropriate education on how to self-monitor daily activity levels may improve intervention outcomes in groups who are new to exercise. Strategies to sustain incidental and light physical activity should be offered to help empower individuals as they develop and maintain healthy and long-lasting lifestyle habits.


Main scientific results of the WHO International Programme on the Health Effects of the Chernobyl Accident (IPHECA).
Scientific results obtained within the WHO International Programme on the Health Effects of the Chernobyl Accident (IPHECA) have confirmed the increase of thyroid cancer cases in children who were exposed to radiation due to the accident in 1986. In the zones under surveillance in Belarus, the Russian Federation and Ukraine, the general morbidity for leukaemia and related diseases did not undergo a significant change after the accident. Accident recovery workers ("liquidators") are an especially high-risk group and need further medical follow-up.


Optically trapped SiO2@Au particle-dye hybrid-based SERS detection of Hg2+ ions.
The selective ultra-sensitive detection of a very low concentration of analyte in a liquid environment using surface-enhanced Raman spectroscopy (SERS) is a challenging task owing to the poor reproducibility of the Raman signals arising from the nonstationary nature of the substrate. However, plasmonic metal particle-incorporated microparticles can be effectively 3-D arrested in a liquid environment that can serve as a stable SERS substrate by employing an optical trapping force. Herein, we demonstrate a 3-D optically trapped Au-attached SiO2 microparticle as an efficient SERS substrate that can detect 512 pM for Rhodamine6G and 6.8 pM for crystal violet. Further, the substrate allows the simultaneous detection of multiple analytes. By utilizing the Raman signal from Rhodamine 6G as the probe beam, the selective detection of Hg2+ ions as low as 100 pM is demonstrated.


Interaction of soybean beta-amylase with glucose.
The interaction of soybean beta-amylase with glucose was investigated by inhibition kinetics studies and spectroscopic measurements. The inhibition type, inhibitor constant (Ki) and dissociation constant (Kd) of beta-amylase-glucose complex were dependent on pH. At pH 8.0, glucose behaved as a competitive inhibitor (Ki = 34 mM). Binding of glucose produced a characteristic difference spectrum and a change of circular dichroism (CD) at pH 8.1. By using difference absorbance at 292 nm and difference ellipticity at 290 nm, Kd values for beta-amylase-glucose complex were determined to be 45 and 46 mM, respectively. In contrast to pH 8.0, glucose behaved as a mixed-type inhibitor (Ki = 320 mM) at pH 5.4. The Kd values obtained from the difference spectrum were increased by lowering the pH from 8. The pH dependence of the Ki and Kd values suggested that one ionizable group of pK = 8.0, which is shifted to 6.9 by the binding of glucose, controls the binding affinity of glucose. The binding of glucose competed with the binding of cyclohexaamylose and maltose at pH 8.0. The modification of SH groups of the enzyme affected the binding of glucose but did not affect the binding of maltose or cyclohexaamylose at pH 8.0. It was concluded from these results that the binding site of glucose is different from that of maltose and cyclohexaamylose. Presumably, glucose may bind to the subsite 1 of soybean beta-amylase.


[Impulse activity of neurons in the nucleus pontis oralis in cats during sleep--wakefulness cycle].
The nucleus pontis oralis contains several populations of neurons showing distinct sleep-waking discharge patterns. PS-on, PS-off cells, and neurons that discharged in association with phasic movements during paradoxical sleep and/or waking, were found. The findings suggest that different populations of the nucleus pontis oralis neurons take a distinct part in paradoxical sleep control.


Disgust elevates core body temperature and up-regulates certain oral immune markers.
Recent findings suggest that disgust can activate particular aspects of the immune system. In this study we examine whether disgust can also elevate core body temperature (BT), a further feature of an immune response to disease. In addition, we also examined whether food based disgust--a core eliciting stimulus--may be a more potent immune stimulus than non-food based disgust. Healthy males were randomly assigned to view one of four sets of images--food disgust, non-food disgust, food control and negative emotion control. Measures of BT, salivary immune and related markers, and self-report data, were collected before, and at two time points after image viewing. Disgust elevated BT relative to the negative emotion control condition, as did food images. Different mechanisms appeared to account for these effects on BT, with higher initial levels of Tumor Necrosis Factor alpha (TNF-a) and disgust, predictive of BT increases in the disgust conditions. Disgust also increased TNF-a, and albumin levels, relative to the control conditions. Type of disgust exerted little effect. These findings further support the idea that disgust impacts upon immune function, and that disgust serves primarily a disease avoidance function.


Future ocean warming may prove beneficial for the northern population of European seabass, but ocean acidification will not.
The world's oceans are acidifying and warming as a result of increasing atmospheric CO2 concentrations. The thermal tolerance of fish greatly depends on the cardiovascular ability to supply the tissues with oxygen. The highly oxygen-dependent heart mitochondria thus might play a key role in shaping an organism's tolerance to temperature. The present study aimed to investigate the effects of acute and chronic warming on the respiratory capacity of European sea bass (Dicentrarchus labrax L.) heart mitochondria. We hypothesized that acute warming would impair mitochondrial respiratory capacity, but be compensated for by life-time conditioning. Increasing PCO2 may additionally cause shifts in metabolic pathways by inhibiting several enzymes of the cellular energy metabolism. Among other shifts in metabolic pathways, acute warming of heart mitochondria of cold life-conditioned fish increased leak respiration rate, suggesting a lower aerobic capacity to synthesize ATP with acute warming. However, thermal conditioning increased mitochondrial functionality, e.g. higher respiratory control ratios in heart mitochondria of warm life-conditioned compared with cold life-conditioned fish. Exposure to high PCO2 synergistically amplified the effects of acute and long-term warming, but did not result in changes by itself. This high ability to maintain mitochondrial function under ocean acidification can be explained by the fact that seabass are generally able to acclimate to a variety of environmental conditions. Improved mitochondrial energy metabolism after warm conditioning could be due to the origin of this species in the warm waters of the Mediterranean. Our results also indicate that seabass are not yet fully adapted to the colder temperatures in their northern distribution range and might benefit from warmer temperatures in these latitudes.