Treatment of a population based sample of men diagnosed with testicular cancer in the United States.
Testicular cancer is the most common cancer in men age 25 to 35 years. We examined therapy, compliance with guidelines, and survival in a population based sample of men newly diagnosed with testicular cancer. We analyzed the National Cancer Institute's (NCI) patterns of care data on 702 men diagnosed with testicular cancer in 1999. These studies supplement routine data collection by verifying therapy with the patients' treating physicians. Follow-up for vital status was available through December 31, 2004. The majority of the men with seminoma were diagnosed while their cancer was localized and more than 80% of received orchiectomy with radiation. For men with seminoma and nonseminoma germ cell tumors (NSGCT), the percent receiving chemotherapy increased markedly as stage increased. More than 90% of men with regional and distant NSGCT received chemotherapy. Less than 25% of men with localized NSGCT received orchiectomy and retroperitoneal lymph node dissection (RPLND), about 40% had surveillance following an orchiectomy alone, and 30% received orchiectomy and chemotherapy. The majority of these patients received therapy consistent with guidelines. While there was no significant difference in the use of RPLND in men with localized NSGCT by geographic region, chemotherapy use varied widely. Over 90% of men with localized or regional disease diagnosed in 1999 were alive at the end of 2004. The excellent survival rates point to the need to monitor for late effects of therapy.


[Sedoheptulose-1,7-diphosphate as a source of pentose phosphates in heart muscle].
A possibility and some peculiarities of phosphatase degradation of sedoheptulose-1,7-diphosphate in the myocardium has been demonstrated. The reaction products are inorganic phosphate and sedoheptulose-7-phosphate; the latter product is the substrate of the transketolase reaction during pentose phosphates production. The process is largely localized in the soluble fraction of heart cells; in cellular organelles it is represented in a lesser degree. Possible regulatory mechanisms of pentose phosphate biosynthesis in animal tissues are discussed.


Prenatal Depression and Risk of Short Interpregnancy Interval in a Predominantly Puerto Rican Population.
Background: Short interpregnancy interval (IPI) is associated with risk of adverse pregnancy outcomes; however, few studies have evaluated the role of depression as a risk factor for short IPI. Puerto Rican women in the United States experience disparities in adverse birth outcomes and have the highest birth rates. Methods: We analyzed the association between prenatal depressive symptoms and IPI in Proyecto Buena Salud, a prospective cohort of predominantly Puerto Rican women in Western Massachusetts (2006-2011). Depression was measured using the Edinburgh Postnatal Depression Scale (EPDS) in early, mid, and late pregnancy. We calculated follow-up time as the difference between the date of delivery of the index pregnancy and the last menstrual period of the subsequent pregnancy using medical records and billing data. We defined short IPI as ≤18 months. Results: Of 1262 eligible women, 35% (n = 440) had at least probable minor depression (EPDS scores ≥13) and 25% (n = 315) had probable major depression (EPDS scores ≥15). Participants were followed for a median of 3.7 years (interquartile range = 1.4-6.0 years) and 240 (20.6%) participants experienced a short IPI. After adjusting for risk factors, women with probable minor depression (adjusted odds ratio [aOR] = 1.39, 95% confidence interval [CI] = 1.02-1.88) and probable major depression (aOR = 1.42, 95% CI = 1.02-1.97) during pregnancy had increased odds of short IPI. Conclusions: Prenatal depressive symptoms were common in this Puerto Rican population and were associated with a modest increase in odds of short IPI. Further examination of the pathways through which mental health may affect IPI in vulnerable populations is warranted.


Low-energy scapular body fracture: a case report.
Scapula fractures are relatively rare and most often the result of high-energy trauma. However, they should always be included in a physician's differential diagnosis when a patient has a complaint of shoulder pain after trauma or violent muscular contraction about the shoulder. Because the vast majority are the result of a high-energy mechanism of injury, the physician should, as always, completely evaluate the patient for associated injuries. Most scapula fractures can be diagnosed on physical examination with localized tenderness, swelling, and hematoma formation over the fracture site. Radiographic confirmation and evaluation is routinely made using the three-view trauma series of the shoulder; additional views are rarely indicated. Treatment, consisting of a sling or sling and swath for comfort, mild narcotic medication, and early range-of-motion exercises virtually always leads to union and good glenohumeral function. Operative treatment is rarely indicated. A case of an low-energy isolated scapular body fracture sustained by a 41-year-old man is presented.


Osteogenic Potential of Mouse Adipose-Derived Stem Cells Sorted for CD90 and CD105 In Vitro.
Adipose tissue-derived stromal cells, termed ASCs, play an important role in regenerative applications. They resemble mesenchymal stem cells owing to their inexhaustibility, general differentiation potential, and plasticity and display a series of cell-specific and cluster-of-differentiation (CD) marker profiles similar to those of other somatic stem cells. Variations in phenotypes or differentiation are intimately associated with CD markers. The purpose of our study was to exhibit distinct populations of ASCs with differing characteristics for osteogenic differentiation. The primary cell batch of murine-derived ASCs was extracted from subcutaneous adipose tissue and the cells were sorted for the expression of the surface protein molecules CD90 and CD105 using flow cytometry. Each cell population sorted for CD90 and CD105 was analyzed for osteogenic potency after cell culture. The results suggested that ASCs exhibit distinct populations with differing characteristics for osteogenic differentiation: unsorted ASCs stimulated comparable mineralized nodule formation as bone marrow stromal cells (BMSCs) in osteogenic medium and viral transfection for BMP2 accelerated the formation of mineralized nodules in CD90 and/or CD105 positive ASCs with observation of decrease in CD105 expression after 14 days. Future studies assessing different immunophenotypes of ASCs should be undertaken to develop cell-based tissue engineering.


Polymer-augmented liposomes enhancing antibiotic delivery against intracellular infections.
Pulmonary intracellular infections, such as tuberculosis, anthrax, and tularemia, have remained a significant challenge to conventional antibiotic therapy. Ineffective antibiotic treatment of these infections can lead not only to undesired side effects, but also to the emergence of antibiotic resistance. Aminoglycosides (e.g., streptomycin) have long been part of the therapeutic regiment for many pulmonary intracellular infections. Their bioavailability for intracellular bacterial pools, however, is limited by poor membrane permeability and rapid elimination. To address this challenge, polymer-augmented liposomes (PALs) were developed to provide improved cytosolic delivery of streptomycin to alveolar macrophages, an important host cell for intracellular pathogens. A multifunctional diblock copolymer was engineered to functionalize PALs with carbohydrate-mediated targeting, pH-responsive drug release, and endosomal release activity with a single functional polymer that replaces the pegylated lipid component to simplify the liposome formulation. The pH-sensing functionality enabled PALs to provide enhanced release of streptomycin under endosomal pH conditions (70% release in 6 hours) with limited release at physiological pH 7.4 (16%). The membrane-destabilizing activity connected to endosomal release was characterized in a hemolysis assay and PALs displayed a sharp pH profile across the endosomal pH development target range. The direct connection of this membrane-destabilizing pH profile to model drug release was demonstrated in an established pyranine/p-xylene bispyridinium dibromide (DPX) fluorescence dequenching assay. PALs displayed similar sharp pH-responsive release, whereas PEGylated control liposomes did not, and similar profiles were then shown for streptomycin release. The mannose-targeting capability of the PALs was also demonstrated with 2.5 times higher internalization compared to non-targeted PEGylated liposomes. Finally, the streptomycin-loaded PALs were shown to have a significantly improved intracellular antibacterial activity in a Francisella-macrophage co-culture model, compared with free streptomycin or streptomycin delivered by control PEGylated liposomes (13× and 16×, respectively). This study suggests the potential of PALs as a useful platform to deliver antibiotics for the treatment of intracellular macrophage infections.


Carp horizontal cells in culture respond selectively to L-glutamate and its agonists.
Horizontal cells were enzymatically isolated from the carp retina and maintained in culture for 2-7 days. Cultured horizontal cells typically had resting membrane potentials of -50 to -70 mV and input resistances of 100-150 m omega. The cells were treated with a number of neurotransmitter agents and their analogues. Significant responses were evoked only by 3,4-dihydroxyphenylalanine (dopamine), L-glutamate, and certain glutamate analogues. The responses to dopamine were inconsistent; most often, the membrane hyperpolarized and input resistances increased. However, highly characteristic responses to L-glutamate and its analogues, quisqualate and kainate, were observed in virtually all of the cells tested. The responses consisted of an initial graded depolarization accompanied by a resistance increase, followed in most cases by a prolonged (1- to 2-min) regenerative depolarization. The regenerative component of the response appears to be Ca2+ dependent, while the underlying graded potential may be due to a decrease in K+ conductance of the membrane.


A Decade of Experience Using mTor Inhibitors in Liver Transplantation.
Some studies suggest that Sirolimus (SRL) is associated with an increased risk of death in liver transplant recipients compared to treatment with calcineurin inhibitors (CNIs). We compared patients who received SRL or CNI in the first year after liver transplant. Our database included 688 patients who received a liver transplant. The patients were divided into groups. (1) CNI + MPS (mycophenolate sodium) at time of discharge. (2) CNI + MPS at time of discharge; SRL was added within the first 6 months and continued through the first year. (3) CNI + MPS at time of discharge; SRL was added within the first 6 months and discontinued before the first year. (4) SRL as primary immunosuppression. (5) SRL as primary immunosuppression and discontinued before the first year. We used mortality and graft loss as the primary measures of outcome. We also quantified renal function using the change in glomerular filtration rate (GFR), the presence of biopsy proven acute cellular reject (ACR), and steroid-resistant rejection (SRR). There were no significant differences in mortality or graft loss. There was no difference in patient or graft survival. Patients that received SRL as primary immunosuppression had 50% less rejection compared to controls.


Spectroscopic characterization of a green copper site in a single-domain cupredoxin.
Cupredoxins are widespread copper-binding proteins, mainly involved in electron transfer pathways. They display a typical rigid greek key motif consisting of an eight stranded β-sandwich. A fascinating feature of cupredoxins is the natural diversity of their copper center geometry. These geometry variations give rise to drastic changes in their color, such as blue, green, red or purple. Based on several spectroscopic and structural analyses, a connection between the geometry of their copper-binding site and their color has been proposed. However, little is known about the relationship between such diversity of copper center geometry in cupredoxins and possible implications for function. This has been difficult to assess, as only a few naturally occurring green and red copper sites have been described so far. We report herein the spectrocopic characterization of a novel kind of single domain cupredoxin of green color, involved in a respiratory pathway of the acidophilic organism Acidithiobacillus ferrooxidans. Biochemical and spectroscopic characterization coupled to bioinformatics analysis reveal the existence of some unusual features for this novel member of the green cupredoxin sub-family. This protein has the highest redox potential reported to date for a green-type cupredoxin. It has a constrained green copper site insensitive to pH or temperature variations. It is a green-type cupredoxin found for the first time in a respiratory pathway. These unique properties might be explained by a region of unknown function never found in other cupredoxins, and by an unusual length of the loop between the second and the fourth copper ligands. These discoveries will impact our knowledge on non-engineered green copper sites, whose involvement in respiratory chains seems more widespread than initially thought.


Two key concepts in the life course approach in medicine: allostatic load and cumulative life course impairment.
According to the biopsychosocial model, psychosocial and biological factors interact in a number of ways influencing onset and course of medical disease. In a longitudinal perspective, such factors may elicit different effects on health depending on their accumulation mechanisms and timing of exposure over the life course. These aspects have become particularly relevant in the field of chronic diseases such as chronic dermatological conditions, where complete healing is unlikely to occur. Two key concepts may aid understanding of chronic medical conditions in a more comprehensive manner. In the first place, the concept of allostatic load may represent the link between the cumulative effect of various challenging situations and the disease onset through the progressive 'wear and tear' induced by chronic exposure to fluctuating allostatic responses. In addition, the allostatic overload model emphasizes the fact that the cumulative interaction of stressors, psychological symptoms and impaired psychological well-being may constitute a danger to health. In the second place, the concept of cumulative life course impairment, which takes into account the multiple dimensions of chronic disease, underlines the fact that illness is only one of many recordable parameters which ultimately determine, through their mutual interaction, the 'life trajectory of individuals'. In a broader sense, both concepts of allostatic load and cumulative life course impairment allow more light to be shed on a new perspective on illness - the life course perspective - and on its interactions with psychological, social and environmental factors. This perspective may ultimately result not only in a substantial improvement of clinical care, but also in a different and long-lasting approach to interventions in chronic illness, with wide economic, political and social consequences whose entity has yet to be appreciated.


The shear bond strength of MTA with three different types of adhesive systems: An in vitro study.
To evaluate the shear bond strength of MTA with three different types of adhesive systems- self-adhering flowable composite, etch and rinse adhesive system and self etch adhesive system. MTA specimens (n = 60) were prepared using cylindrical acrylic blocks, having a central cavity with 4 mm diameter and 2 mm depth. MTA was mixed and placed in the prepared cavity, and was covered with a moist cotton pellet and temporary filling material. The specimens were divided into 3 groups which were further divided into 2 sub-groups (45 Minutes and 24 hours). After the application of bonding agents composite resin was placed over the MTA surface. The specimens were tested for shear bond strength and readings were statically analyzed. After 24 hrs the mean value of etch and rinse group was significantly higher than self etch and the self adhering composite groups. Among the 45 minutes groups there were no significant difference. In single visit after 45 minutes self adhering flowable can be used successfully as a final restorative material in place of conventional flowable composite without using any alternative adhesive system over MTA.


The effect of watching live arthroscopic views on postoperative anxiety of patients.
Surgery is a stressful experience. Many minor interventions have been shown to cause considerable anxiety in patients, but whether arthroscopy leads to such anxiety is not well-known. Methods for lowering perioperative anxiety have been sought and listening to music or watching a movie have been recommended. The method of permitting patients to watch their own endoscopy has been studied infrequently. Our aim in this study was to find out the effect of watching simultaneous arthroscopic views on postoperative anxiety. A total of 63 patients were randomly divided into two groups: those watching their own arthroscopy formed group W, while patients that were only verbally informed formed group NW. The mean age of patients in both groups were 33 and 34, respectively. Meniscal surgery was the most commonly performed procedure (49/63 patients). The patients filled in state scale of State-trait anxiety inventory (STAI) forms and the study questionnaire (SQ) prepared for this study, just before and after the arthroscopy. Group W had significantly lower postoperative scores of STAI-S, whole questionnaire (Q-score) and all but one of individual statements in SQ. Having a previous operation history did not affect STAI scores. Age and level of education was not correlated with any of the studied parameters either. The ratio of patients that were pleased with the arthroscopy experience in group W and NW were 94 and 63%, respectively. Watching live arthroscopic views has led to a significant decrease in postoperative anxiety and worries about the surgery and the postoperative period, while increasing overall understanding and satisfaction of the patient.


[The use of immunomodulators in the surgical treatment of complicated gastric disease].
While examination of 83 patients it was established that in the presence of complicated gastric and duodenal ulcer disease the secondary immune deficiency is developing, which deepens after the surgical intervention conduction. Tiotriazolin, promoting the immune system state and the blood biochemistry indexes normalization, the immune system state and the blood biochemistry indexes stimulation, hemopoiesis stimulation, the treatment results improvement, was applied for immunomodulation.


Historical database cohort study addressing the clinical patterns prior to idiopathic pulmonary fibrosis (IPF) diagnosis in UK primary care.
To explore the clinical pathways, including signs and symptoms, and symptom progression patterns preceding idiopathic pulmonary fibrosis (IPF) diagnosis. A historical cohort study was conducted using primary care patient records from the Optimum Patient Care Research Database. Patients included were at least 30 years, had IPF diagnosis, identified via clinical-coding and free-text records and had a consultation with a chest specialist prior to IPF diagnosis. The signs and symptoms in the year prior to IPF diagnosis from clinical codes and free-text in primary care electronic records included: cough, dyspnoea, dry cough, weight loss, fatigue/malaise, loss of appetite, crackles and clubbed fingers. The time course of presentations of clinical features and investigations in the years prior to IPF diagnosis were mapped. Within 462 patients identified, the majority (77.9%) had a respiratory consultation within 365 days prior to the chest specialist visit preceding the IPF diagnosis recorded in their primary care records. The most common symptoms recorded in the 1 year prior to IPF diagnosis were dyspnoea (48.7%) and cough (40.9%); other signs and symptoms were rarely recorded (<5%). The majority of patients with cough (58.0%) and dyspnoea (55.0%) in the 1 year before IPF diagnosis had multiple recordings of the respective symptoms. Both cough and dyspnoea were recorded in 23.4% of patients in the year prior to diagnosis. Consultation rates for cough, dyspnoea and both, but not other signs or symptoms, began to increase 4 to 5 years prior diagnosis, with the sharpest increase in the last year. Cough and dyspnoea were often preceded by a reduction in measured weight over 5 years leading to IPF diagnosis. Prolonged cough and/or progressive dyspnoea, especially if accompanied with weight loss, should signal for a referral to specialist assessment at the earliest opportunity.


In Vitro Effect of Pitavastatin and Its Synergistic Activity with Isavuconazole against Acanthamoeba castellanii.
Acanthamoeba keratitis (AK) can occur in healthy individuals wearing contact lenses and it is a painful, blinding infection of the cornea caused by a free-living ameba Acanthamoeba. Current treatment for AK relies on a combination of chlorhexidine, propamidine isethionate, and polyhexamethylene biguanide. However, the current regimen includes an aggressive disinfectant and in 10% of cases recurrent infection ensues. Therefore, development of efficient and safe drugs is a critical unmet need to avert blindness. Acanthamoeba sterol biosynthesis includes two essential enzymes HMG-CoA reductase (HMGR) and sterol 14-demethylase (CYP51), and we earlier identified a CYP51 inhibitor isavuconazole that demonstrated nanomolar potency against A. castellanii trophozoites. In this study, we investigated the effect of well-tolerated HMGR inhibitors and identified pitavastatin that is active against trophozoites of three different clinical strains of A.castellanii. Pitavastatin demonstrated an EC50 of 0.5 to 1.9 µM, depending on strains. Combination of pitavastatin and isavuconazole is synergistic and led to 2- to 9-fold dose reduction for pitavastatin and 11- to 4000-fold dose reduction for isavuconazole to achieve 97% of growth inhibition. Pitavastatin, either alone or in combination with isavuconazole, may lead to repurposing for the treatment of Acanthamoeba keratitis.


A necessity not a luxury: preparing advanced practice nurses to care for older adults.
Of today's 2.7 million registered nurses, less than 1% are certified in gerontological nursing and only 3% of advanced practice nurses (APNs) have specialized training in this area. These statistics indicate that there are not enough gerontological nurse practitioners or geriatric clinical nurse specialists to care for the burgeoning older adult population. Relying solely on certified geriatric APNs to care for older adults is not a viable solution. Educating all APNs with grounding in gerontological nursing care may well be the answer to expanding our nation's capacity to competently care for our rapidly aging population. As part of the 4-year Enhancing Geriatric Nursing Education in Baccalaureate and Advanced Practice Nursing Grant, the American Association of Colleges of Nursing developed a set of core gerontological competencies for graduate APN programs. These competencies, entitled Nurse Practitioner and Clinical Nurse Specialist Competencies for Older Adult Care, delineate guidelines for APNs who are not specialists in gerontology but provide care to older adults. This article describes the competency development process, provides an overview of broad categories and examples of competency statements, and highlights model case studies for integrating gerontological content throughout APN curricula to ensure that graduates are equipped to provide competent care to older adults.


Regulation of prostate-specific antigen expression by the junctional adhesion molecule A.
Prostate-specific antigen (PSA) is a protein specifically expressed in prostate cells. Therefore, the expression levels of PSA in the blood are an important indicator when diagnosing prostate cancer. Defining the mechanism of PSA expression in prostate cells will be helpful for interpreting the expression of this protein during prostate cancer progression. Reports show that a membrane protein, claudin-7 (CLDN-7), is involved in the expression of PSA. However, the mechanism by which CLDN-7 regulates PSA expression is not clear. Here we identify proteins that interact with CLDN-7 and determine whether such proteins can regulate PSA expression in a pattern similar to that of CLDN-7. Our previous studies have demonstrated that in prostate cells, PSA can be regulated by a membrane protein, CLDN-7. It is important to identify the proteins that associate with CLDN-7 in its pathway of regulating PSA expression, because it is very unlikely that CLDN-7 can directly regulate PSA expression in the nucleus. To identify potential proteins that may directly interact with CLDN-7, we studied proteins that can interact with claudins. We found that CLDN-7 interacts with the junctional adhesion molecule A (JAM-A), which is expressed in the prostate cancer cell line, LNCaP, which expresses PSA, but not the PSA-negative prostate cell line, DU145. JAM-A regulates the expression of the prostate-specific antigen in LNCaP cells in a pattern similar to CLDN-7. Our results suggest that JAM-A associates with CLDN-7 and it is a component in the pathway by which CLDN-7 regulates the expression of PSA.


Are Changes in Alcohol Consumption Among Swedish Youth Really Occurring 'in Concert'? A New Perspective Using Quantile Regression.
Recent studies of youth alcohol consumption indicate a collective downward drinking trend at all levels of consumption, i.e. reductions occurring 'in concert'. We re-examine the collectivity of drinking theory by applying quantile regression methods to the analysis and interpretation of Swedish youth alcohol consumption. Changes in youth alcohol consumption between 2000 and 2014 were assessed using a school-based survey conducted in Stockholm (n = 86,402). Participants were Swedish youth aged 15-18 years. The rate of change in consumption was examined using quantile regression, and compared to Ordinary Least Squares modelling. The hypothesis of parallelism or 'in concert' changes in consumption was assessed using the test of the equality of linear regression slopes corresponding to different quantiles of log consumption. In both models, changes in consumption over time did not occur in parallel, contrary to the collectivity of drinking theory. Instead, a clear divergence in the rate of drinking was observed, with most adolescent quantiles reducing consumption, while heavy consuming remained stable. Contrary to previous studies, our findings do not support a collectivity of drinking behaviour among Swedish youth. Quantile regression is a robust and appropriate method for analysing temporal changes in alcohol consumption data.


Temporal integration in the echolocating bat, Megaderma lyra.
Temporal integration is a crucial feature of auditory temporal processing. We measured the psychophysical temporal integration of acoustic intensity in the echolocating bat Megaderma lyra using a two-alternative forced-choice procedure. A measuring paradigm was chosen in which the absolute threshold for pairs of short tone pips was determined as a function of the temporal separation between the pips. The time constants determined with this paradigm are a crucial characteristic of the sonar system of M. lyra, a species orientating in its environment by very short broadband sonar calls emitted at high rates. Two different carrier frequencies for the tone pips were used to obtain data from the lower and the higher half of the hearing area of M. lyra. Both in the lower and in the higher frequency range, M. lyra showed very short time constants of about 220 microseconds. Our results are comparable to data from the echolocating dolphin, Tursiops truncatus, showing click integration times of about 260 microseconds and to estimates of auditory temporal integration in the context of echo clutter interference in the big brown bat.


Molecular mechanisms involved in NSAID-induced gastropathy.
A growing body of experimental evidence indicates that leukocyte-endothelial cell interactions may play an important role in the pathogenesis of NSAID-induced gastropathy. Using a newly described, dual radiolabeled monoclonal antibody technique to quantify adhesion molecule surface expression in vivo, we have demonstrated increases in surface expression of ICAM-1 and P-selectin in the gastric mucosa after oral administration of indomethacin. We have also found that CD18-, ICAM-1-, or P-selectin-deficient mice are less sensitive to the ulcerogenic effects of orally administered indomethacin. Although there is virtually no information regarding the regulation of expression of endothelial cell adhesion molecules (ECAMs) in experimental NSAID-induced gastropathy, the nuclear transcription factor KB (NFKB) may represent a potential modulator of transcriptional activation of ECAM expression. We have demonstrated that two structurally distinct yet highly selective proteasome inhibitors (MG341, lactacystin) inhibit tumor necrosis factor (TNF)-induced NFKB activation as well as ECAM expression in human endothelial cells in vitro. In addition, we found that these proteasome inhibitors significantly reduced indomethacin-induced gastric mucosal injury as well as gastric mucosal ICAM-1 expression in the rat in vivo. We conclude from these studies that indomethacin activates NFKB (possibly via TNF synthesis) in gastric microvascular endothelial cells, thereby enhancing surface expression of ICAM-1 which binds the CD18 on polymorphonuclear leukocytes (PMNs). These adherent PMNs are then believed to mediate endothelial and/or epithelial cell injury either directly or indirectly.


Wash-in and wash-out curves of sevoflurane and isoflurane in morbidly obese patients.
The aim of this prospective, randomized study is to compare sevoflurane and isoflurane pharmacokinetics in morbidly obese patients. With Ethical Committee approval and written informed consent, 14 obese patients (BMI >35 kg/m2), ASA physical status II, undergoing laparoscopic, silicone-adjustable gastric banding were randomly allocated to receive either sevoflurane (n=7) or isoflurane (n=7) as main anesthetic agents. General anesthesia was induced with 1 mg x kg-1 fentanyl, 6 mg x kg-1 sodium thiopental, and 1 mg x kg-1 succinylcholine followed by 0.4 mg kg-1 x h-1 atracurium bromide (doses were referred to ideal body weight). Intermittent positive pressure ventilation (IPPV) was applied using a Servo-900C ventilator with a nonrebreathing circuit and a 15 l x min-1 fresh gas flow (tidal volume: of 10 ml x kg-1; respiratory rate: 12 breaths/min; inspiratory to expiratory time ratio of 1:2) using an oxygen/air mixture (FiO2=50%), while supplemental boluses of thiopental or fentanyl were given as indicated in order to maintain blood pressure and heart rate values within +/-20% from baseline. After adequate placement of tracheal tube and stabilization of the ventilation parameters, 2% sevoflurane or 1.2% isoflurane was given for 30 min via a nonrebreathing circuit. End-tidal samples were collected at 1, 5, 10, 15, 20, 25 and 30 min, and measured using a calibrated infrared gas analyzer. General anesthesia was then maintained with the same inhalational agents, while supplemental fentanyl was given as indicated. After the last skin suture the inhalational agents were suspended, and the end tidal samples were collected at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, and 5 min. Then the lungs were manually ventilated until extubation. No differences in age, gender and body mass index were reported between the two groups. Surgical procedure required 91+/-13 in the sevoflurane group and 83+/-32 min in the isoflurane group. The FA/FI ratio was higher in the sevoflurane group from the 5th to the 30th min. Also the washout curve was faster in the sevoflurane group during the observation period; however, the observed differences were statistically significant only 30 and 60 sec after discontinuation of the inhalational agents. The results of this prospective, randomized study confirmed that sevoflurane provides more rapid wash-in and wash-out curves than isoflurane also in the morbid obese patient.


Modelling ion-pair geometries and dynamics in a 1-ethyl-1-methylpyrrolidinium-based ion-conductive crystal.
Full conformational and energy explorations are conducted on an organic ionic plastic crystal, 1-ethyl-1-methylpyrrolidium tetrafluoroborate [C2mpyr][BF4]. The onsets of various stages of dynamic behaviour, which appear to account for low-temperature solid-solid phase transitions, are investigated by using quantum-chemical simulations. It is suggested that pseudorotation of the pyrrolidine ring occurs in the first instance; the partial rotation of the entire cation subsequently occurs and may be accompanied by reorientation of the ethyl chain as the temperature increases further. A cation-anion configuration, whereby BF4(-) interacts with the C2 mpy cation from the side of the ring, is the most likely structure in the low-temperature phase IV region. These interpretations are supported by (13)C nuclear magnetic resonance chemical-shift analysis.


Coronavirus disease-related in-hospital mortality: a cohort study in a private healthcare network in Brazil.
COVID-19-related in-hospital mortality has been reported at 30.7-47.3% in Brazil, however studies assessing exclusively private hospitals are lacking. This is important because of significant differences existing between the Brazilian private and public healthcare systems. We aimed to determine the COVID-19-related in-hospital mortality and associated risk factors in a Brazilian private network from March/2020 to March/2021. Data were extracted from institutional database and analyzed using Cox regression model. Length of hospitalization and death-related factors were modeled based on available independent variables. In total, 38,937 COVID-19 patients were hospitalized of whom 3058 (7.8%) died. Admission to the intensive care unit occurred in 62.5% of cases, and 11.5% and 3.8% required mechanical ventilation (MV) and renal replacement therapy (RRT), respectively. In the adjusted model, age ≥ 61 years-old, comorbidities, and the need for MV and/or RRT were significantly associated with increased mortality (p < 0.05). Obesity and hypertension were associated with the need for MV and RRT (p < 0.05).


Embryonic lethality resulting from disruption of both N-myc alleles in mouse zygotes.
The N-myc gene is considered to play a major regulatory role in embryogenesis of the mouse because of its high expression in the organogenesis period and its encoding of nuclear proteins with DNA binding motifs. To elucidate the putative regulatory function of N-myc in embryogenesis, we undertook to inactivate this gene in ES cells. The N-myc alleles were disrupted in ES cells, line E14, by means of homologous recombination of targeting vectors that carry neomycin or hygromycin resistant genes. Homologous recombinants were obtained at the frequency of one in 6 x 10(5) electroporated cells. The inactivated N-myc alleles were transmitted through mouse germ lines. Crosses of heterozygous mice resulted in production of wild-type, heterozygous, and N-myc-null pups and fetuses at a ratio of 1:2:0, indicating embryonic lethality of the homozygotes. ES cells totally deficient in N-myc expression were also obtained by consecutive gene disruption with the use of the targeting vectors, demonstrating the non-essentiality of N-myc expression in the stem-cell state. N-myc-null ES cells offer a valuable tool in chimera analysis to elucidate the requirement for N-myc function in embryogenesis.


Fisetin effects on cell proliferation and apoptosis in glioma cells.
This research investigated the antiproliferative effects of 1-500 μM fisetin in T98G and BEAS-2B cells by MTT assay. The IC50 of fisetin in T98G cells for 24 and 48 h were 93 and 75 μM, respectively. Apoptotic alterations of fisetin-treated T98G cells were observed by transmission electron microscopy. BEAS-2B was then used in comparison to T98G cells to determine the cytotoxic effects of fisetin. The IC50 of fisetin for 24 and 48 h were recorded as 270 and 90 μM in BEAS-2B cells, respectively. Different concentrations of fisetin were selected to determine the apoptotic and necrotic effects. Consequently, fisetin was determined to have more apoptotic effects in T98G than BEAS-2B cells, dose- and time-dependently. Moreover, fisetin was found to have cytotoxicity at lower doses in T98G cells compared to carmustine, as positive control. CASPASE 3, CASPASE 9, CASPASE 8, and BAX expressions were increased by the selected fisetin doses of 25 and 50 μM, while that of BCL-2 and survivin was reduced in T98G cells. These results will serve as an essential basis of future in vitro and in vivo studies, in the continuous search for alternative treatment agents for gliomas.


Physical activity level and lifestyle-related risk factors from Catalan physicians.
Physicians' own Physical Activity (PA) and other health-related habits influence PA promotion. The current study identifies the PA level, according to the current PA recommendations and other health-related habits of physicians from the Catalan Medical Council. 2400 physicians (30-55 years) were randomly selected; each received a self-administered mailed questionnaire identifying medical specialization, work setting, health self-perception, body mass index (BMI), PA, and smoking habits. 762 physicians responded (52% female). Almost 1 in 2 (49.3%) exercised sufficiently, nearly all self-perceived good health, while 80.5% were nonsmokers. Almost 6 in 10 males reported overweight or obesity (56.9%) versus 18.2% of females. Active physicians dominated specific groups: (1) aged 45-55 years, (2) specializing either in primary care or surgery, (3) working in the private sector, (4) BMI < 25 kg/m2, (5) perceiving themselves in good health, or (6) having free leisure time. Only half of Catalan physicians met current PA recommendations; male physicians were particularly at risk for overweight/obesity. Overweight and under-exercise were associated with private workplaces and positive health perceptions, meaning that it is it is now possible to target inactive and/or overweight Catalan physicians in future interventions.


[Nutritional analysis of breakfast on rising and mid-morning snack in a college population].
To carry out a descriptive study on the breakfast model in a college population and to analyze the energy and nutrients provided, in connection with established nutritional requirements. Registry of food intake for breakfast (on rising and mid-morning snack) of a school day in a sample of 740 college students (286 men and 454 women) with ages ranging 19-24 years. Gender, age, weight, height, and body mass index, and type of residence were collected from each interviewee. Percentages intakes of nutrients have been calculated in proportion to established dietary recommendations (%IR). 93.2% had breakfast on rising and 83.8% took a mid-morning snack daily, and 53.5% do both intakes. The most common foods were dairy products (92.6%), cereals (58.8%) and sweet food (57.9%) at breakfast, and cereals (46.6%), fruits (40.7%) and sausages (34.9%) at mid-morning. The %IR of the calorie intake was 24.4% in males and 24.6% in females (n.s.). The %IR of the cholesterol intake was 38.2% in males and 23.9% in females (p < 0.05). The %IR for minerals and vitamins were greater (p < 0.05) in early breakfast. This breakfast model differs from the prototype of a healthy diet through an excessive consumption of sweet foods (early breakfast) and meat and derivatives (snack). Half of interviewee did not a mid-morning snack and the morning caloric intake was below recommended. In the case of university students concerned about the potentially negative effect it may have on academic performance.


Gene expression profile in circulating mononuclear cells after exposure to ultrafine carbon particles.
Exposure to particulate matter (PM) is associated with systemic health effects, but the cellular and molecular mechanisms are unclear. We hypothesized that, if circulating mononuclear cells play an important role in mediating systemic effects of PM, they would show gene expression changes following exposure. Peripheral blood samples were collected before (0 h) and at 24 h from healthy subjects exposed to filtered air (FA) and ultrafine carbon particles (UFPs, 50 microg/m(3)) for 2 h in a previous study (n = 3 each). RNA from mononuclear cell fraction (> 85% lymphocytes) was extracted, amplified and hybridized to Affymetrix HU133 plus 2 microarrays. Selected genes were confirmed in five additional subjects from the same study. We identified 1713 genes (UFP 24 h vs. FA 0 and 24 h, P < 0.05, false discovery rate of 0.01). The top 10 upregulated genes (fold) were CDKN1C (1.86), ZNF12 (1.83), SRGAP2 (1.82), FYB (1.79), LSM14B (1.79), CD93 (1.76), NCSTN (1.70), DUSP6 (1.69), TACC1 (1.68), and H2AFY (1.68). Upregulation of CDKN1C and SRGAP2 was confirmed by real-time-PCR. We entered 1020 genes with a ratio >1.1 or <-1.1 into the Ingenuity Pathway Analysis and identified pathways related to inflammation, tissue growth and host defense against environmental insults, such as, insulin growth factor 1 signaling, insulin receptor signaling and NF-E2-related factor-2-mediated oxidative stress response pathway. Two-hour exposures to UFP produced gene expression changes in circulating mononuclear cells. These gene changes provide biologically plausible links to PM-induced systemic health effects, especially those in the cardiovascular system and glucose metabolism.


Advanced flexible transvaginal mesh with high visibility under computerized tomography (CT) scan.
Pelvic floor disorders, including pelvic organ prolapse (POP) and stress urinary incontinence (SUI), are serious and very common. Surgery is commonly undertaken to restore the strength of the vaginal wall using transvaginal surgical mesh (TVM). However, up to 15% of TVM implants result in long-term complications, including pain, recurrent symptoms, and infection.Clinical Relevance- In this study, a new bioengineered TVM has been developed to address these issues. The TVM is visible using noninvasive imaging techniques such as computed tomography (CT); it has a highly similar structural profile to human tissue and potential to reduce pain and inflammation. These combined technological advances have the potential to revolutionize women's health.


[Abdominal aortal plexus in fur animals (order Carnivora)].
Abdominal aortal plexus was studied in foxes, polar foxes, sables and minks using macro-microscopic method of V.P. Vorobjov. Nerve ganglia of the abdominal aortal plexus in all examined fur animals are located at the roots of the largest arterial vessels originating from abdominal aorta and they are represented by paired abdominal, unpaired cranial mesenterial (excluding minks), inconstant visceral and aorto-renal, plural intermesenterial, single or plural caudal mesenterial nerve ganglia.


Stroke hospitalization under prospective payments: analysis of diagnosis related group 14.
Development of a hospital prospective payment system (PPS) for Medicare patients based on diagnosis related groups (DRGs) should generate renewed interest in acute care utilization by stroke patients. Within the PPS, these patients are classified as DRG 14--specific cerebrovascular disorders except transient ischemic attacks. Hospitals are paid a relatively fixed rate for each Medicare patient within this category. In order to investigate patterns of inpatient care for this DRG, hospital utilization patterns in four United States metropolitan areas with a variety of acute and long-term care utilization characteristics were compared. The study involved a total of 4,593 discharges in DRG 14. Hospital discharge and admission rates and mean stays of the four sample populations were evaluated. Data demonstrated that discharge and admission rates of the four areas in this DRG were similar. However, the results also indicated that mean stays for DRG 14 varied by over 100%. These differences could not be explained by differences in age level and payor status of sample populations. Some variations appeared to be related to limitations in the availability of nursing home beds for posthospital care stroke patients. These results suggest that efforts to improve the efficiency of hospital care for stroke patients under DRGs must increasingly focus on long-term care services.


Can Eye Fixation During the Grooved Pegboard Test Distinguish Between Planning and Online Correction?
The Grooved Pegboard Test, in its standard use, has well-documented utility. However, a revised methodology needs further study, leading us to investigate whether duration of eye fixation could predict performance on different task conditions of the Grooved Pegboard Test (place and remove pegs) with the preferred and nonpreferred hands. Fifty-two right-handed undergraduate students (33 male and 19 female), with a mean age of 22.22 (±3.57) years, performed the Grooved Pegboard Test. SensoMotoric eye-tracking glasses with a binocular time resolution of 30 Hz were used to measure eye fixation. The videos were recorded in iView software, and data were analyzed using BeGaze software. The number and duration of eye fixations were statistically different with preferred and nonpreferred hands and also differed across tasks. Simple linear regression showed eye fixation duration to predict movement time in the place task (preferred hand: R2 = 31%; nonpreferred hand: R2 = 41%) and in the remove task (preferred hand: R2 = 11%; nonpreferred hand: R2 = 25%). Thus, duration of eye fixation during the Grooved Pegboard Test differentially predicted performance with each hand and on preferred and different subtests of this instrument.


Immunohistochemical Method and Histopathology Judging for the Systemic Synuclein Sampling Study (S4).
Immunohistochemical (IHC) α-synuclein (Asyn) pathology in peripheral biopsies may be a biomarker of Parkinson disease (PD). The multi-center Systemic Synuclein Sampling Study (S4) is evaluating IHC Asyn pathology within skin, colon and submandibular gland biopsies from 60 PD and 20 control subjects. Asyn pathology is being evaluated by a blinded panel of specially trained neuropathologists. Preliminary work assessed 2 candidate immunoperoxidase methods using a set of PD and control autopsy-derived sections from formalin-fixed, paraffin-embedded blocks of the 3 tissues. Both methods had 100% specificity; one, utilizing the 5C12 monoclonal antibody, was more sensitive in skin (67% vs 33%), and was chosen for further use in S4. Four trainee neuropathologists were trained to perform S4 histopathology readings; in subsequent testing, their scoring was compared to that of the trainer neuropathologist on both glass slides and digital images. Specificity and sensitivity were both close to 100% with all readers in all tissue types on both glass slides and digital images except for skin, where sensitivity averaged 75% with digital images and 83.5% with glass slides. Semiquantitative (0-3) density score agreement between trainees and trainer averaged 67% for glass slides and 62% for digital images.


Midlife psychological stress and risk of dementia: a 35-year longitudinal population study.
The number of people with dementia has increased dramatically with global ageing. Nevertheless, the pathogeneses of these diseases are not sufficiently understood. The present study aims to analyse the relationship between psychological stress in midlife and the development of dementia in late-life. A representative sample of females (n = 1462) aged 38-60 years were examined in 1968-69 and re-examined in 1974-75, 1980-81, 1992-93 and 2000-03. Psychological stress was rated according to a standardized question in 1968, 1974 and 1980. Dementia was diagnosed according to Diagnostic and Statistical Manual of Mental Disorders criteria based on information from neuropsychiatric examinations, informant interviews, hospital records and registry data. During the 35-year follow-up, 161 females developed dementia (105 Alzheimer's disease, 40 vascular dementia and 16 other dementias). We found that the risk of dementia (hazard ratios, 95% confidence intervals) was increased in females reporting frequent/constant stress in 1968 (1.60, 1.10-2.34), in 1974 (1.65, 1.12-2.41) and in 1980 (1.60, 1.01-2.52). Frequent/constant stress reported in 1968 and 1974 was associated with Alzheimer's disease. Reporting stress at one, two or three examinations was related to a sequentially higher dementia risk. Compared to females reporting no stress, hazard ratios (95% confidence intervals) for incident dementia were 1.10 (0.71-1.71) for females reporting frequent/constant stress at one examination, 1.73 (1.01-2.95) for those reporting stress at two examinations and 2.51 (1.33-4.77) at three examinations. To conclude, we found an association between psychological stress in middle-aged women and development of dementia, especially Alzheimer's disease. More studies are needed to confirm our findings and to study potential neurobiological mechanisms of these associations.


Associations between enteric pathogen carriage and height-for-age, weight-for-age and weight-for-height in children under 5 years old in urban Dhaka, Bangladesh.
Nutritional factors and infectious agents may contribute to paediatric growth deficits in low- and middle-income countries; however, the contribution of enteric pathogens is only beginning to be understood. We analysed the stool from children <5 years old from an open cohort, cluster-randomised controlled trial of a point-of-collection water chlorinator in urban Bangladesh. We compared the presence/absence of 15 enteric pathogens detected via multiplex, molecular methods in the stool with concurrent Z-scores/Z-score cut-offs (-2 standard deviations (s.d.)) for height-for-age (HAZ/stunting), weight-for-age (WAZ/underweight) and weight-for-height (WHZ/wasting), adjusted for sociodemographic and trial-related factors, and measured caregiver-reported diarrhoea. Enteric pathogen prevalence in the stool was high (88% had ≥1 enteric pathogen, most commonly Giardia spp. (40%), Salmonella enterica (33%), enterotoxigenic E. coli (28%) and Shigella spp. (27%)) while reported 7-day diarrhoea prevalence was 6%, suggesting high subclinical infection rates. Many children were stunted (26%) or underweight (24%). Adjusted models suggested Giardia spp. detection was associated with lower HAZ (-0.22 s.d., 95% CI -0.44 to 0.00; prevalence ratio for stunting: 1.39, 95% CI 0.94-2.06) and potentially lower WAZ. No pathogens were associated with reported diarrhoea in adjusted models. Giardia spp. carriage may be associated with growth faltering, but not diarrhoea, in this and similar low-income settings. Stool-based enteric pathogen detection provides a direct indication of previous exposure that may be useful as a broader endpoint of trials of environmental interventions.


A Two-Phase Model for Adsorption from Solution Using Quartz Crystal Microbalance with Dissipation.
Quartz crystal microbalance with dissipation (QCM-D) conveniently monitors mass and mechanical property changes of thin films on solid substrates with exquisite resolution. QCM-D is frequently used to measure dissolved solute/sol adsorption isotherms and kinetics. Unfortunately, currently available methodologies to interpret QCM-D data treat the adlayer as a homogeneous medium, which does not adequately describe solution-adsorption physics. Tethering of the adsorbate to the solid surface is not explicitly recognized, and the liquid solvent is included in the adsorbate mass, which is especially in error for low coverages. Consequently, the areal mass of adsorbate (i.e., solute adsorption) is overestimated. Further, friction is not considered between the bound adsorbate and the free solvent flowing in the adlayer. To overcome these deficiencies, we develop a two-phase (2P) continuum model that self-consistently determines adsorbate and liquid-solvent contributions and includes friction between the attached adsorbate and flowing liquid solvent. We then compare the proposed 2P model to those of Sauerbrey for a rigid adlayer and Voinova et al. for a viscoelastic-liquid adlayer. Effects of 2P-adlayer properties are examined on QCM-D-measured frequency and dissipation shifts, including adsorbate volume fraction and elasticity, adlayer thickness, and overtone number, thereby guiding data interpretation. We demonstrate that distinguishing between adsorbate adsorption and homogeneous-film adsorption is critical; failing to do so leads to incorrect adlayer mass and physical properties.


Effects of a topical anesthetic on non-socially maintained self-injurious behavior.
In the present study we hypothesized that the self-injurious behavior (SIB) of a 12-year-old male diagnosed as having autism and severe mental retardation was maintained by automatic reinforcement. Further, we hypothesized SIB served a sensory reinforcement function related to sensation at the skin surface. The participant engaged in high rates of SIB in the form of self-slapping. A functional analysis resulted in undifferentiated findings. Additional observations indicated that SIB occurred only to exposed skin surfaces. To test for a sensory function, we applied a topical anesthetic to the participant's skin. SIB was reduced by 20 to 60% after application of the dermal anesthetic. These results support an automatic reinforcement hypothesis. Implications for treatment are discussed.


Feature Map Distillation of Thin Nets for Low-Resolution Object Recognition.
Intelligent video surveillance is an important computer vision application in natural environments. Since detected objects under surveillance are usually low-resolution and noisy, their accurate recognition represents a huge challenge. Knowledge distillation is an effective method to deal with it, but existing related work usually focuses on reducing the channel count of a student network, not feature map size. As a result, they cannot transfer "privilege information" hidden in feature maps of a wide and deep teacher network into a thin and shallow student one, leading to the latter's poor performance. To address this issue, we propose a Feature Map Distillation (FMD) framework under which the feature map size of teacher and student networks is different. FMD consists of two main components: Feature Decoder Distillation (FDD) and Feature Map Consistency-enforcement (FMC). FDD reconstructs the shallow texture features of a thin student network to approximate the corresponding samples in a teacher network, which allows the high-resolution ones to directly guide the learning of the shallow features of the student network. FMC makes the size and direction of each deep feature map consistent between student and teacher networks, which constrains each pair of feature maps to produce the same feature distribution. FDD and FMC allow a thin student network to learn rich "privilege information" in feature maps of a wide teacher network. The overall performance of FMD is verified in multiple recognition tasks by comparing it with state-of-the-art knowledge distillation methods on low-resolution and noisy objects.


Interactions of amines with silicon species in undersaturated solutions leads to dissolution and/or precipitation of silica.
The biogeochemical silicon cycle is the focus for many researchers studying the dissolution of silicon species from quartz, amorphous, and biogenic silica. Furthermore, the precipitation of biogenic silica by diatoms, radiolarian, sponges, and plants is also a popular focus for research. The ornate silica structures created by these species has attracted interest from biomaterial scientists and biochemists who have studied mineral formation in an attempt to understand how biogenic silica is formed, often in the presence of proteins and long chain polyamines. This article is at the interface of these seemingly distinct research areas. Here we investigate the effect of a range of amines in globally undersaturated silicon environments. Results are presented on the effect of amine-containing molecules on the formation of silica from undersaturated solutions of orthosilicic acid and globally undersaturated silicon environments. We sought to address two questions: can silica be precipitated/harvested from undersaturated solutions, and can we identify the silicon species that are most active in silica formation? We demonstrate that none of the bioinspired additives investigated here (e.g., poly(allylamine hydrochloride), pentaethylenehexamine, and propylamines) have any influence on orthosilicic acid at undersaturated concentrations. However, under globally undersaturated silicon concentrations, small molecules and polymers containing amine groups were able to interact with oligomers of silicic acid to either generate aggregated materials that can be isolated from solution or increase rates of oligomer dissolution back to orthosilicic acid. Additional outcomes of this study include an extended understanding of how polyelectrolytes and small molecules can promote and/or inhibit silica dissolution and a new method to explore how (bio)organic molecules interact with a forming mineral phase.


Histamine and parathyroid activity.
The effect of histamine on parathyroid function was studied in two patients. 2.75 mg histamine phosphate administered intravenously over 120 minutes induced the well known clinical effects such as facial flushing, fall in blood pressure and increase in heart rate. But the serum calcium concentration, serum immunoreactive parathormone concentration, urinary excretion of cAMP and tubular phosphate reabsorption did not change significantly. It is concluded that stimulation of histamine receptors does not play an important role in the regulation of parathyroid activity.


Conditional survival estimate in patients with Barcelona Clinic Liver Cancer stage B/C hepatocellular carcinoma treated with hepatic arterial infusion chemotherapy with/without concurrent radiotherapy.
Conditional survival (CS) provides a prognosis of patients who have already survived several years after treatment. We investigated CS in Barcelona Clinic Liver Cancer (BCLC) stage B/C hepatocellular carcinoma (HCC) patients treated with hepatic arterial infusion chemotherapy (HAIC) with or without concurrent radiotherapy (CRT). A total of 181 patients diagnosed with HCC who were treated with HAIC with or without CRT between 2011 and 2015 were retrospectively reviewed. Overall survival (OS) and CS were calculated and a subgroup analysis was performed. The 1- and 5-year survival rates of all patients were 57.0% and 24.3%. OS was significantly higher in patients with BCLC stage B than BCLC stage C patients. Patients who achieved disease control after treatment also showed longer OS than who did not respond to treatment. Provided that the patient had already survived for 0, 1, 2, and 3 years, the CS estimates of surviving an additional 2 years were 35.6%, 55.1%, 82.0%, and 77.4%, respectively. A subgroup analysis was performed to compare BCLC stage B and C patients and revealed that CS has a tendency to increase and the difference in CS between two groups decreased over time. CS reflects the change of prognosis over time and may provide a more accurate prognosis and hopeful message to patients who have already survived with treatment.


Asthma aggravation, combustion, and stagnant air.
The relationship between current concentrations of ambient air pollution and adverse health effects is controversial. We report a meteorological index of air stagnation that is associated with daily visits to the emergency department for asthma in two urban areas. Data on daily values of a stagnation persistence index and visits to the emergency department for asthma were collected for approximately two years in Spokane, Washington, USA and for 15 months in Seattle, Washington, USA. The stagnation persistence index represents the number of hours during the 24 hour day when surface wind speeds are less than the annual hourly median value, an index readily available for most urban areas. Associations between the daily stagnation persistence index and daily emergency department visits for asthma were tested using a generalised additive Poisson regression model. A factor analysis of particulate matter (PM(2.5)) composition was performed to identify the pollutants associated with increased asthma visits. The relative rate of the association between a visit to the emergency department for asthma and the stagnation persistence index was 1. 12 (95% CI 1.05 to 1.19) in Spokane and 1.21 (95% CI 1.09 to 1.35) in Seattle for an increase of 11 and 10 hours, respectively, of low wind speed in a given day. The stagnation persistence index was only correlated with one set of factor loadings; that cluster included the stagnation persistence index, carbon monoxide, and organic/elemental carbon. Increased air stagnation was shown to be a surrogate for accumulation of the products of incomplete combustion, including carbon monoxide and fine particulate levels of organic and elemental carbon, and was more strongly associated with asthma aggravation than any one of the measured pollutants.


Saccharomyces cerevisiae accumulates GAPDH-derived peptides on its cell surface that induce death of non-Saccharomyces yeasts by cell-to-cell contact.
During wine fermentations, Saccharomyces cerevisiae starts to excrete antimicrobial peptides (AMPs) into the growth medium that induce death of non-Saccharomyces yeasts at the end of exponential growth phase (24-48 h). Those AMPs were found to derive from the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH). On the other hand, the early death of non-Saccharomyces yeasts during wine fermentations was also found to be mediated by a cell-to-cell contact mechanism. Since GAPDH is a cell-wall-associated protein in S. cerevisiae, we put forward the hypothesis that the GAPDH-derived AMPs could accumulate on the cell surface of S. cerevisiae, thus inducing death of non-Saccharomyces yeasts by cell-to-cell contact. Here we show that 48-h grown (stationary phase) cells of S. cerevisiae induce death of Hanseniaspora guilliermondii and Lachancea thermotolerans by direct cell-to-cell contact, while 12-h grown cells (mid-exponential phase) do not. Immunological tests performed with a specific polyclonal antibody against the GAPDH-derived AMPs revealed their presence in the cell wall of S. cerevisiae cells grown for 48 h, but not for 12 h. Taken together, our data show that accumulation of GAPDH-derived AMPs on the cell surface of S. cerevisiae is one of the factors underlying death of non-Saccharomyces yeasts by cell-to-cell contact.


miR-26b promoter analysis reveals regulatory mechanisms by lipid-related transcription factors in goat mammary epithelial cells.
MicroRNA (miRNA) regulate protein abundance and control diverse aspects of cellular processes and biological functions associated with lipid metabolism. MiR-26b and its host gene CTDSP1 regulate triacylglycerol synthesis by synergistically suppressing the insulin-induced gene 1 (INSIG1); however, the direct regulators of miR-26b expression remain unknown. In the present study, we characterized the activity of a novel putative promoter region in miR-26b. Results revealed that promoter activity and miR-26b expression are dynamically regulated by different transcription factors including peroxisome proliferator-activated receptor gamma (PPARG), sterol regulatory element binding transcription factor 1 (SREBF1), and liver X receptor α (LXRα). Two binding sites for the SREBF1 (SRE1 and SRE3) and the PPARG (peroxisome proliferator response element 1 and 2; PPRE1 and PPRE2), respectively, were identified in the miR-26b promoter, which demonstrated that those binding sites are responsible for the activation by PPARG and SREBF1. In silico analysis and site-directed mutagenesis of LXRα binding elements (LXRE) and SREBF1 binding elements (SRE) revealed that the effects of Ad-LXRα + T0901317 requires the presence of SRE, whereas potential LXRE had no effects on miR-26b expression. This suggested that regulation of miR-26b by LXRα is indirectly via an SRE, and miR-26b is regulated by transcription factors dually through DNA methylation and directly through binding to its promoter, all of which implies that regulation of miR-26b in ruminant mammary epithelial cells results from various mechanisms. In conclusion, we demonstrate a novel dual-regulatory mechanism whereby transcription factors regulate the expression of miR-26b. Overall, these findings contribute to our understanding of the interactions between specific promoter elements and the control of transcription and translation of miRNA.


Drug Reimbursement Regulation in 6 Peer Countries.
The US has nearly 4.5% of the world's population but accounts for more than 40% of global drug spending. With the upcoming 2020 election, a top priority of many voters is to better control drug prices and reform the pharmaceutical market. In this Special Communication, the drug price mechanisms and government regulations used in 6 representative peer countries are evaluated: Australia, France, Germany, Norway, Switzerland, and the United Kingdom. Drug price regulation is compared with that currently used in the US. Eight key lessons from the regulations used in these countries and which elements are incorporated into the bills currently making their way through the US Congress are evaluated (2 from the US House of Representatives and 1 from the US Senate). None of these bills is as systemic or comprehensive in its drug pricing mechanisms and regulations as the schemes in the other countries.


Perceptually guided polygon reduction.
The properties of the human visual system are taken into account, along with the geometric aspects of an object, in a new surface remeshing algorithm and a new mesh simplification algorithm. Both algorithms have a preprocessing step and are followed by the remeshing or mesh simplification steps. The preprocessing step computes an importance map that indicates the visual masking potential of the visual patterns on the surface. The importance map is then used to guide the remeshing or mesh simplification algorithms. Two different methods are proposed for computing an importance map that indicates the masking potential of the visual patterns on the surface. The first one is based on the Sarnoff visual discrimination metric, and the second one is inspired by the visual masking tool available in the current JPEG2000 standard. Given an importance map, the surface remeshing algorithm automatically distributes few samples to surface regions with strong visual masking properties due to surface texturing, lighting variations, bump mapping, surface reflectance and inter-reflections. Similarly, the mesh simplification algorithm simplifies more aggressively where the light field of an object can hide more geometric artifacts.


Causes of death in Canadians with haemophilia 1980-1995. Association of Hemophilia Clinic Directors of Canada.
The life expectancy of individuals with haemophilia was close to that of the general population in the early 1980s. Since then, life expectancy has decreased, due to transfusion-transmitted virus infections. Deaths in individuals with haemophilia were investigated by analysing 2450 records from the Canadian Hemophilia Registry, for the years 1980-1995. Deaths were tabulated by age, year and cause, and compared with that of the Canadian male population by calculating standardized mortality ratios (SMRs). The median life expectancy at 1 year of age was calculated for various subpopulations and the impact of various population characteristics was assessed by survival regression modelling. There were 359 deaths and the annual number of deaths increased significantly after 1986. Risk factors were seropositivity to human immunodeficiency virus (relative risk 16.7, 95% CI 11.1-25.1), severe haemophilia (1.9, 1.3-2.7) and moderate haemophilia (1.8, 1.2-2.6). In HIV antibody negative individuals, the overall death rate was not increased (SMR 0.9, 95% CI 0.7-1.1) and only haemorrhage was significantly increased. In HIV antibody positive individuals, causes of death which were significantly increased were acquired immunodeficiency syndrome, liver failure, haemorrhage, lymphoma, liver cancer, nonspecific infections, and trauma or violence. Deaths due to the acquired immunodeficiency syndrome accounted for only 66% of the excess deaths in individuals who were HIV antibody positive. Life expectancy has markedly decreased since the onset of the HIV epidemic. The impact of HIV is underestimated by considering only deaths due to the acquired immunodeficiency syndrome; other HIV-linked causes need also to be considered.


One step poly(rutin) particle preparation as biocolloid and its characterization.
Poly(rutin) p(RT) particles were prepared for the first time via a simple microemulsion polymerization/crosslinking method using l-α lecithin as surfactant, cyclohexane as organic phase and glycerol diglycidyl ether (GDE) as a crosslinking agent. Highly negatively charged p(RT) particles, -48.2 mV, were obtained due to phenolic groups on the particles. It was also confirmed that p(RT) particles are thermally more stable than RT and degradable in PBS at pH7.4., e.g., 11 wt.% can degrade in 1 day and little further degradation was observed over 9 days. The prepared p(RT) particles showed insignificant antibacterial characteristics against common bacteria such as Escherichia coli ATCC8739, Staphylococcus aureus ATCC6538, and Bacillus subtilis ATCC6633 whereas the RT molecules showed significantly better antibacterial characteristics even at low concentrations. Moreover, p(RT) particles were demonstrated for use as drug delivery devices by loading rosmarinic acid (RA) as model drug and showed release capability for up to 6 days by releasing 85% of the loaded RA. Intriguingly, p(RT) particles illustrated enhanced fluorescent properties providing great potential for fluorescent active antioxidant and antibacterial materials in biomedical use.


Relationship of Preceptor Ad-hoc Entrustment Decisions to Students' Clinical Skills Performance.
This article was migrated. The article was marked as recommended. Using a workplace evaluation instrument that included clinical skills evaluation and supervisory EPA scale, this study provided empirical evidence of the relationship between preceptor evaluation of student clinical ability and their entrustment decisions at the medical student level, and advanced the understanding of general conditions that ad-hoc entrustment decision are based upon. A total of 4217 evaluations from 353 third-year medical students were included in the study. The analyses focused on entrustment decisions for seven EPAs (EPA1, 2, 3, 5, 6, 7, and 9) and the relationship with related clinical skill (e.g. history taking) performance. Pearson's correlations showed statistically significant and positive correlations within clerkships (r= 0.43-0.75) and across clerkships (r= 0.70-0.77). Analyses of individual entrustment level and skill rating also revealed that the lowest level of entrustment was predominantly associated with the rating of developing on corresponding skills, whereas the highest level of entrustment with the rating of approaching advanced/ advanced; the link between the three middle entrustment levels and particular skill ratings were less salient. Overall, these patterns of association between individual entrustment level and skill rating varied by EPAs as well as level of entrustment. Limitations of the current study were also discussed.


Estimating GFR using serum cystatin C alone and in combination with serum creatinine: a pooled analysis of 3,418 individuals with CKD.
Serum cystatin C was proposed as a potential replacement for serum creatinine in glomerular filtration rate (GFR) estimation. We report the development and evaluation of GFR-estimating equations using serum cystatin C alone and serum cystatin C, serum creatinine, or both with demographic variables. Test of diagnostic accuracy. Participants screened for 3 chronic kidney disease (CKD) studies in the United States (n = 2,980) and a clinical population in Paris, France (n = 438). Measured GFR (mGFR). Estimated GFR using the 4 new equations based on serum cystatin C alone, serum cystatin C, serum creatinine, or both with age, sex, and race. New equations were developed by using linear regression with log GFR as the outcome in two thirds of data from US studies. Internal validation was performed in the remaining one third of data from US CKD studies; external validation was performed in the Paris study. GFR was measured by using urinary clearance of iodine-125-iothalamate in the US studies and chromium-51-EDTA in the Paris study. Serum cystatin C was measured by using Dade-Behring assay, standardized serum creatinine values were used. Mean mGFR, serum creatinine, and serum cystatin C values were 48 mL/min/1.73 m(2) (5th to 95th percentile, 15 to 95), 2.1 mg/dL, and 1.8 mg/L, respectively. For the new equations, coefficients for age, sex, and race were significant in the equation with serum cystatin C, but 2- to 4-fold smaller than in the equation with serum creatinine. Measures of performance in new equations were consistent across the development and internal and external validation data sets. Percentages of estimated GFR within 30% of mGFR for equations based on serum cystatin C alone, serum cystatin C, serum creatinine, or both levels with age, sex, and race were 81%, 83%, 85%, and 89%, respectively. The equation using serum cystatin C level alone yields estimates with small biases in age, sex, and race subgroups, which are improved in equations including these variables. Study population composed mainly of patients with CKD. Serum cystatin C level alone provides GFR estimates that are nearly as accurate as serum creatinine level adjusted for age, sex, and race, thus providing an alternative GFR estimate that is not linked to muscle mass. An equation including serum cystatin C level in combination with serum creatinine level, age, sex, and race provides the most accurate estimates.


Past presidents I have known.
This paper is an account of the accomplishments of some of the early past presidents of the Medical Library Association known personally to the author in his career as a medical librarian. It demonstrates the qualities that made these librarians leaders of our profession and also indicates their personal attributes that contributed to the advancement of medical librarianship. It is hoped that the historical presentation of some of the giants of our profession will inspire present and future presidents and other medical librarians with an understanding of some of the qualities necessary to the continuing success of our profession. Sir William Osler, who was a great believer in libraries and librarians and himself a Past President of MLA, summed up four qualities in his advice to medical students equally applicable to past and present leadership in the library profession-(1) the art of detachment, (2) the virtue of method, (3) the quality of thoroughness, (4) the grace of humility (Osler, Sir William. Teacher and Student. In his Aequanimitas: with Other Addresses to Medical Students. 3d ed. Philadelphia, Blakiston Company, 1904. p. 27-31.). It is thought that our past presidents possessed all of these qualities.


Simultaneous targeting of CD44 and EpCAM with a bispecific aptamer effectively inhibits intraperitoneal ovarian cancer growth.
CD44 and EpCAM play crucial roles in intraperitoneal ovarian cancer development. In this study, we developed an RNA-based bispecific CD44-EpCAM aptamer that is capable of blocking CD44 and EpCAM simultaneously by fusing single CD44 and EpCAM aptamers with a double stranded RNA adaptor. With the aid of a panel of ovarian cancer cell lines, we found that bispecific CD44-EpCAM aptamer was much more effective than either single CD44 or EpCAM aptamer in the ability to inhibit cell growth and to induce apoptosis. When these aptamers were tested in intraperitoneal ovarian cancer xenograft model, bispecific CD44-EpCAM aptamer suppressed intraperitoneal tumor outgrowth much more significantly than single CD44 and EpCAM aptamer either alone or in combination. The enhanced efficacy of bispecific CD44-EpCAM aptamer is most likely to be attributed to its increased circulation time over the single aptamers. Moreover, we showed that bispecific CD44-EpCAM aptamer exhibited no toxicity to the host and was unable to trigger innate immunogenicity. Our study suggests that bispecific CD44-EpCAM aptamer may represent a promising therapeutic agent against advanced ovarian cancer.


["The break in care": Mothers' experiences with alcohol abuse and care in Mexico].
This article aims to analyze the experiences related to motherhood and care among mothers who attend mutual support groups to address alcohol-related harm in Mexico City and the State of Mexico. Drawing on the conceptual framework of collective health from a gender perspective, we contend that socioeconomic and gender-related factors influence the social determination of alcoholism and the health-disease-attention-care process. A qualitative study was conducted between May 2020 and January 2021, which included interviews with ten women who were selected based on specific criteria, as well as non-participant observation in a women's Alcoholics Anonymous group. The main findings show how trajectories of alcohol abuse and its management are interconnected with trajectories of care. From there, it was possible to identify a "break in care," a category that sheds light on mistreatment and the precariousness of life and health of women and their children.


Infrared ocular thermography in dogs with and without keratoconjunctivitis sicca.
Infrared thermography was used to measure temperature differences of the corneal surface between nasal and temporal limbus regions and central cornea of normal dogs and dogs with keratoconjunctivitis sicca (KCS), in order to establish temperature values in normal canine eyes and in patients with decreased Schirmer tear tests (STT) values. Dogs investigated were all either patients seen at the Veterinary Teaching Hospital of Federal University of Paraná or normal dogs that belonged to the same institution. STT were performed in all eyes. A total of 40 control eyes (STT ≥15 mm/min) and 20 eyes with low STT values (STT ≤14 mm/min) were examined. The mean STT value for eyes with normal STT values was 22.9 ± 3.9 mm/min (mean ± standard deviation), and the mean STT value for eyes with low STT value was 7.2 ± 4.8 mm/min. The mean corneal temperature was significantly lower in eyes with low STT values than in control eyes (P < 0.0001). The following significant correlations were found: (i) Schirmer and breakup time (BUT) (P = 0.0001, r = 0.5); (ii) STT values and corneal surface temperature (P = 0.001, r = 0.256); (iii) STT values and age (P = 0.0001, r = -0.448); (iv) age and corneal surface temperature (P = 0.0001, r = -0.281); and (v) BUT and corneal surface temperature (P = 0.0001, r = 0.36). Thermography is a method that can differentiate between eyes with normal and abnormal STT values. In the future, thermography might be incorporated as part of the ophthalmic examination and perhaps become a popular ancillary test for the diagnoses of ocular surface disorders.


Integrative analysis of immune-related signature profiles in eosinophilic chronic rhinosinusitis with nasal polyposis.
Eosinophilic chronic rhinosinusitis with nasal polyps (ECRSwNP) is a subtype of chronic rhinosinusitis (CRS) that is associated with the nasal cavity and sinus polyps, elevated levels of eosinophils, and dysregulated immune responses to environmental triggers. The underlying cause of ECRSwNP is not well understood, and few studies have focused on the unique features of this subtype of CRS. Our study integrated proteomic and transcriptomic data with multi-omic bioinformatics analyses. We collected nasal polyps from three ECRSwNP patients and three control patients and identified 360 differentially expressed (DE) proteins, including 119 upregulated and 241 downregulated proteins. Functional analyses revealed several significant associations with ECRSwNP, including focal adhesion, hypertrophic cardiomyopathy, and extracellular matrix (ECM)-receptor interactions. Additionally, a protein-protein interaction (PPI) network revealed seven hub proteins that may play crucial roles in the development of ECRSwNP. We also compared the proteomic data with publicly available transcriptomic data and identified a total of 1077 DE genes. Pathways enriched by the DE genes involved angiogenesis, positive regulation of cell motility, and immune responses. Furthermore, we investigated immune cell infiltration and identified biomarkers associated with eosinophil and M2 macrophage infiltration using CIBERSORT and Weighted Gene Correlation Network Analysis (WGCNA). Our results provide a more complete picture of the immune-related mechanisms underlying ECRSwNP, which could contribute to the development of more precise treatment strategies for this condition.


Efficacy of the ivomec SR bolus for control of horn flies (Diptera: Muscidae) on cattle in South Texas.
The concentration of ivermectin in the serum of Hereford heifers treated with a single Ivomec SR bolus reached a maximum of 8.8 +/- 0.9 ppb at 2 wk post-treatment. The single bolus treatment resulted in <10% mortality of adult horn flies feeding on the blood of the treated animals over the 21-wk trial. Bioassays of the manure from treated cattle showed complete inhibition of development of immature horn flies through week 19 post-treatment. When the trial was repeated using two Ivomec SR boluses/heifer, the concentration of ivermectin in the serum of the treated cattle reached a maximum level of 31.2 +/- 3.9 ppb at week 13 post-treatment. During the first 17 wk of treatment, the use of two boluses/heifer resulted in 96.2 and 81.2% mortality of adult male and female horn flies feeding on the blood of treated animals, respectively. From these studies, we conclude that a single Ivomec SR bolus used as an anthelmintic treatment can be expected to provide significant control of immature horn flies developing in the manure, but not of adults feeding on the treated cattle.


Variability in sperm suppression during testosterone administration to adult monkeys is related to follicle stimulating hormone suppression and not to intratesticular androgens.
Sex steroid-based male contraceptive regimens do not induce consistent azoospermia. The reason for this variable response is obscure. We used normal adult male monkeys, Macaca fascicularis (n = 9) as a model of testosterone (T)-induced gonadotropin suppression to understand the basis for variability in spermatogenic suppression during hormonal contraception. As observed in men, T administration to these monkeys induced azoospermia in some animals and variable degrees of spermatogenic suppression in others. Based on their sperm counts, we divided these animals into two groups: azoospermic (azoo; n = 4) and nonazoospermic (nonazoo; n = 5) groups. Sperm density, testis volumes, and serum T, bioassayable LH (bioLH), immunoassayable FSH (immunoFSH), bioassayable FSH (bioFSH), and inhibin B were examined every 2 wk during the control period, 20 wk of T administration using SILASTIC brand (Dow Corning Corp.) implants, and recovery. Testes were biopsied for estimation of intratesticular T, dihydrotestosterone, and 5alpha-androstane-3alpha,17beta-diol. Serum T levels increased 1.5- to 2-fold, leading to decreased bioLH levels (48% of control) and intratesticular T levels (15% of control); neither LH nor intratesticular T levels differed between the azoo and nonazoo groups. In contrast, serum levels of FSH, by both bio- and immunoassay, during T administration were significantly lower in the azoo than in the nonazoo group. These results suggest that the degree of suppression of spermatogenesis is closely related to the degree of suppression of FSH levels and not to the levels of intratesticular androgens or to serum LH. These results imply that FSH plays a key role in supporting spermatogenesis in monkeys in this experimental regimen and suggest that maximal suppression of FSH may be essential to ensure consistent azoospermia in men during hormonal contraception.


Identification of microRNAs differentially expressed between lung squamous cell carcinoma and lung adenocarcinoma.
Recent advances in the treatment of non-small cell lung cancer (NSCLC) with new agents require accurate histological subtyping at diagnosis to avoid the higher risk of an adverse response and to obtain the maximum therapeutic response. However, interobserver variability, tumor heterogeneity and the degree of differentiation may affect the decision concerning a pathological diagnosis of NSCLC. Therefore, the aim of this study was to identify specific microRNAs (miRNAs) as standardized biomarkers with high sensitivity and specificity in order to distinguish between squamous cell carcinoma (SCC) and adenocarcinoma (AC). Quantitative polymerase chain reaction (qPCR)‑based miRNA array analysis was performed to identify microRNAs differentially expressed between SCC and AC using 86 resected NSCLC samples in addition to adjacent normal tissues. The results were confirmed by independent qRT-PCR assays with the same test samples and 88 additional validation samples, and from this we evaluated the usefulness of the identified miRNAs as biomarkers to distinguish between SCC and AC. Three miRNAs (hsa-miR-196b, hsa-miR-205 and hsa-miR-375) were identified. Discriminant analysis combining the three miRNAs appeared to distinguish SCC from AC accurately in the test and validation samples, demonstrating a sensitivity and specificity of 76 and 80%, and 85 and 83%, respectively. hsa-miR-196b, hsa-miR-205 and hsa-miR-375 were identified as biomarkers capable of distinguishing between lung SCC and lung AC. These newly identified miRNAs may prove to be highly valuable molecular markers for the classification of NSCLC histological subtypes and may contribute to the pathogenesis of each subtype of NSCLC.


Noise-free recovery of optodigital encrypted and multiplexed images.
We present a method that allows storing multiple encrypted data using digital holography and a joint transform correlator architecture with a controllable angle reference wave. In this method, the information is multiplexed by using a key and a different reference wave angle for each object. In the recovering process, the use of different reference wave angles prevents noise produced by the nonrecovered objects from being superimposed on the recovered object; moreover, the position of the recovered object in the exit plane can be fully controlled. We present the theoretical analysis and the experimental results that show the potential and applicability of the method.


Cultured trout gill epithelia enriched in pavement cells or in mitochondria-rich cells provides insights into Na+ and Ca 2+ transport.
The lack of a suitable flat epithelial preparation isolated directly from the freshwater fish gill has led, in recent years, to the development of cultured gill epithelia on semipermeable supports. To date, their minimal capacity to actively transport ions has limited their utility as ionoregulatory models. The current study describes a new method of culturing gill epithelia consisting either of an enriched population of pavement (PV) cells or a mixed population of PV cells and mitochondria-rich (MR) cells from the gills of adult rainbow trout. Although the cell culture approach is similar to the double-seeded insert (DSI) technique described previously, it makes use of Percoll density centrifugation to first separate populations of PV and MR cells, which are then seeded on cell culture supports in varying proportions on successive days so as to produce preparations enriched in one or the other cell types. Based on rhodamine staining, the MR cell-rich epithelia exhibited a threefold higher enrichment of MR cells compared to traditional DSI preparations. In general, MR cell-rich epithelia developed extremely high transepithelial resistances (TER; >30 kOmega cm(2)) and positive transepithelial potentials (TEP) under symmetrical conditions (i.e., L15 medium on both apical and basolateral sides). Apical exposure of cell cultures to freshwater reduced TER and produced a negative TEP in all the epithelial preparations, although MR cell-rich epithelia maintained relatively high TER and negative TEP for over 2 d under these asymmetrical conditions. Measurement of unidirectional Na(+) fluxes and application of the Ussing flux ratio criterion demonstrated active Na(+) uptake in PV cell-rich and MR cell-rich epithelia under both symmetrical and asymmetrical conditions. In comparison, Ca(2+) uptake and Na(+)/K(+)-ATPase activity were significantly elevated in MR cell-rich preparations relative to the traditional DSI or PV cell-rich cultures under symmetrical conditions. This new methodology enhances our ability to tailor cultured gill epithelia on semipermeable supports with different proportions of PV cells and MR cells, thereby illuminating the ionoregulatory functions of the two cell types.


Clarifying the complex chemistry of cobalt(II) thiocyanate-based tests for cocaine using single-crystal X-ray diffraction and spectroscopic techniques.
Cobalt(II) thiocyanate-based tests are routinely used to screen cocaine products, with the formation of a blue species interpreted as a positive response. An array of other organic bases has been identified as false positives - including well-documented cocaine product adulterant lidocaine and its salt. False positives prompt continued test development, though improvements are hindered by unresolved product structures and reaction pathways. Toward greater clarity, cobalt(II) thiocyanate reactions with cocaine hydrochloride, along with lidocaine and its salt, were investigated using multiple analytical techniques. Reactions involving cocaine hydrochloride yielded glassy, amorphous blue material while reactions of lidocaine hydrochloride monohydrate produced larger, needle-like crystals whose structure was determined via single-crystal X-ray diffraction to be an ion pair (Hlidocaine+ )2 ([Co(SCN)4 ]2- )·H2 O. While the blue precipitate isolated from reactions involving cocaine hydrochloride was unsuitable for crystallographic structure determination, comparative ultraviolet-visible, attenuated total reflectance infrared, and Raman spectroscopic analysis - along with elemental analysis - supports that this solid is comprised of a comparable ion pair (Hcocaine+ )2 [Co(SCN)4 ]2- . Pink crystals isolated from lidocaine reaction vessels were identified as coordination compounds cis-[CoL2 (SCN)2 ] and trans-[CoL2 (SCN)2 ] where L = lidocaine, while pink crystals from both cocaine hydrochloride and lidocaine hydrochloride monohydrate reaction vessels were the coordination polymer trans-[Co(H2 O)2 (SCN)2 ]·H2 O. The results presented herein enable reaction optimization to favor a desired product, whether ion pair or coordination species.


Combination of aspirin and rosuvastatin for reduction of venous thromboembolism in severely injured patients: a double-blind, placebo-controlled, pragmatic randomized phase II clinical trial (The STAT Trial).
Venous thromboembolism (VTE) remains a significant source of postinjury morbidity and mortality. Beta-hydroxy beta-methylglutaryl-CoA (HMG-CoA) reductase inhibitors (rosuvastatin) significantly reduced pathologic clotting events in healthy populations in a prior trial. Furthermore, acetylsalicylic acid (ASA) has been shown to be noninferior to prophylactic heparinoids for VTE prevention following orthopedic surgery. We hypothesized that a combination of rosuvastatin/ASA, in addition to standard VTE chemoprophylaxis, would reduce VTE in critically ill trauma patients. This was a double-blind, placebo-controlled, randomized trial, evaluating VTE rates in two groups: ASA + statin (Experimental) and identical placebos (Control). Injured adults, 18-65 years old, admitted to the surgical intensive care unit without contraindications for VTE prophylaxis were eligible. Upon initiation of routine VTE chemoprophylaxis (i.e. heparin/heparin-derivatives), they were randomized to the Experimental or Control group. VTE was the primary outcome. Of 112 potentially eligible patients, 33% (n = 37, median new injury severity scale = 27) were successfully randomized, of whom 11% had VTEs. The Experimental group had no VTEs, while the Control group had 6 VTEs (4 PEs and 2 DVTs) in 4 (22%) patients (P = 0.046). The Experimental treatment was not associated with any serious adverse events. Due to the COVID-19 pandemic, the study was interrupted at the second interim analysis at <10% of the planned enrollment, with significance declared at P < 0.012 at that stage. The combination of ASA and rosuvastatin with standard VTE prophylaxis showed a favorable trend toward reducing VTEs with no serious adverse events. An appropriately powered phase III multicenter trial is needed to further investigate this therapeutic approach. Level II, Therapeutic.


Structure of stochastic dynamics near fixed points.
We analyze the structure of stochastic dynamics near either a stable or unstable fixed point, where the force can be approximated by linearization. We find that a cost function that determines a Boltzmann-like stationary distribution can always be defined near it. Such a stationary distribution does not need to satisfy the usual detailed balance condition but might have instead a divergence-free probability current. In the linear case, the force can be split into two parts, one of which gives detailed balance with the diffusive motion, whereas the other induces cyclic motion on surfaces of constant cost function. By using the Jordan transformation for the force matrix, we find an explicit construction of the cost function. We discuss singularities of the transformation and their consequences for the stationary distribution. This Boltzmann-like distribution may be not unique, and nonlinear effects and boundary conditions may change the distribution and induce additional currents even in the neighborhood of a fixed point.


Human squamous cell carcinomas evade the immune response by down-regulation of vascular E-selectin and recruitment of regulatory T cells.
Squamous cell carcinomas (SCCs) of the skin are sun-induced skin cancers that are particularly numerous in patients on T cell immunosuppression. We found that blood vessels in SCCs did not express E-selectin, and tumors contained few cutaneous lymphocyte antigen (CLA)(+) T cells, the cell type thought to provide cutaneous immunosurveillance. Tumors treated with the Toll-like receptor (TLR)7 agonist imiquimod before excision showed induction of E-selectin on tumor vessels, recruitment of CLA(+) CD8(+) T cells, and histological evidence of tumor regression. SCCs treated in vitro with imiquimod also expressed vascular E-selectin. Approximately 50% of the T cells infiltrating untreated SCCs were FOXP3(+) regulatory T (T reg) cells. Imiquimod-treated tumors contained a decreased percentage of T reg cells, and these cells produced less FOXP3, interleukin (IL)-10, and transforming growth factor (TGF)-beta. Treatment of T reg cells in vitro with imiquimod inhibited their suppressive activity and reduced FOXP3, CD39, CD73, IL-10, and TGF-beta by indirect mechanisms. In vivo and in vitro treatment with imiquimod also induced IL-6 production by effector T cells. In summary, we find that SCCs evade the immune response at least in part by down-regulating vascular E-selectin and recruiting T reg cells. TLR7 agonists neutralized both of these strategies, supporting their use in SCCs and other tumors with similar immune defects.


Depletion of a microtubule-associated motor protein induces the loss of dendritic identity.
Dendrites are short stout tapering processes that are rich in ribosomes and Golgi elements, whereas axons are long thin processes of uniform diameter that are deficient in these organelles. It has been hypothesized that the unique morphological and compositional features of axons and dendrites result from their distinct patterns of microtubule polarity orientation. The microtubules within axons are uniformly oriented with their plus ends distal to the cell body, whereas microtubules within dendrites are nonuniformly oriented. The minus-end-distal microtubules are thought to arise via their specific transport into dendrites by the motor protein known as CHO1/MKLP1. According to this model, CHO1/MKLP1 transports microtubules with their minus ends leading into dendrites by generating forces against the plus-end-distal microtubules, thus creating drag on the plus-end-distal microtubules. Here we show that depletion of CHO1/MKLP1 from cultured neurons causes a rapid redistribution of microtubules within dendrites such that minus-end-distal microtubules are chased back to the cell body while plus-end-distal microtubules are redistributed forward. The dendrite grows significantly longer and thinner, loses its taper, and acquires a progressively more axon-like organelle composition. These results suggest that the forces generated by CHO1/MKLP1 are necessary for maintaining the minus-end-distal microtubules in the dendrite, for antagonizing the anterograde transport of the plus-end-distal microtubules, and for sustaining a pattern of microtubule organization necessary for the maintenance of dendritic morphology and composition. Thus, we would conclude that dendritic identity is dependent on forces generated by CHO1/MKLP1.