Early Magnetic Resonance Imaging-Based Changes in Patients With Meniscal Tear and Osteoarthritis: Eighteen-Month Data From a Randomized Controlled Trial of Arthroscopic Partial Meniscectomy Versus Physical Therapy.
The present study was undertaken to evaluate changes in knee magnetic resonance imaging (MRI) findings over the course of 18 months in subjects with osteoarthritic change and meniscal tear treated with arthroscopic partial meniscectomy (APM) or nonoperatively with physical therapy (PT). We used 18-month follow-up data from the Meniscal Tear in Osteoarthritis Research Trial. MRI results were read with reference to the MRI Osteoarthritis Knee Score. We focused on 18-month change in bone marrow lesions (BMLs), cartilage thickness, cartilage surface area, osteophyte size, effusion-synovitis, and Hoffa-synovitis. We used multinomial logistic regression to assess associations between MRI-based changes in each feature and treatment type. A total of 351 subjects were randomized, and 225 had both baseline and 18-month MRI results. In both treatment groups, patients experienced substantial changes in several MRI-based markers. In 60% of the APM group, versus 33% of the PT group, cartilage surface area damage advanced in ≥2 subregions (adjusted odds ratio 4.2 [95% confidence interval 2.0-9.0). Patients who underwent APM also had greater advancement in scores for osteophytes and effusion-synovitis. We did not find significant associations between treatment type and change in cartilage thickness, BMLs, or Hoffa-synovitis. This cohort of patients with meniscal tear and osteoarthritis showed marked advancement in MRI-based features over 18 months. Patients treated with APM showed more advancement in some features compared to those treated nonoperatively. The clinical relevance of these early findings is unknown and requires further study.


Epigallocatechin-3-gallate and resveratrol attenuate hydrogen peroxide induced damage in neuronal cells.
The purpose of this study is to investigate how the antioxidants resveratrol and epigallocatechin-3-gallate (EGCG) protect SH-SY5Y cells against damage caused by hydrogen peroxide (H2O2). SH-SY5Y cells were pretreated with EGCG and resveratrol at concentrations of 0.1 μM, 1 μM, and 10 μM, individually and in various combinations. Cells were exposed to 250 μM H2O2 for 1-hour following a 24-hour pretreatment. The effects of EGCG and resveratrol on cellular survival against hydrogen peroxide toxicity were evaluated with the MTS. Caspase 3 levels were measured with caspase 3 ELISA test for evaluating survival. The clonogenic test was utilized to assess the colony forming capacity. The MTS test revealed that pretreatment of SH-SY5Y cells for 24 hours with EGCG and Resveratrol enhanced cellular survival against hydrogen peroxide damage at all dosages (p < 0.005). The caspase 3 ELISA test revealed that EGCG and resveratrol statistically substantially decreased caspase 3 levels and improved cellular survival via the caspase 3 pathway (p < 0.005). The clonogenic test findings show that resveratrol and EGCG statistically boost SH-SY5Y cells' potential to form colonies (p<0.005). By reducing caspase 3 levels in exposure to hydrogen peroxide damage, EGCG and resveratrol promote cellular viability (Tab. 1, Fig. 3, Ref. 37). Text in PDF www.elis.sk Keywords: epigallocatechin-3-gallate, resveratrol, hydrogen peroxide, neurodegeneration.


Protamine-induced condensation of peptide nanofilaments into twisted bundles with controlled helical geometry.
Chiral self-assembly of peptides is of fundamental interest in the field of biology and material science. Protamine, an alkaline biomacromolecule which is ubiquitous in fish and mammalian, plays crucial roles in directing the helical twisting of DNA. Inspired by this, we reported a bioinspired pathway to direct the hierarchical chiral self-assembly of a short synthetic dipeptide. The peptide could self-assemble into negatively charged chiral micelles in water that spontaneously formed a nematic liquid crystalline phase. By incorporation with protamine, the micelles condensed with the protamine into large helical bundles with precisely controlled diameter. Furthermore, to simulate the intracellular environments, we investigated macromolecular crowding on the coassembly of peptide and protamine, which leads to the formation of much thinner helical structures. The results highlight the roles of highly charged biomacromolecules and macromolecular crowding on peptide self-assembly, which are beneficial for the practical applications of self-assembling peptides in biomedicine and sensing.


Single-action versus dual-action antidepressants.
Selective serotonin reuptake inhibitors (SSRIs) have become the most popular antidepressants over the last decade, largely because they have a better side effect profile than the medications that were widely used previously, the tricyclic antidepressants (TCAs) and the monoamine oxidase inhibitors (MAOIs). The SSRIs mostly have one main mechanism of action, inhibition of serotonin reuptake. A few of the TCAs are single action but many are dual action, acting mainly on the neurochemicals serotonin and norepinephrine, among others. The MAOIs are multiple-action medications, acting on monoamines, which include serotonin and norepinephrine. While the selectivity of the SSRIs results in an improved side effect profile over the earlier dual-action antidepressants, it may also reduce their antidepressant effect. SSRIs may have a slower onset of action, result in lower remission rates, and be less effective for the physical symptoms associated with depression than TCAs and MAOIs. Newer dual-action medications have been developed that inhibit the reuptake of both serotonin and norepinephrine. These medications, called serotonin-norepinephrine reuptake inhibitors, may have fewer side effects than the earlier dual-action medications and potentially reduce the symptoms of depression more effectively than the SSRIs.


Knowledge about vaccine trials and willingness to participate in an HIV/AIDS vaccine study in the Ugandan military.
In preparation for HIV vaccine trials, knowledge about vaccines, willingness to participate in a vaccine study, and motivations for participation must be assessed. The Preparation for AIDS Vaccine Evaluation study assessed knowledge about vaccines and vaccine trials and willingness to participate in a hypothetical trial in 1,182 Ugandan military men (aged 18-30 years). Participants received education about vaccine trials and were interviewed during 24 months of follow-up observation. Its key findings are that: 1) throughout follow-up, most participants expressed willingness to participate in a hypothetical HIV vaccine trial; 2) participants are familiar with vaccines but do not clearly distinguish the use of vaccines for prevention or curing; 3) the most common reason given for being interested in participating in a vaccine trial was to be protected from HIV/AIDS; 4) trials' procedures (e.g., placebos, randomization, and blinding) were unfamiliar; and 5) knowledge about trials' procedures increased incrementally over follow-up, but at different rates for different concepts. These data demonstrate that potential vaccine trials' participants may benefit from vaccine trial education if adequate time is allowed to ensure that participants are able to master the complex information required for trial participation.


Genetic and molecular analysis of wings apart-like (wapl), a gene controlling heterochromatin organization in Drosophila melanogaster.
Mutations in the X-linked gene wings apart-like (wapl) result in late larval lethality associated with an unusual chromosome morphology. In brain cell metaphases of wapl mutants, sister chromatids of all chromosomes are aligned parallel to each other instead of assuming the typical morphology observed in wild type. This effect is due to a loosening of the adhesion between sister chromatids in the heterochromatic regions of the chromosomes. Despite this aberrant chromosome morphology, mutant brains exhibit normal mitotic parameters, suggesting that heterochromatin cohesion is not essential for proper centromere function. On the basis of these observations, we examined the role of wapl in meiotic chromosome segregation in females. wapl exhibits a clear dominant effect on achiasmate segregation, giving further support to the hypothesis that proximal heterochromatin is involved in chromosome pairing during female meiosis. We also examined whether wapl modulates position-effect variegation (PEV). Our analyses showed that wapl is a dominant suppressor of both white and Stubble variegation, while it is a weak enhancer of brown variegation. wapl maps to region 2D of the X chromosome between Pgd and pn. We identified the wapl gene within a previously conducted chromosomal walk in this region. The wapl transcriptional unit gives rise to two alternatively spliced transcripts 6.5- and 5-kb long. The protein encoded by the larger of these transcripts appears to be conserved among higher eukaryotes and contains a tract of acidic amino acids reminiscent of many chromatin-associated proteins, including two [HP1 and SU(VAR)3-7] encoded by other genes that act as suppressors of PEV.


Clinical outcome of hyperuricemia in IgA nephropathy: a retrospective cohort study and randomized controlled trial.
Hyperuricemia is an independent risk factor for renal progression in IgA nephropathy (IgAN). However, no study has evaluated the effect of allopurinol on the clinical outcome in hyperuricemic IgAN. First,a retrospective cohort study of 353 IgAN patients was conducted to explore the relationship between uric acid (UA) and the progression of renal disease over a mean period of 5 years. Then, 40 hyperuricemic IgAN patients were randomized to receive allopurinol (100-300 mg/day) or usual therapy for 6 months. The study outcomes were renal disease progression and/or blood pressure. Hyperuricemia independently predicted renal survival at 1, 3, and 5 years after adjustment for different baseline estimated glomerular filtration rates. In the randomized controlled trial, allopurinol did not significantly alter renal progression or proteinuria. The antihypertensive drug dosage was reduced in 7 of 9 cases with hypertension in the allopurinol group compared to 0 of 9 cases in the control group (p < 0.01). UA levels correlated with mean arterial pressure in normotensive patients (r = 0.388, p < 0.001). Hyperuricemia predicts the progression of IgAN independently of baseline estimated glomerular filtration rate. Allopurinol may improve the control of blood pressure. Further studies are required to explore the effects of lowering UA on renal protection in IgAN.


Review of basic science advances in HIV.
The Conference on Retroviruses and Opportunistic Infections (CROI) is held annually to provide a forum for scientists to hear the most recent advances in the field of HIV and AIDS research. Although the conference has a primary mission to showcase advances in the prevention and management of HIV-1 infection and opportunistic infections (in particular, tuberculosis and hepatitis C virus [HCV]), there continues to be a strong basic research component. Research on cellular factors that influence the interplay between the virus and the host cell, and especially, cellular factors that antagonize viral replication, had the greatest presence at the conference. In the area of retroviral pathogenesis, research on viral reservoirs and mechanisms of viral persistence in the face of antiretroviral therapy generated considerable interest. Research on mechanisms of viral persistence is beginning to reveal strategies, some of which were the focus of presentations at CROI, to eliminate long-lived viral reservoirs.


Different Induction of PD-L1 (CD274) and PD-1 (CD279) Expression in THP-1-Differentiated Types 1 and 2 Macrophages.
Phorbol 12-myristate 13-acetate (PMA)-induced differentiation of human monocytic THP-1 cells is an experimental model for preparing resting macrophages (M0) for cell polarization toward the different functional specializations of macrophages. In this study, we examined the expression of immune checkpoints by using flow cytometry following multicolor staining. The blockade of immune checkpoint by using neutralizing antibodies was performed to assess their role in PMA-induced THP-1-differentiated macrophages. Upon the inducible macrophage differentiation caused by PMA, increased expression levels of CD11b and CD68 were measured and characterized according to their adherent phenotype accompanied by the generation of cellular complexity. While the cell growth rate was abolished post-differentiation, some cells underwent cell death. Notably, we found increases in the expression of programmed cell death protein 1, also known as PD-1 (CD279), and its ligand PD-L1 (CD274), mainly in differentiated M0 (CD68+CD11b+) macrophages. However, neutralizing PD-L1/PD-1 neither blocked THP-1 cell differentiation toward macrophages nor inhibited macrophage polarization in M1 and M2. In specializing macrophages, a decrease both in CD274 and CD279 was found in M2. These results revealed the inducible expression of PD-L1/PD-1 in PMA-induced THP-1-differentiated M0 macrophages followed by a decrease in M2 macrophages.


[Difficult or Complex Bile duct stones in ERCP: Large Balloon Dilation and other stone management methods. Accumulated experience in a referral Endoscopic Center 2009- 2018.]
Bile duct stones constitutes 20% of symptomatic gallbladder disease and difficult stones are one third of this. Endoscopic papillary large balloon dilation (EPLBD) with or without prior endoscopic sphincterotomy (EST) produces excellent outcomes for the treatment of complex or difficult common bile duct (CBD) stones, alone or combined with previous therapeutic options as mechanical lithotripsy (ML) and temporary or definitive stenting. Show success rate, complications and adverse events. Show that higher success rates are obtained combining ERCP techniques with no increase in complications. We evaluated the safety and therapeutic outcomes of EPLBD with vs. without EST and other combinations for the removal of difficult bile duct stones. We described our procedures for a decade and compare them with the previous decade without balloon dilation. Of 865 patients and procedures, 223 (25.78%) had difficult stones. Treatments where EPLBD with EST (n=183), EPLBD alone group (n=40). Additional modalities where required in 15.25% (n=34). These two groups were compared with respect to overall procedure-related adverse events, overall stone removal success rate, number of sessions required for complete stone removal, need for mechanical lithotripsy, temporal or definite stenting and total procedure time. Results Safety removal of stones was achieved in one session on 84.75% of cases with EPLBD. The incidence of adverse events was not significantly different between the groups (EPLBD alone vs. EPLBD with EST: overall adverse events 12.5% vs. 10.38% (including pain); pancreatitis 2.7% vs. 2.5%, p=0.62). Overall success similar, initial success similar, and the need for additional techniques were also similar between groups. Median total procedure time tended to be greater in the EPLBD alone group (20.5 minutes) than in the EPLBD with EST group. Conclusion DPBGD in ERCP allows bile duct stone extraction rates close to 99.65% (90% in previous decade) according to other reports of literature. Adverse events of EPLBD alone or with EST are similar between them and with classic ERCP without statistical difference and similar to other world series.


The pharmaceutical industry and the lay press: the industry's point of view.
The general public has a high degree of interest in information relating to health and illness. Family magazines and daily newspapers play an important role as sources of information about these subjects. Journalists writing about medicines in newspapers in the Netherlands have been found to use a series of complementary sources to obtain ideas and information on this subject; the pharmaceutical industry is one of the sources used by them. In this paper we explore the role of the lay press as a communication channel for pharmaceutical companies. The results of this study show that information from the pharmaceutical industry to the general public has become increasingly extensive and emphatic. Pharmaceutical companies consider that it is important to inform a lay audience about their products and about the diseases for which they can be used. The lay press, both daily newspapers and family magazines, can play an important role in informing a lay audience about diseases and new or improved products. If the lay press pays attention to these products many potential 'users' can be reached. Pharmaceutical companies do approach mass media journalists with information about products in various ways at different moments. As long as independent and critical journalists and editors decide for themselves whether information about drugs coming from pharmaceutical companies is newsworthy enough to be published, what reaches the printed page is likely be genuine news and not hidden advertising. A journalist should make very clear to the reader which sources have been used to compile the article, so that the reader can decide for himself whether he wishes to regard the information as reliable.


Allosteric modulatory effects of SRI-20041 and SRI-30827 on cocaine and HIV-1 Tat protein binding to human dopamine transporter.
Dopamine transporter (DAT) is the target of cocaine and HIV-1 transactivator of transcription (Tat) protein. Identifying allosteric modulatory molecules with potential attenuation of cocaine and Tat binding to DAT are of great scientific and clinical interest. We demonstrated that tyrosine 470 and 88 act as functional recognition residues in human DAT (hDAT) for Tat-induced inhibition of DA transport and transporter conformational transitions. Here we investigated the allosteric modulatory effects of two allosteric ligands, SRI-20041 and SRI-30827 on cocaine binding on wild type (WT) hDAT, Y470 H and Y88 F mutants. Effect of SRI-30827 on Tat-induced inhibition of [3H]WIN35,428 binding was also determined. Compared to a competitive DAT inhibitor indatraline, both SRI-compounds displayed a similar decrease (30%) in IC50 for inhibition of [3H]DA uptake by cocaine in WT hDAT. The addition of SRI-20041 or SRI-30827 following cocaine slowed the dissociation rate of [3H]WIN35,428 binding in WT hDAT relative to cocaine alone. Moreover, Y470H and Y88F hDAT potentiate the inhibitory effect of cocaine on DA uptake and attenuate the effects of SRI-compounds on cocaine-mediated dissociation rate. SRI-30827 attenuated Tat-induced inhibition of [3H]WIN35,428 binding. These observations demonstrate that tyrosine 470 and 88 are critical for allosteric modulatory effects of SRI-compounds on the interaction of cocaine with hDAT.


Aromatic tripodal receptors for (C(60)-I(h))[5,6]fullerene.
Monotopic and ditopic tripodal benzene platforms featuring aromatic and perfluoroaromatic side-arms have been synthesized, and their binding properties toward C(60)-fullerene have been investigated by HPLC examining retention times on a fullerene-modified silica stationary phase, using highly polar eluants (acetonitrile and acetonitrile/water). By comparison of structurally homogeneous sets of receptors, a clear trend could be found, pointing to an increased retention for ditopic derivatives, in which binding can occur on both sides of the benzene platform, over their monotopic counterparts. Among the latter, monotopic receptors containing H-substituted aromatic residues showed stronger retention than their perfluorinated analogues. This effect was ascribed to the greater availability of the pi-electrons in a H-substituted aromatic ring with respect to the corresponding F-substituted counterpart in participating in a pi-pi interaction with the electron-poor surface of fullerene. Several NMR experiments aimed to investigate binding interactions in solution, using the much less polar solvents required by the fullerene solubility (1,1,2,2-tetrachloroethane, chloroform, toluene, and CS(2)), did not provide any evidence of binding interactions. We concluded that pi-pi interactions between fullerene and the investigated flexible tripodal receptors cannot compete with solvation in poorly polar solvents, and that the binding interactions observed by HPLC were essentially forced by the strongly polar eluant employed for the HPLC analysis.


[Self-medication with over-the-counter analgesics among 15-16 year-old teenagers].
OTC analgesics were released for sale outside pharmacies in Norway in 2003. This study assesses indications and frequency of use of these drugs among 15-16 year-old teenagers in Norway after 2003. We developed a questionnaire, which contained 65 questions with one or more response options. This was given to all pupils in the final grade at six junior high schools in a town with 60,000 inhabitants (Drammen). 367 of 626 (58.6 %) pupils participated. 50 % of the boys and 71 % of the girls had used OTC analgesics during the last four weeks; 26 % of them on a daily or weekly basis. Girls experienced episodes of pain more frequently than boys, but the proportion of episodes treated with analgesics did not differ between the sexes. Headache and muscle pain were common. Half of those with severe headache/migraine used OTC analgesics on a daily or weekly basis. The teenagers reported several reasons for experiencing pain and discomfort, such as long time spent in front of various screens, tight time schedules with physical exercise and friends, drinking too little and much noise in the classroom. Use of OTC analgesics has increased considerably among Norwegian teenagers. Drug-induced headache may occur as an adverse event. If more effort is made to improve life situations that adolescents perceive as painful and a cause of discomfort, the need for OTC analgesics may be reduced.


Readmission rates and long-term hospital costs among survivors of an in-hospital cardiac arrest.
Although an in-hospital cardiac arrest is common, little is known about readmission patterns and an inpatient resource use among survivors of an in-hospital cardiac arrest. Within a large national registry, we examined long-term inpatient use among 6972 adults aged ≥65 years who survived an in-hospital cardiac arrest. We examined 30-day and 1-year readmission rates and inpatient costs, overall and by patient demographics, hospital disposition (discharge destination), and neurological status at discharge. The mean age was 75.8±7.0 years, 56% were men, and 12% were black. There were a total of 2005 readmissions during the first 30 days (cumulative incidence rate, 35 readmissions/100 patients; 95% confidence interval, 33-37) and 8751 readmissions at 1 year (cumulative incidence rate, 185 readmissions/100 patients; 95% confidence interval, 177-190). Overall, mean inpatient costs were $7741±$2323 at 30 days and $18 629±$9411 at 1 year. Thirty-day inpatient costs were higher in patients of younger age (≥85 years, $6052 [reference]; 75-84 years, $7444 [adjusted cost ratio, 1.23; 1.06-1.42; 65-74 years, $8291 [adjusted cost ratio, 1.37; 1.19-1.59; both P<0.001) and black race (whites, $7413; blacks, $9044; adjusted cost ratio, 1.22; 1.05-1.42; P<0.001), as well as those discharged with severe neurological disability or to skilled nursing or rehabilitation facilities. These differences in resource use persisted at 1 year and were largely because of higher readmission rates. Survivors of an in-hospital cardiac arrest have frequent readmissions and high follow-up inpatient costs. Readmissions and inpatient costs were higher in certain subgroups, including patients of younger age and black race.


[Vaccines: adverse events surveillance].
The objective of the surveillance systems of vaccine adverse events is monitoring events temporally related to vaccination, to evaluate their causality with the vaccine and to detect events after the introduction of new vaccines. The ultimate goal of these systems is to provide the population with the best safety standard of the vaccines. The surveillance system can be passive (spontaneous reports) or active (active follow up of vaccinees); the majority of them are passive. The article gives a brief review of the most known vaccine adverse events surveillance systems, including the American Vaccine Adverse Events Report System (VAERS), the Canadian and European systems, a commentary about the Chilean one, highlighting its main advantages and also its limitations.


Missing risks in opportunistic screening for type 2 diabetes - CroDiabGP study.
Aim To examine two methods of extracting risks for undetected type 2 diabetes (T2D): derived from electronic medical record(EMR) and family medicine (FM) assessment during pre-consultation phase. All risks were structured in three lists of patients' data using Wonca International Classification Committee(WICC). Missing data were detected in each list. Methods A prospective study included a group of 1883 patients(aged 45-70) identified with risks. Risks were assessed based on EMR for continuity variables and FM's assessment for episodes of disease and personal related information. Patients were categorized with final diagnostic test in normoglycaemia, impaired fasting glycaemia and undetected T2D. Results Total prevalence of diabetes was 10.9% (new 1.4%), of which 59.3% were females; mean age was 57.4. The EMR risks were hypertension in 1274 patients (yes 67.6%, no 27.9%, missing 4.4%), hypolipemic treatment in 690 (yes 36.6%, no 30.9%, miss 32.5%). In the episodes of disease: gestational diabetes mellitus in 31 women (yes 2.8%, missing 97.2%). Personal information: family history of diabetes in 649 (yes 34.5%, no 12.4%, missing 53.1%), overweight in 1412 (yes 75.0%, no 8.4%, missing 16.6%), giving birth to babies >4000g in 11 women (yes 0.9%, missing 99.1%). Overweight alone was the best predictor for undiagnosed type 2 diabetes, OR: 2.11 (CI: 1.41-3.15) (p<.001). Conclusion Two methods of extraction could not detect data for episodes of the disease. In the list of personal information, FMs could not assess overweight for one in six patients and family history for every other patient. The study can stimulate improving coded and structured data in EMR.


Rotational step-cut osteotomy for treatment of metacarpal and phalangeal malunion.
Metacarpal and phalangeal malunion after fracture or replantation frequently causes rotational deformities with scissoring during digital flexion. Transverse osteotomy at the metacarpal base has been advocated for derotation, but this only partially corrects scissoring resulting from phalangeal malunion. We describe the results of rotational step-cut osteotomies at the site of malunion. There were twenty-three osteotomies in eighteen patients; seven metacarpal and sixteen in the proximal phalanx. The value of the technique is supported by the results; speedy healing of bone, satisfactory alleviation of deformity, and a useful gain in range of motion in many patients.


Pathway sampling by regenerating peripheral axons.
A century ago, Ramon y Cajal described the generalized response of regenerating peripheral axons to their environment. By using mice that express fluorescent proteins in their axons, we are now able to quantify the response of individual axons to nerve transection and repair. Sciatic nerves from nonexpressing mice were grafted into those expressing a yellow variant of green fluorescent protein, then examined at 5, 7, or 10 days after repair. Regeneration was found to be a staggered process, with only 25% of axons crossing the repair in the first week. In the setting of Wallerian degeneration, this stagger will expose growth cones to an evolving menu of molecular cues upon which to base pathway decisions. Many axons arborize, allowing them to interact simultaneously with several pathways. Arborization could serve as the anatomical substrate for specificity generation through collateral pruning. Axons often travel laterally across the face of the distal stump before choosing a pathway. As a result, the average unbranched axon has access to over 100 distal Schwann cell tubes. This extensive access, however, does not ensure correct matching of axon and end organ, suggesting that pathway choice is made on the basis of factors other than end organ identity. These observations explain the failure of refined surgical techniques to restore normal function after nerve injury. The apparent wandering of axons across the repair defies surgical control and mandates a biological approach to reuniting severed axons with appropriate distal pathways.


Use of a two-compartment model to assess the pharmacokinetics of human ethanol metabolism.
The relationship between blood ethanol concentration and hepatic ethanol metabolism commonly is calculated using the Michaelis-Menten equation and a one-compartment model that assumes equality of blood and hepatic ethanol concentrations. However, at low blood concentrations, most of the ethanol arriving at the liver is metabolized, and hepatic ethanol concentrations may fall far below that of the entering blood. We have developed a two-compartment model of ethanol metabolism that accounts for the fall in ethanol concentration that may occur as blood traverses the liver and used this model to make predictions concerning ethanol metabolism at various blood ethanol concentrations. The two-compartment model predicts that near-complete saturation will occur more abruptly and at a lower blood concentration (approximately 3 mM) than is the case with the one-compartment model. Thus, the two-compartment model predicts a near-constant ethanol elimination rate for blood ethanol concentrations above 3 mM (as commonly observed in human subjects), whereas the one-compartment model predicts an increasing elimination rate over the range of concentrations observed in experimental studies. In agreement with observed data, the two-compartment model predicts that first-pass metabolism should be extremely sensitive to the rate of ethanol absorption. Application of this model to previously published data indicated that, when absorption was slowed via concomitant food ingestion, first-pass metabolism accounts for approximately 50% and 10% of ethanol dosages of 0.15 g/kg and 0.3 g/kg, respectively. When ingested without food, there is negligible first-pass metabolism of even very small ethanol dosages (0.15 g/kg). These findings suggest that first-pass metabolism is an unimportant determinant of the blood ethanol response to ingestion of potentially inebriating doses of ethanol.


Effectiveness of a hospital school mathematics literacy program.
To receive treatment for cancer, patients in Brazil often travel to larger hospitals that may be located far away from their families and communities. Pediatric patients miss time in the classroom and may achieve educational milestones later than other students. They may also struggle with some educational topics after receiving certain types of cancer treatment. The Hospital School at the GRAACC helps to close this education gap by providing educational support to school-age students receiving treatment for cancer. In addition to providing educational services during treatment, teachers at the hospital school, Mobile School - Specific Student (EMAE). The objective of this preliminary study is to build knowledge about the impact of school enrollment on mathematics literacy in hospitalized cancer patients undergoing treatment. We followed 15-year-old patients (n = 54) with at last 1 year inside the hospital school for a period of 8 years (2001-2008). Study participants were affected by a variety of diseases including bone tumors (n = 39), Hodgkin lymphoma (n = 08) and non-Hodgkin lymphoma (n = 07). The level of participants' mathematical literacy was regularly assessed by reviewing the results of formative assessments completed by students. Using that information, students were grouped into categories according to mathematics literacy levels established by the Programme for International Student Assessment (PISA). The formative assessment is based on the analysis of all the material produced by the student and the EMAE teacher across the years of the study, including the recordings of working meetings that were held with all the teachers every class day.


Antioxidant activity of isoflavones and their major metabolites using different in vitro assays.
Isoflavone phytoestrogens found mainly in soybeans and clover are widely studied phytochemicals. Genistein and daidzein, the major isoflavones found in soy, have received the most attention. However, they undergo extensive metabolism in the intestine and the liver, which might affect their biological properties, e.g. their antioxidant capacities. Furthermore, the biological activities of other naturally occurring isoflavones, for instance, glycitein from soy or biochanin A from red clover, have not yet been studied in detail. The aim of this study was to investigate the antioxidant activities of six naturally occurring isoflavones and their corresponding oxidative and bacterial metabolites. The oxygen radical absorbance capacity assay as well as the in vitro oxidation of low density lipoproteins with the conjugated diene and the thiobarbituric acid reacting substances formation as end points were used. The oxidative metabolites of genistein and daidzein as well as equol exhibited the highest antioxidant activities in all three assays. With few exceptions, they were more effective than the positive controls quercetin and ascorbic acid. Formononetin, the 4'-O-methyl ether of daidzein, showed the lowest antioxidant property. Because the antioxidant efficacy of isoflavones as effective antioxidants is evident at concentrations well within the range found in the plasma of subjects consuming soy products, this biological activity could be of physiological relevance.


Acute Kidney Injury is Associated with Worse Prognosis In COVID-19 Patients: A Systematic Review and Meta-analysis.
The association between acute kidney injury (AKI) and outcome of coronavirus disease 2019 (COVID-19) has not yet been conclusively established. Therefore, we conducted a meta-analysis of recent scientific literature to assess whether AKI may be associated with worse prognosis and increased mortality in COVID-19 patients. A systematic search of literature was conducted between 1st November 2019 and 15th May 2020 on Medline (PubMed interface) and China National Knowledge Infrastructure (CNKI) to identify potentially eligible studies. Cohort or case-control studies reporting data on AKI in patients with or without severe COVID-19 were included. Studies were divided into separate cohorts for analysis based on two endpoints (severity [severe vs non-severe] and mortality [non-survivors vs survivors]). Data were pooled into a meta-analysis to estimate pooled odds ratio (OR) with 95% confidence interval (95% CI) for either outcome. A total of 15 studies (n= 5,832 patients) were included in the analysis. Overall, AKI was found to be associated with significantly increased odds of COVID-19 severity (OR= 18.5; 95% CI 8.99-38.08) and mortality (OR= 23.9; 95% CI 18.84-30.31). No heterogeneity was observed for both outcomes (Cochran's Q= 6.21, p=0.52, I2=0% and Cochran's Q= 4.56, p=0.47, I2=0% respectively). -Conclusion: According to current data, AKI seems to be associated with worse prognosis in COVID-19 -patients. -Further investigation of the underlying mechanism of renal disease in COVID-19 would be needed to clarify possible therapeutic targets. AKI could be used as a clinical characteristic in severity classification and risk -stratification.


The potential role for management of U.S. public lands in greenhouse gas mitigation and climate policy.
Management of forests, rangelands, and wetlands on public lands, including the restoration of degraded lands, has the potential to increase carbon sequestration or reduce greenhouse gas (GHG) emissions beyond what is occurring today. In this paper we discuss several policy options for increasing GHG mitigation on public lands. These range from an extension of current policy by generating supplemental mitigation on public lands in an effort to meet national emissions reduction goals, to full participation in an offsets market by allowing GHG mitigation on public lands to be sold as offsets either by the overseeing agency or by private contractors. To help place these policy options in context, we briefly review the literature on GHG mitigation and public lands to examine the potential for enhanced mitigation on federal and state public lands in the United States. This potential will be tempered by consideration of the tradeoffs with other uses of public lands, the needs for climate change adaptation, and the effects on other ecosystem services.


Altered attentional control over the salience network in complex regional pain syndrome.
The degree and salience of pain have been known to be constantly monitored and modulated by the brain. In the case of maladaptive neural responses as reported in centralized pain conditions such as complex regional pain syndrome (CRPS), the perception of pain is amplified and remains elevated even without sustained peripheral pain inputs. Given that the attentional state of the brain greatly influences the perception and interpretation of pain, we investigated the role of the attention network and its dynamic interactions with other pain-related networks of the brain in CRPS. We examined alterations in the intra- and inter-network functional connectivities in 21 individuals with CRPS and 49 controls. CRPS-related reduction in intra-network functional connectivity was found in the attention network. Individuals with CRPS had greater inter-network connectivities between the attention and salience networks as compared with healthy controls. Furthermore, individuals within the CRPS group with high levels of pain catastrophizing showed greater inter-network connectivities between the attention and salience networks. Taken together, the current findings suggest that these altered connectivities may be potentially associated with the maladaptive pain coping as found in CRPS patients.


Dynamic changes in nitric oxide and mitochondrial oxidative stress with site-dependent differential tissue response during anoxic preconditioning in rat heart.
In this study, dynamic changes in nitric oxide (NO) and mitochondrial superoxide (O(2)(*-)) were examined during anoxic preconditioning (AP) in rat heart model. AP and anoxia-reoxygenation (A/R) were performed on isolated hearts and single cardiomyocytes. The cellular insult in the form of infarct size and DNA damage were localized and correlated with NO synthases (endothelial and inducible) expression levels. The results showed that endocardium was the most affected region in AP groups, whereas the larger area of infarct was confined to mid- and epicardium in the A/R group. Interestingly, a high-level expression of immunofluorescent NO synthases was restricted to viable areas in the AP. In contrast to the gradual increase in O(2)(*-) level that occurred in the AP group, a sudden massive increase in its level was demonstrated at the onset of reoxygenation in the A/R group. The observed increase in NO production during reoxygenation in the AP group was attenuated by inducible NO synthase inhibitor. The study revealed, on a real-time basis, the role played by preconditioning for modulating NO and O(2)(*-) levels on behalf of cell survival. The results afford a better understanding of cardiac-adapting mechanism during AP and the role of inducible NO synthase in this important phenomenon.


Comparison of laser speckle contrast imaging with laser Doppler for assessing microvascular function.
To compare the inter-day reproducibility of post-occlusive reactive hyperaemia (PORH) and sympathetic vasomotor reflexes assessed by single-point laser Doppler flowmetry (SP-LDF), integrating-probe LDF (IP-LDF) and laser speckle contrast imaging (LSCI), and the spatial variability of PORH assessed by IP-LDF and LSCI. We also evaluated the relationship between IP-LDF and LSCI perfusion values across a broad range of skin blood flows. Eighteen healthy adults (50% male, age 27 ± 4 years) participated in this study. Using SP-LDF, IP-LDF and LSCI, indices of skin blood flow were measured on the forearm during PORH (1-, 5- and 10-min occlusions) and on the finger pad during inspiratory gasp and cold pressor tests. These tests were repeated 3-7 days later. Data were converted to cutaneous vascular conductance (CVC; laser Doppler flow/mean arterial pressure) and expressed as absolute and relative changes from pre-stimulus CVC (ΔCVC(ABS) and ΔCVC(REL), respectively), as well as normalised to peak CVC for the PORH tests. Reproducibility was expressed as within-subjects coefficients of variation (CV, in %) and intraclass correlation coefficients. The reproducibility of PORH on the forearm was poorer when assessed with SP-LDF and IP-LDF compared to LSCI (e.g., CV for 5-min PORH ΔCVC(ABS)=35%, 27% and 19%, respectively), with no superior method of data expression. In contrast, the reproducibility of the inspiratory gasp and cold pressor test responses on the finger pad were better with SP-LDF and IP-LDF compared to LSCI (e.g., CV for inspiratory gasp ΔCVC(REL)=13%, 7% and 19%, respectively). The spatial variability of PORH responses was poorer with IP-LDF compared to LSCI (e.g., CV ranging 11-35% versus 3-16%, respectively). The association between simultaneous LSCI and IP-LDF perfusion values was non-linear. The reproducibility of cutaneous PORH was better when assessed with LSCI compared to SP-LDF and IP-LDF; probably due to measuring larger skin areas (lower inter-site variability). However, when measuring sympathetic vasomotor reflexes on the finger pad, reproducibility was better with SP-LDF and IP-LDF, perhaps due to the high sensitivity of LSCI to changes in skin blood flow at low levels.


Complement-mediated killing of Ureaplasma urealyticum by antibody directed against components of the growth medium.
Many strains of Ureaplasma urealyticum were inactivated, in the presence of complement, by a control antiserum prepared in guinea-pigs against the uninfected culture medium used to grow ureaplasmas. This mycoplasmacidal activity of the control serum, unlike that of the specific antisera prepared against the organisms themselves, was removed by treatment with dithiothreitol or by absorption with the horse-serum component of the medium, suggesting that the activity was due to an antibody of the IgM class acting on horse-serum proteins that had become associated with the surface of the ureaplasmas. The mycoplasmacidal activity in the specific ureaplasma antisera appeared to be due mainly to antibody of the IgG class. A similar complement-dependent mycoplasmacidal antibody to U. urealyticum apparently active against serum components, was present in normal rabbit sera.


Increased rates of adverse outcomes for gestational diabetes and pre-pregnancy diabetes in on-reserve First Nations Women in Ontario, Canada.
To compare the prevalence of diabetes in pregnancy, pregnancy care and adverse pregnancy outcomes in on-reserve First Nations women vs. non-First Nations women in Ontario, Canada. A retrospective population-based cohort study was performed. All 487368 live singleton hospital deliveries between 1 April 2002 and 31 March 2010 were identified. Outcomes were defined by linking mothers and infants to provincial healthcare administrative databases. Diabetes in pregnancy was more prevalent in First Nations women (10.3 vs. 6.0%). They received less pregnancy care and had higher rates of adverse outcomes than non-First Nations women with diabetes. First Nations women are at a higher risk of diabetes in pregnancy and adverse outcomes. This highlights the need for increased care for pregnant First Nations women.


Differential regulation of spo0A transcription in Bacillus subtilis: glucose represses promoter switching at the initiation of sporulation.
We have shown by S1 nuclease mapping with in vivo transcripts that the differential expression of a sporulation-regulatory gene, spo0A, is regulated by switching of two discrete promoters during the initiation of sporulation in Bacillus subtilis; vegetative mRNA was transcribed from an upstream promoter (Pv, vegetative promoter), and sporulation-specific mRNA was transcribed from the other promoter (Ps, sporulation-specific promoter) about 150 bp downstream of the Pv promoter. Transcription from the Pv promoter was at a low level and shut off at T0.5. On the other hand, transcription from the Ps promoter was strongly induced at T0.5 and increased until T2.5. In the presence of 2% glucose, Pv-directed transcription was not shut off and was observed even at T1.5, whereas the induction of Ps-directed transcription was completely repressed. A mutant in which the spo0A gene was transcribed only from the Ps promoter could sporulate normally in the presence of 0.1% glucose but could not sporulate at all in the presence of 2% glucose. In a catabolite-resistant sporulation mutant carrying crsA47 (sigA47), a mutation within the gene encoding sigma A, normal promoter switching from Pv to Ps was observed in the presence of 2% glucose.


In vitro enamel sealing of self-etch adhesives.
The use of self-etch adhesives has increased in spite of reports of deficient enamel bonding. Some clinicians etch enamel separately to circumvent this shortfall. Therefore, the objective of this study was to assess the influence of acid-etching on the enamel sealing of 3 self-etch adhesives after thermal fatigue. Two box-type preparations were restored in each of 30 bovine incisors with 1 of 3 self-etch adhesives: Adper Prompt L-Pop (3M ESPE); Clearfil SE Bond (Kuraray America); or iBond (Heraeus Kulzer), with and without phosphoric acid enamel etching, followed by Filtek Z250 (3M ESPE). After half of the restorations were fatigued for 1,500 thermal cycles, marginal sealing was challenged with 50% ammoniacal silver nitrate. Silver penetration was ranked from 0 to 4 and interfaces analyzed under a field-emission scanning electron microscope (FESEM) with a backscattered detector. Nonparametric statistical analyses were carried out at a 95% confidence level. Clearfil SE Bond resulted in significantly less enamel leakage than the other 2 self-etch adhesives. Acid etching significantly reduced silver infiltration for all adhesives when specimens were thermocycled. When specimens were not thermocycled, acid etching only reduced silver infiltration for iBond. Under the FESEM, silver deposition was observed inside the adhesive layer for Adper Prompt L-Pop and iBond. For Clearfil SE Bond only 2 of 10 specimens displayed silver infiltration along the enamel-adhesive interface. Etching with phosphoric acid improved the enamel marginal sealing of the 3 self-etch adhesives when specimens were subjected to thermal fatigue.


Dissecting the mechanisms of squirrel monkey (Saimiri boliviensis) social learning.
Although the social learning abilities of monkeys have been well documented, this research has only focused on a few species. Furthermore, of those that also incorporated dissections of social learning mechanisms, the majority studied either capuchins (Cebus apella) or marmosets (Callithrix jacchus). To gain a broader understanding of how monkeys gain new skills, we tested squirrel monkeys (Saimiri boliviensis) which have never been studied in tests of social learning mechanisms. To determine whether S. boliviensis can socially learn, we ran "open diffusion" tests with monkeys housed in two social groups (N = 23). Over the course of 10 20-min sessions, the monkeys in each group observed a trained group member retrieving a mealworm from a bidirectional task (the "Slide-box"). Two thirds (67%) of these monkeys both learned how to operate the Slide-box and they also moved the door significantly more times in the direction modeled by the trained demonstrator than the alternative direction. To tease apart the underlying social learning mechanisms we ran a series of three control conditions with 35 squirrel monkeys that had no previous experience with the Slide-box. The first replicated the experimental open diffusion sessions but without the inclusion of a trained model, the second was a no-information control with dyads of monkeys, and the third was a 'ghost' display shown to individual monkeys. The first two controls tested for the importance of social support (mere presence effect) and the ghost display showed the affordances of the task to the monkeys. The monkeys showed a certain level of success in the group control (54% of subjects solved the task on one or more occasions) and paired controls (28% were successful) but none were successful in the ghost control. We propose that the squirrel monkeys' learning, observed in the experimental open diffusion tests, can be best described by a combination of social learning mechanisms in concert; in this case, those mechanisms are most likely object movement reenactment and social facilitation. We discuss the interplay of these mechanisms and how they related to learning shown by other primate species.


Occlusal perceptions of children seeking orthodontic treatment: impact of ethnicity and socioeconomic status.
With the growth of orthodontic intervention at younger ages and increased interest in improving dentofacial appearance among the general public, it is important to assess whether demand for treatment is uniform across ethnic and socioeconomic groups. This study compared 3 groups of children who varied by location, payment source, and ethnicity. The sample consisted of 150 children in the Bronx, NY, and 100 in Seattle, Wash, who were undergoing or anticipating orthodontic treatment in publicly funded dental clinics. Ethnic minorities comprised 69% and 92%, respectively, of these groups. The third group consisted of 84 children in Seattle, Anchorage (Alaska), and Chicago who had sought treatment by private practitioners; ethnic minorities comprised 22% of this group. Data were collected from children and parents or guardians by questionnaires. Desire for treatment was higher among children in the publicly funded clinics and among black children than whites or Asian Americans. Children in publicly funded clinics rated themselves as having worse occlusions as determined by anterior crowding, overbite, overjet, diastema, and open bite. Children in the Bronx clinic accepted a wider range of occlusion as attractive. Stage of treatment affected judgments of attractiveness. Vicarious experience with orthodontics through parents or siblings made children more tolerant of dentofacial disharmony, with more favorable ratings of malocclusion in this group than among children who had no family experience with orthodontics. Hispanic and mixed-ethnicity children rated themselves more negatively on all dimensions. These results suggest that both socioeconomic status and ethnicity play roles in children's desire for treatment, self-assessed need, and judgments of esthetics. A clinician's sensitivity to such differences can improve patient cooperation with treatment.


Microbiological Safety of Non-Food Products: What Can We Learn from the RAPEX Database?
For consumer protection across borders, the European Union has established the rapid alert system for dangerous non-food products (RAPEX), with the overarching goal of preventing or limiting the sale and use of non-food products that present a serious risk for the health and safety of consumers. In our study, we comprehensively analyzed RAPEX notifications associated with products posing a microbiological risk from 2005 through 2017. Additional information was retrieved from national laboratory reports. A total of 243 microbiologically harmful consumer products triggered notifications in 23 out of 31 participating countries. About half of the products were reported by Spain, Germany, and Italy. Notifications mainly included contaminated toys, cosmetics, and chemical products. Depending on the notifying country, measures taken to prevent the spread of dangerous products were predominantly ordered either by public authorities or economic operators. The interval between microbiological diagnosis and the date of RAPEX notifications considerably varied between RAPEX member states, ranging between a few days and 82 weeks. The nature and extent of RAPEX usage substantially differed among member states, calling for harmonization and optimization. Slight modifications to RAPEX could help to systematically record microbiological hazards, which may improve the assessment of potential health risks due to contaminated non-food products.


Albuminuria and risk of cardiovascular events, death, and heart failure in diabetic and nondiabetic individuals.
Microalbuminuria is a risk factor for cardiovascular (CV) events. The relationship between the degree of albuminuria and CV risk is unclear. To estimate the risk of CV events in high-risk individuals with diabetes mellitus (DM) and without DM who have microalbuminuria and to determine whether levels of albuminuria below the microalbuminuria threshold increase CV risk. The Heart Outcomes Prevention Evaluation study, a cohort study conducted between 1994 and 1999 with a median 4.5 years of follow-up. Community and academic practices in North and South America and Europe. Individuals aged 55 years or more with a history of CV disease (n = 5545) or DM and at least 1 CV risk factor (n = 3498) and a baseline urine albumin/creatinine ratio (ACR) measurement. Cardiovascular events (myocardial infarction, stroke, or CV death); all-cause death; and hospitalization for congestive heart failure. Microalbuminuria was detected in 1140 (32.6%) of those with DM and 823 (14.8%) of those without DM at baseline. Microalbuminuria increased the adjusted relative risk (RR) of major CV events (RR, 1.83; 95% confidence interval [CI], 1.64-2.05), all-cause death (RR, 2.09; 95% CI, 1.84-2.38), and hospitalization for congestive heart failure (RR, 3.23; 95% CI, 2.54-4.10). Similar RRs were seen for participants with or without DM, even after adjusting for other CV risk factors (eg, the adjusted RR of the primary aggregate end point was 1.97 [95% CI, 1.68-2.31] in those with DM and 1.61 [95% CI, 1.36-1.90] in those without DM). Compared with the lowest quartile of ACR (<0.22 mg/mmol), the RRs of the primary aggregate end point in the second quartile (ie, ACR range, 0.22-0.57 mg/mmol) was 1.11 (95% CI, 0.95-1.30); third quartile, 1.38 (95% CI, 1.19-1.60; ACR range, 0.58-1.62 mg/mmol); and fourth quartile, 1.97 (95% CI, 1.73-2.25; ACR range, >1.62 mg/mmol) (P for trend <.001, even after excluding those with microalbuminuria). For every 0.4-mg/mmol increase in ACR level, the adjusted hazard of major CV events increased by 5.9% (95% CI, 4.9%-7.0%). Our results indicate that any degree of albuminuria is a risk factor for CV events in individuals with or without DM; the risk increases with the ACR, starting well below the microalbuminuria cutoff. Screening for albuminuria identifies people at high risk for CV events.


HIV-associated Guillain-Barré syndrome.
Human immunodeficiency virus-associated Guillain-Barré syndrome (HIV-GBS) has been reported since 1985. Based on previous reports, this neuropathy typically occurs early in HIV infection, even at seroconversion, prior to developing acquired immunodeficiency syndrome (AIDS). Patients with GBS and CD4 counts of <50 have been proposed to have cytomegalovirus (CMV) infection and empiric gancyclovir is recommended. We reviewed medical records of 10 patients with HIV-GBS at five hospitals from 1986 to 1999. The mean CD4 count was 367/mm(3) (range 55-800). GBS was the first symptom of HIV infection in three patients. Four patients had AIDS with CD4 counts ranging from 55 to 190. CSF white blood cell (WBC) was 0 wbc/mm(3) in four patients, 2-10 wbc/mm(3) in three and 11-17 wbc/mm(3) in two. Three had recurrent weakness from 9 weeks to 4 years after the onset of symptoms, which persisted. HIV-GBS occurs in early and late stages of HIV infection, and may follow the onset of AIDS. No patients were seen with severe immunosuppression (CD4<50). A mild cerebrospinal fluid (CSF) pleocytosis in GBS suggests HIV infection, but is frequently absent. Compared to HIV-negative people, HIV-GBS may be associated with more frequent recurrent episodes or the development of CIDP.


Probiotic roles of Lactobacillus sp. in swine: insights from gut microbiota.
The use of lactobacilli as probiotics in swine has been gaining attention due to their ability to improve growth performance and carcass quality, prevent gastrointestinal infection and most importantly, their 'generally recognized as safe' status. Previous studies support the potential of lactobacilli to regulate host immune systems, enhance gut metabolic capacities and maintain balance in the gut microbiota. Research on swine gut microbiota has revealed complex gut microbial community structure and showed the importance of Lactobacillus to the host's health. However, the species- and strain-specific characteristics of lactobacilli that confer probiotic benefits are still not well understood. The diversity of probiotic traits in a complex gut ecosystem makes it challenging to infer the relationships between specific functions of Lactobacillus sp. and host health. In this review, we provide an overview of how lactobacilli play a pivotal role in the swine gut ecosystem and identify key characteristics that influence gut microbial community structure and the health of pigs. In addition, based on recent and ongoing meta-omics and omics research on the gut microbiota of pigs, we suggest a workflow combining culture-dependent and culture-independent approaches for more effective selection of probiotic lactobacilli.


Surface waves on cylindrical solids: numerical and experimental study.
The use of Rayleigh waves enables the solution of several important inspection problems. Propagation of surface waves along straight boundaries has been properly studied but investigations about their propagation on cylindrical surfaces are not sufficient, despite they can be still of interest for NDE applications. It has been proved experimentally that a surface wave pulse suffers a phase shift during its propagation along a cylindrical surface. A numerical approach has been developed to efficiently study these effects for different materials, curvatures and frequencies. This study can help the scientific community to better understand the phenomenon, quite complex and not yet fully explored.


Cellular distribution of smooth muscle actins during mammalian embryogenesis: expression of the alpha-vascular but not the gamma-enteric isoform in differentiating striated myocytes.
The cellular distribution of the alpha-vascular and gamma-enteric smooth muscle actin isoforms was analyzed in rat embryos from gestational day (gd) 8 through the first neonatal week by in situ antigen localization using isoactin specific monoclonal antibodies. The alpha-vascular actin isoform was first detected on gd 10 in discrete cells lining the embryonic vasculature. By gd 14, this isoform was also present in the inner layers of mesenchymal cells condensing around the developing airways and gut. The gamma-enteric actin, however, was not detected until gd 15 when cells surrounding the developing aorta, airways, and gut labeled with the gamma-enteric-specific probe. There was continued expression of these two actin isoforms in regions of developing smooth muscle through the remainder of gestation and first neonatal week at which time their distribution coincided with that found in the adult. In addition to developing smooth muscle, the alpha-vascular actin isoform was expressed in differentiating striated muscle cells. On gd 10, there was intense labeling with the alpha-vascular specific probe in developing myocardiocytes and, within 24 h, in somitic myotomal cells. Although significant levels of this smooth muscle actin were present in striated myocytes through gd 17, by the end of the first postnatal week, alpha-vascular actin was no longer detectable in either cardiac or skeletal muscle. Thus, the normal developmental sequence of striated muscle cells includes the transient expression of the alpha-vascular smooth muscle actin isoform. In contrast, the gamma-enteric smooth muscle actin was not detected at any time in embryonic striated muscle. The differential timing of appearance and distribution of these two smooth muscle isoforms indicates that their expression is independently regulated during development.


Theoretical and experimental study on passively Q-switched intracavity frequency-doubled solid-state yellow Raman lasers.
Normalized space-dependent rate equations of passively Q-switched intracavity frequency-doubled Raman lasers are deduced for the first time. The normalized rate equations are solved numerically to investigate the influences of the normalized variables on the yellow laser performance. The LD end-pumped passively Q-switched Nd:YAG/SrWO(4)/KTP/Cr:YAG yellow Raman laser is realized, and the maximum yellow laser output power is 350 mW with the incident pump power of 5.9 W with Cr:YAG of 85% initial transmission. The theoretical analysis and optimization are taken out for the experiment, and the theoretical results are in accordance with the experimental ones.


Fractures of the tibial plafond. The pilon fracture.
The fracture of the tibial plafond or pilon fracture is an uncommon but difficult fracture to manage. Fracture of the plafond occurs when the talus is driven into the tibia from axial compression. The type of fracture that occurs will depend on the position and rotation of the foot at the time of impact. Historically, these fractures have been treated in a number of manners, but the best results have occurred when stable internal fixation is accomplished using plates and screws. Basic steps in reconstruction are restoration of anatomic length of the fibula with plate fixation, reconstruction of the tibial articular surface, cancellous bone grafting of the metaphyseal defect, and buttress plating either anteriorly or medially of the distal tibia. If anatomic reconstruction of the joint surface can be restored and stable fixation achieved, early motion of the ankle is made possible. This early motion reduces stiffness of the ankle and will yield the most satisfying results.


The need for immune biomarkers for treatment prognosis and response in genitourinary malignancies.
Immune biomarkers encompass a wide range of blood-borne and cell-associated molecules whose detection or expression may change in response to an immune therapy. These immune therapies encompass a range of platforms including autologous cellular products, in other words, dendritic cells, prime boost DNA vaccines, chimeric antigen receptor (CAR) T cells and checkpoint inhibitors. The response to checkpoint inhibitors by a particular cancer may not be necessarily associated with a change in a particular immune biomarker; other immune biomarkers are needed to assess their association with treatment response or a change in the biology that can impact on the immunologic milieu. How these potential biomarkers can be incorporated into clinical trial design, and their role in interrogating the immunologic milieu will be discussed.


P40SDB25, a putative CDK inhibitor, has a role in the M/G1 transition in Saccharomyces cerevisiae.
The Saccharomyces cerevisiae protein kinase Dbf2 carries out an essential function in late mitosis, and its kinase activity is cell-cycle regulated around anaphase/telophase. We have isolated SDB25, a high copy suppressor of temperature-sensitive dbf2 mutants, and genetic analysis suggests that the two proteins may function in parallel pathways in late mitosis. SDB25 encodes p40, a previously characterized substrate and potent inhibitor of Cdc28 kinase activity. Sdb25 is a phosphoprotein, and Sdb25 immunoprecipitates have a histone H1 kinase activity that is CDC28-dependent. Remarkably, Sdb25 transcript levels, protein levels, and associated kinase activity are precisely cell-cycle regulated, sharing a common peak in late mitosis. Moreover, Sdb25 protein levels and associated kinase activity are sharply up-regulated at the peak of Dbf2 kinase activity in cells released from a dbf2 ts block. The Sdb25 protein then disappears around Start in the next cell cycle. This indicates that SDB25 function is confined to M/G1, and morphological analysis of sdb25 delta cells supports this conclusion. Our data suggest that Sdb25 functions in a pathway in late mitosis leading to the down-regulation of Cdc28 kinase activity as cells traverse the M/G1 boundary.


New mechanism of organophosphorus pesticide-induced immunotoxicity.
Organophosphorus pesticides (OPs) are widely used throughout the world as insecticides in agriculture and as eradicating agents for termites around homes. The main toxicity of OPs is neurotoxicity, which is caused by the inhibition of acetylcholinesterase. OPs also affect the immune response, including effects on antibody production, interleukin-2 production, T cell proliferation, decrease of CD5 cells, and increases of CD26 cells and autoantibodies, Th1/Th2 cytokine profiles, and the inhibition of natural killer (NK) cell, lymphokine-activated killer (LAK) cell, and cytotoxic T lymphocyte (CTL) activities. However, there have been few studies of the mechanism of OP-induced immunotoxicity, especially the mechanism of OP-induced inhibition of cytolytic activity of killer cells. This study reviews new mechanisms of OP-induced inhibition of the activities of NK cells, LAK cells, and CTLs. It has been reported that NK cells, LAK cells, and CTLs induce cell death in tumors or virus-infected target cells by two main mechanisms. The first mechanism is direct release of cytolytic granules that contain the pore-forming protein perforin, several serine proteases termed granzymes, and granulysin by exocytosis to kill target cells, which is called the granule exocytosis pathway. The second mechanism is mediated by the Fas ligand (Fas-L)/Fas pathway, in which FasL (CD95 L), a surface membrane ligand of the killer cell cross links with the target cell's surface death receptor Fas (CD95) to induce apoptosis of the target cells. To date, it has been reported that OPs inhibit NK cell, LAK cell, and CTL activities by at least the following three mechanisms: 1) OPs impair the granule exocytosis pathway of NK cells, LAK cells, and CTLs by inhibiting the activity of granzymes, and by decreasing the intracellular levels of perforin, granzyme A, and granulysin, which were mediated by inducing degranulation of NK cells and by inhibiting the transcription of the mRNAs of perforin, granzyme A, and granulysin. 2) OPs impair the FasL/Fas pathway of NK cells, LAK cells, and CTLs, as investigated by using perforin-knockout mice, in which the granule exocytosis pathway of NK cells does not function and only the FasL/Fas pathway remains functional. 3) OPs induce apoptosis of immune cells.


Understanding the mechanisms of placebo and nocebo effects.
Although placebos have long been considered a nuisance in clinical research, over recent years they have become an active and productive field of research. Indeed, the placebo effect represents an elegant model to understand how the brain works. It is worth knowing that there is not a single but many placebo effects, with different mechanisms across different systems, medical conditions and therapeutic interventions. For example, brain mechanisms of expectation, anxiety and reward are all involved, as well as a variety of learning phenomena. There is also some experimental evidence of different genetic variants in placebo responsiveness. Pain and Parkinson's disease represent the most productive models to better understand the neurobiology of the placebo effect. In these medical conditions the neural networks involved have indeed been identified: that is, opioid, cannabinoid, cholecystokinin, cyclooxygenase, and dopamine modulatory networks in pain; and part of the basal ganglia circuitry in Parkinson's disease. Overall, there is today compelling evidence that placebos and drugs share common biochemical pathways and activate the same receptor pathways, which suggests possible interference between social stimuli and therapeutic rituals on one hand and pharmacological agents on the other. The same holds true for the nocebo effect, the opposite phenomenon of placebo. The assessment of patients' expectations should become the rule in clinical trials in order to allow us a better interpretation of therapeutic outcomes when comparing placebo and active treatment groups. Administering drugs covertly is another way to identify the placebo psychobiological component without the administration of any placebo, and this provides important information on the role of patient's expectations in the therapeutic outcome. A further in-depth analysis of placebo and nocebo phenomena will certainly provide important information in the near future for a better understanding of human biology, medicine and society.


Abrogation of nuclear receptors Nr4a3 and Nr4a1 leads to development of acute myeloid leukemia.
Nur77 (NR4A1) and Nor-1 (NR4A3) are highly homologous orphan nuclear receptors that regulate the transcription of overlapping target genes. The transcriptional activity of both proteins is regulated in a ligand-independent manner by cell- and stimulus-specific gene induction and protein phosphorylation. Nor-1 and Nur77 have been implicated in a variety of cellular processes, including the transduction of hormonal, inflammatory, mitogenic, apoptotic and differentiative signals. Cellular responses to these proteins suggest that they may function as homeostatic regulators of proliferation, apoptosis and differentiation, and thus may regulate cellular susceptibility to tumorigenesis. Their physiological functions, however, remain poorly understood. Here we describe a previously unsuspected function of Nor-1 and Nur77-as critical tumor suppressors of myeloid leukemogenesis. The abrogation of these proteins in mice led to rapidly lethal acute myeloid leukemia (AML), involving abnormal expansion of hematopoietic stem cells (HSCs) and myeloid progenitors, decreased expression of the AP-1 transcription factors JunB and c-Jun and defective extrinsic apoptotic (Fas-L and TRAIL) signaling. We found that downregulation of NR4A3 ( NOR-1 ) and NR4A1 ( NUR77 ) was a common feature in leukemic blasts from human AML patients, irrespective of karyotype. Thus Nor-1 and Nur77 may provide potential targets for therapeutic intervention in AML.


The Effect of Preceding Self-Control on Green Consumption Behavior: The Moderating Role of Moral Elevation.
Studies have shown that individuals restrain their egoistic desires to benefit others (eg, the natural world), which require a higher-order psychological process, such as self-control. Therefore, performing a preceding self-control task may subsequently decrease green consumption behavior. However, whether and how moral elevation, which is an important type of positive incidental emotion, moderates the negative effect of exerting self-control on green consumption behavior remains unknown. The present study aimed to examine how exerting self-control and moral elevation influenced green consumption behavior. The product choice task that requires participants to make choices between buying environmentally friendly (eco-friendly) and cheaper (self-interest) products is an index of green consumption behavior. In Experiment 1, we adopted the incongruent Stroop task to induce the exertion of self-control, and participants were asked to make choices in the product choice task. In Experiment 2, participants were provided with moral elevating videos to elicit moral elevation during the interval between the Stroop and product choice tasks. Experiment 1 indicated that, relative to the congruent Stroop task (the control condition), completing the incongruent Stroop task led to less environmentally friendly choices. Experiment 2 indicated that the participants who watched the elevating video in the incongruent Stroop task condition chose environmentally friendly products with greater frequency compared to those who watched the neutral video. Furthermore, the analyses showed that self-reported moral elevation partly moderated the effect of the exertion of self-control on green consumption behavior. Our findings indicate that the exertion of self-control has a negative effect on green consumption behavior; however, moral elevation can counteract this negative effect of exerting self-control on green consumption behavior.


Comparative in vitro activities of LFF571 against Clostridium difficile and 630 other intestinal strains of aerobic and anaerobic bacteria.
The in vitro activities of LFF571, a novel analog of GE2270A that inhibits bacterial growth by binding with high affinity for protein synthesis elongation factor Tu, fidaxomicin, and 10 other antimicrobial agents were determined against 50 strains of Clostridium difficile and 630 other anaerobic and aerobic organisms of intestinal origin. LFF571 possesses potent activity against C. difficile and most other Gram-positive anaerobes (MIC(90), ≤ 0.25 μg/ml), with the exception of bifidobacteria and lactobacilli. The MIC(90)s for aerobes, including enterococci, Staphylococcus aureus (as well as methicillin-resistant S. aureus [MRSA] isolates), Streptococcus pyogenes, and other streptococci were 0.06, 0.125, 2, and 8 μg/ml, respectively. Comparatively, fidaxomicin showed variable activity against Gram-positive organisms: MIC(90)s against C. difficile, Clostridium perfringens, and Bifidobacterium spp. were 0.5, ≤ 0.015, and 0.125 μg/ml, respectively, but >32 μg/ml against Clostridium ramosum and Clostridium innocuum. MIC(90) for S. pyogenes and other streptococci was 16 and >32 μg/ml, respectively. LFF571 and fidaxomicin were generally less active against Gram-negative anaerobes.


Improvement of pea biomass and seed productivity by simultaneous increase of phloem and embryo loading with amino acids.
The development of sink organs such as fruits and seeds strongly depends on the amount of nitrogen that is moved within the phloem from photosynthetic-active source leaves to the reproductive sinks. In many plant species nitrogen is transported as amino acids. In pea (Pisum sativum L.), source to sink partitioning of amino acids requires at least two active transport events mediated by plasma membrane-localized proteins, and these are: (i) amino acid phloem loading; and (ii) import of amino acids into the seed cotyledons via epidermal transfer cells. As each of these transport steps might potentially be limiting to efficient nitrogen delivery to the pea embryo, we manipulated both simultaneously. Additional copies of the pea amino acid permease PsAAP1 were introduced into the pea genome and expression of the transporter was targeted to the sieve element-companion cell complexes of the leaf phloem and to the epidermis of the seed cotyledons. The transgenic pea plants showed increased phloem loading and embryo loading of amino acids resulting in improved long distance transport of nitrogen, sink development and seed protein accumulation. Analyses of root and leaf tissues further revealed that genetic manipulation positively affected root nitrogen uptake, as well as primary source and sink metabolism. Overall, the results suggest that amino acid phloem loading exerts regulatory control over pea biomass production and seed yield, and that import of amino acids into the cotyledons limits seed protein levels.


[Divergent differentiation during embryonal histogenesis of skeletal muscle tissue].
Morphometric analysis of the developmental processes of the satellite cells and myosimplasts has been performed in embryonal histogenesis of the skeletal muscle tissue in 17 human fetuses 8-27 weeks of the intrauterine development. The sequence of death of some myoblasts in embryonal histogenesis is described in details. Basing on the data obtained, a conception on existance of muscular-proliferative units (MPU) in composition of the skeletal muscles is put forward. The amount of the MPU determines the whole number of muscle fibers in the muscle. The anlage of the MPU occurs as a result of divergent differentiation of the stem myogenic cells at early stages of myogenesis (myosimplasts and myotubes) from the cells commited to mutual fusion. The fund of these cells is determined by the number of myogenic elements that are at the state of the proliferative rest. One of the mechanisms regulating the number of the resting cells is the growth rate of the simplast lengthwise. The resting cells, appearing at late stages of myogenesis (of the muscle fibers), are the sources for development of the myosatellites in mature muscle fibers. In dying myotubes there is a sharp disturbance in growth processes lengthwise, in biosynthesis of contractile proteins, in correlation between the number of nuclei in the satellite cells and those of simplasts.


Controversies about guidelines to prevent the transmission of human immunodeficiency virus in hospitals in Britain.
The widespread screening of donors of blood, organs and semen for HIV antibody has contributed greatly to the prevention of spread of HIV to patients in British hospitals. The chances of patients acquiring HIV from a contaminated blood transfusion are now estimated at less than 1 in 1 million and factor VIII for haemophiliacs, which is also heat treated, is now virtually always free of HIV contamination. However, the wider use of HIV antibody tests to identify infected patients and rationalize the application of additional 'inoculation risk' precautions, so as to protect staff, is controversial. The risks of hospital staff acquiring HIV following occupational exposure, without such a screening-programme, are extremely low provided a high standard of hygiene is maintained and inoculation injuries are avoided. When needlestick injuries occur, involving HIV infected patients, the chances of transmission of HIV to hospital staff are less than 1 in 100. Current guidelines in Britain depend on use of additional inoculation precautions for patients belonging to HIV risk groups but in practice most of these 'risk patients' are not infected with HIV. Screening HIV antibody tests, preferably with consent, can help the smooth running of operating theatres in areas where many 'risk patients' require surgery, as extra precautions are not necessary for most of these patients who are HIV negative. All antenatal patients should be screened especially in areas of high prevalence of HIV, as this helps to prevent vertical transmission as well as facilitating the rational use of extra precautions to protect health care workers.


Decoding Imagined Speech Based on Deep Metric Learning for Intuitive BCI Communication.
Imagined speech is a highly promising paradigm due to its intuitive application and multiclass scalability in the field of brain-computer interfaces. However, optimal feature extraction and classifiers have not yet been established. Furthermore, retraining still requires a large number of trials when new classes are added. The aim of this study is (i) to increase the classification performance for imagined speech and (ii) to apply a new class using a pretrained classifier with a small number of trials. We propose a novel framework based on deep metric learning that learns the distance by comparing the similarity between samples. We also applied the instantaneous frequency and spectral entropy used for speech signals to electroencephalography signals during imagined speech. The method was evaluated on two public datasets (6-class Coretto DB and 5-class BCI Competition DB). We achieved a 6-class accuracy of 45.00 ± 3.13% and a 5-class accuracy of 48.10 ± 3.68% using the proposed method, which significantly outperformed state-of-the-art methods. Additionally, we verified that the new class could be detected through incremental learning with a small number of trials. As a result, the average accuracy is 44.50 ± 0.26% for Coretto DB and 47.12 ± 0.27% for BCI Competition DB, which shows similar accuracy to baseline accuracy without incremental learning. Our results have shown that the accuracy can be greatly improved even with a small number of trials by selecting appropriate features from imagined speech. The proposed framework could be directly used to help construct an extensible intuitive communication system based on brain-computer interfaces.


Integrating cytogenetics and genomics in comparative evolutionary studies of cichlid fish.
The availability of a large number of recently sequenced vertebrate genomes opens new avenues to integrate cytogenetics and genomics in comparative and evolutionary studies. Cytogenetic mapping can offer alternative means to identify conserved synteny shared by distinct genomes and also to define genome regions that are still not fine characterized even after wide-ranging nucleotide sequence efforts. An efficient way to perform comparative cytogenetic mapping is based on BAC clones mapping by fluorescence in situ hybridization. In this report, to address the knowledge gap on the genome evolution in cichlid fishes, BAC clones of an Oreochromis niloticus library covering the linkage groups (LG) 1, 3, 5, and 7 were mapped onto the chromosomes of 9 African cichlid species. The cytogenetic mapping data were also integrated with BAC-end sequences information of O. niloticus and comparatively analyzed against the genome of other fish species and vertebrates. The location of BACs from LG1, 3, 5, and 7 revealed a strong chromosomal conservation among the analyzed cichlid species genomes, which evidenced a synteny of the markers of each LG. Comparative in silico analysis also identified large genomic blocks that were conserved in distantly related fish groups and also in other vertebrates. Although it has been suggested that fishes contain plastic genomes with high rates of chromosomal rearrangements and probably low rates of synteny conservation, our results evidence that large syntenic chromosome segments have been maintained conserved during evolution, at least for the considered markers. Additionally, our current cytogenetic mapping efforts integrated with genomic approaches conduct to a new perspective to address important questions involving chromosome evolution in fishes.


Site-Specific Conjugation of Auristatins onto Engineered scFv Using Second Generation Maleimide to Target HER2-positive Breast Cancer in Vitro.
Antibody-drug conjugates (ADC) are spearheading vectorized chemotherapy against cancer, with 4 FDA-approved ADCs and 79 in clinical trials. However, most ADCs are produced using a stochastic bioconjugation method, target hematological cancers, and are derived from a full immunoglobulin-G (IgG). These factors limit their efficacy, especially against solid tumors which remain difficult to treat. Here we report the site-specific conjugation of a single auristatin derivative onto an engineered anti-HER2 single chain fragment variable (scFv) of the trastuzumab antibody, generating new scFv-drug conjugates (SDC). Two cysteines were judiciously incorporated at the beginning of the scFv hexahistidine tag, in order to allow controlled bioconjugation of a heterobifunctional linker including a second generation maleimide (SGM), either cleavable (for monomethyl auristatin E) or noncleavable (for monomethyl auristatin F). Our data indicated that both SDCs conserved their affinity to HER2 in comparison to the native scFv, and were efficiently able to kill in vitro HER2-positive SK-BR-3 cells at subnanomolar concentrations (EC50 of 0.68 nM and 0.32 nM). No effect was observed on HER2-negative MCF-7 cells. Ours results showed efficient targeting of site-specific SDCs against HER2-positive breast cancer cells. This work represents a first important step in the design of more effective small conjugates, paving the way for future in vivo translation to evaluate their full potential.


Current and future role of bispecific T-cell engagers in pediatric acute lymphoblastic leukemia.
The clinical application of immunotherapy has resulted into a significant improvement in the outcome of children with relapsed/refractory B-cell precursor acute lymphoblastic leukemia (r/r BCP-ALL). In this setting, the use of bispecific T-cell-engager antibodies (BiTEs), such as blinatumomab, which harness the cytotoxic activity of T cells against CD19-positive lymphoblasts, has emerged as a most promising and impactful strategy. Areas covered: This review discusses the main structural and functional features of BiTEs, as well as the current status of their clinical application in childhood ALL. Moreover, future prospects to increase the efficacy of BiTEs are addressed. Expert commentary: The promising results obtained in patients with advanced BCP-ALL pave the way for further improvement in the context of less resistant/advanced disease. Future research is rapidly progressing on several aspects, including the use of blinatumomab in first-line protocols, identification of factors predicting response, use of combinatorial approaches and bioengineering of new molecules with dual specificity or increased potency, stability and half-life. The results of these studies, expected to be available in the next future, will provide further advancement in the development of effective, impactful, targeted immunotherapy for treatment of childhood BCP-ALL, with the concrete potential to revolutionize the clinical practice.


Pesticide interactions and risks of sperm chromosomal abnormalities.
Disentangling the separate and synergistic effects of chemicals poses methodological challenges for accurate exposure assessment and for investigating epidemiologically how chemicals affect reproduction. We investigated combined exposures to ubiquitous contemporary use pesticides, specifically organophosphates (OP) and pyrethroids (PYR), and their association with germ cell abnormalities among adult men. Fluorescence in situ hybridization was used to determine disomy in sperm nuclei and urine was analyzed for concentrations of PYR metabolites (3-phenoxybenzoic acid; 3PBA) and OP dialkyl phosphate (DAP) metabolites. Incidence rate ratios using Poisson models were estimated for each disomy type by exposure quartile of DAP metabolites and 3PBA, controlling for confounders. The shape of the associations between PYRs, OPs and disomy were frequently nonmonotonic. There were consistent interactions between OP and PYR metabolite concentrations and the risk for sperm abnormalities. Taking both chemicals into account simultaneously resulted in quantitatively different associations than what was reported previously for OPs and PYRs separately, demonstrating the importance of modeling multiple concentrations simultaneously. Methods investigating interactions using Poisson models are needed to better quantify chemical interactions and their effects on count-based health outcomes, the importance of which was shown here for germ cell abnormalities.


Activity-dependent retinotopic refinement in a low-density retinotectal projection in the goldfish: evidence favoring synaptic cooperation over competition.
During optic nerve regeneration in goldfish, the label from a small retinal spot injection of WGA-HRP has been previously reported to be initially widely dispersed in the tectum and subsequently to condense into a small patch in the retinotopically appropriate location of tectum. This refinement involves two separate processes: one is activity independent and generates gross retinotopy; the other is activity dependent and mediates the formation of fine retinotopy. Since the number of synapses remains constant during this refinement, one or both of these processes may involve some form of competition for a limited number of synaptic sites. To clarify the role of synaptic competition, we created a low-density retinotectal projection in goldfish by deflecting about 20% of the optic fibers from one tectum into the opposite tectum, which was denervated of all other optic fibers. Under this condition, it was previously shown that less than half the normal density of synapses is formed. If competition for synaptic sites is a requirement of refinement, refinement should be prevented or significantly hindered. To monitor refinement during regeneration, 2 nl spot injections of WGA-HRP were made into the retina at various times after deflection. To distinguish between activity-dependent and activity-independent refinement, retinal impulse activity was blocked in some fish with repeated injections of TTX into the eye for the duration of the experiment. It was found that considerable activity-independent refinement occurred under continuous TTX blockade although the fibers remained more dispersed than in previous TTX studies when normal numbers of fibers were present. Surprisingly, in fish with normal impulse activity, the degree of activity-dependent refinement was almost normal. Labeled fibers condensed into a small area roughly comparable in size to that observed when the full complement of fibers was regenerating into tectum. These results suggest that competition for limited synaptic sites is not essential for activity-dependent refinement, which may, instead, be mediated by a cooperative process that actively promotes convergence. The findings further suggest that if synaptic competition plays a role in this system, it is in regulating activity-independent mechanisms that determine the large-scale distribution of fibers within tectum.


[The becoming of fatty cells, biological function of trophology, biological reactions of exo- and endotrophy in phylogenesis. The functional difference between visceral fatty cells and subcutaneous adipocytes].
The becoming of visceral fatty, cells in phylogenesis occurred many billions years before subcutaneous adipocytes. The pool of visceral fatty cells realizes biologic functions of trophology and homeostasis, endoecology, and adaptation from the early stages of phylogenesis. The subcutaneous adipocytes realize phylogenetically late biologic function of locomotion. The visceral fatty cells have no receptors to insulin and all subcutaneous adipocytes are insulin-dependent. In biologic function of trophology, both visceral fatty cells and subcutaneous adipocytes realize biologic reaction of exotrophy, biologic reaction of depositing and biologic reaction of endotrophy. It is supposed that the most common cause of obesity is disorder of biologic reaction of depositing of fatty acids in form of triglycerides. It is considered as a basis of that dysfunction of visceral fatty cells (metabolic syndrome) and insulin-dependent adipocytes (obesity) takes so often a character of metabolic pandemic. The fatty cells absorb fatty acids in form of non-polar triglycerides, deposit them in lipid drops and free fatty acids into intercelluar medium in form of polar unesterified fatty acids. The visceral fatty cells had been formed in paracrin cenosis of enterocytes and in it microsome protein transferring triglycerides formed early type of chylomicrons. The visceral fatty cells and adipocytles are phylogenetically, regulatory, functionally and pathophysiologically different cells. Therefore, they are to be considered separately. Not only visceral fatty cells and adipocytes but all cells of areolar tissue at level of cenosis of cells secrete many humoral mediators of paracrin regulation. The other modes of regulation are unknown. Leptin is a specific mediator of visceral fatty cells and adiponectin is a mediator of subcutaneous adipocytes.


Repair of nonunion of supracondylar femoral osteotomy.
Delayed union and nonunion are uncommon complications of femoral supracondylar osteotomy, and repair attempts usually involve reopening the medial side and readjusting the compression plate. However, the author suggests that better results can be obtained in these cases if the medial hardware is left intact and a T-plate is applied to the lateral side with compression and bone grafting. In lateral compartment arthritis of the knee, a femoral supracondylar osteotomy will return the mechanical axis of the knee to normal if the medial side is in good condition, and will usually produce long-term pain relief. The results are generally good, because 60% to 80% of the load on the knee is normally concentrated on the medial side.


[Cloning of the ADE2 gene of Saccharomyces cerevisiae and localization of the ARS-sequence].
Mutational changes in ADE2 result in the accumulation of red pigment in cells, which serves as an indicator for the selection of mutants. This easily detectable phenotype of red-coloured colonies can account for the wide use of ade2 mutants in yeast genetics. ADE2 gene was cloned in a shuttle vector by complementing the ade2 mutation in the yeast. It was shown that the 2.2 kbp HindIII fragment of yeast DNA contains structural sequences of the ADE2 gene as well as the ARS sequence. Deletion analysis of the 5' end of the ADE2 gene showed the ARS sequence to be situated at the distal end of the 1 kbp HindIII fragment. Removal of the ARS sequence does not influence ADE2 gene complementation ability. Transformants containing the ADE2 gene comprised in their plasmids form white colonies. Loss of the plasmids results in colour change of colonies.


Optimal Combinations of Chemotherapy and Radiotherapy in Low-Grade Gliomas: A Mathematical Approach.
Low-grade gliomas (LGGs) are brain tumors characterized by their slow growth and infiltrative nature. Treatment options for these tumors are surgery, radiation therapy and chemotherapy. The optimal use of radiation therapy and chemotherapy is still under study. In this paper, we construct a mathematical model of LGG response to combinations of chemotherapy, specifically to the alkylating agent temozolomide and radiation therapy. Patient-specific parameters were obtained from longitudinal imaging data of the response of real LGG patients. Computer simulations showed that concurrent cycles of radiation therapy and temozolomide could provide the best therapeutic efficacy in-silico for the patients included in the study. The patient cohort was extended computationally to a set of 3000 virtual patients. This virtual cohort was subject to an in-silico trial in which matching the doses of radiotherapy to those of temozolomide in the first five days of each cycle improved overall survival over concomitant radio-chemotherapy according to RTOG 0424. Thus, the proposed treatment schedule could be investigated in a clinical setting to improve combination treatments in LGGs with substantial survival benefits.


Chemical constituents and bioactivity of tobacco smoke.
Tobacco smoke contains more than 3900 constituents. In this presentation we have summarized our present knowledge as to the physicochemical nature of tobacco smoke and specific agents therein. Emphasis has been placed on the discussion of formation and identification of toxic and, especially, of tumorigenic agents in tobacco smoke. In the concluding Table 13 we have listed those smoke constituents in the mainstream smoke of cigarettes that we regard as important contributors to the toxic and carcinogenic potential of tobacco smoke. This judgement is based on extensive laboratory studies. Finally, data are presented in support of the concept that product modification can reduce the carcinogenic potential of cigarettes. However, it must be emphasized that the only safe way to avoid the cancer risks associated with smoking is to refrain from smoking.


Tolerance does not develop to the decrease in nicotine self-administration produced by repeated bupropion administration.
The atypical antidepressant bupropion has been shown to be an efficacious smoking cessation agent; however, its therapeutic mechanism of action is unknown. To further understand the mechanism by which bupropion reduces smoking, the present study determined the effect of repeated bupropion pretreatment on nicotine self-administration or sucrose-maintained responding. Rats were trained to self-administer intravenous nicotine (0.02 mg/kg/infusion; Experiment 1) or to respond for sucrose pellets (45 mg each; Experiment 2) on a fixed-ratio 5 schedule. Once rats reached stable responding, bupropion (70 mg/kg, subcutaneously) or vehicle was injected 15 min before the session for 14 consecutive sessions. Bupropion acutely decreased both nicotine self-administration and sucrose-maintained responding by approximately 60%-70%. With repeated bupropion pretreatment, however, responding for nicotine decreased completely. In contrast, the bupropion-induced decrease in responding for sucrose following acute administration did not change significantly with repeated bupropion administration. These results suggest that bupropion acquired some specificity with repeated use, decreasing the intake of nicotine and producing an extinction-like pattern in nicotine self-administration. Thus the present results parallel human clinical studies with bupropion demonstrating its smoking cessation properties following repeated treatment. These results indicate that the rat nicotine self-administration paradigm is a useful animal model for assessing smoking cessation pharmacotherapies.