[Alcohol use disorders in elderly people calls for treatment].
The complications related to use of alcohol occur at lower levels of alcohol use in the elderly. Alcohol use disorders (AUD) in the elderly are underestimated and often incorrectly diagnosed. However, evidence indicates that elderly are as likely to benefit from treatment as younger. Screening using Alcohol Use Disorders Identification Test seems to be accurate in identifying AUD among elderly, if the cut-off point is tailored for this age group. The recommended treatment strategy is naltrexone and brief approaches such as motivational interview and supportive consultation in general practice.


Herbal remedies used by selected migrant farmworkers in El Paso, Texas.
Little is known about the use of complementary and alternative medicine among the approximately 1.6 million migrant farmworkers in the United States. To evaluate the use of medicinal plants and natural remedies among a convenience sample of 100 migrant farmworkers living temporarily in a migrant worker center in El Paso, Texas. A structured interview instrument was designed to elicit information about reasons for medicinal herb use, form in which herbs were ingested, serious side effects experienced, location of purchase, effectiveness of treatment, and use of allopathic medications. The majority of workers used herbal remedies or other natural products because they believed them to be more effective than pharmaceuticals and because of tradition. Most learned about herbal remedies from a relative, primarily from their mother, and the majority who used herbal remedies believed them to be very helpful in treating specific illnesses. No adverse reactions to any herbal remedy were reported. The majority of participants did not inform their physician about their use of herbal remedies. According to the literature, potential adverse interactions between herbal remedies used and allopathic medications included gastrointestinal irritation, renal toxicity, and hypoglycemia. Health care providers must be knowledgeable about the use of herbal remedies among migrant farmworkers. By showing an understanding of and sensitivity to the use of these remedies, health care providers will be able to conduct more comprehensive health assessments of migrant workers and their families and provide them with more culturally competent care.


Defects in Stratum Corneum Desquamation Are the Predominant Effect of Impaired ABCA12 Function in a Novel Mouse Model of Harlequin Ichthyosis.
Harlequin Ichthyosis is a severe skin disease caused by mutations in the human gene encoding ABCA12. Here, we characterize a novel mutation in intron 29 of the mouse Abca12 gene that leads to the loss of a 5' splice donor site and truncation of the Abca12 RNA transcript. Homozygous mutants of this smooth skin or smsk allele die perinatally with shiny translucent skin, typical of animal models of Harlequin Ichthyosis. Characterization of smsk mutant skin showed that the delivery of glucosylceramides and CORNEODESMOSIN was defective, while ultrastructural analysis revealed abnormal lamellar bodies and the absence of lipid lamellae in smsk epidermis. Unexpectedly, mutant stratum corneum remained intact when subjected to harsh chemical dissociation procedures. Moreover, both KALLIKREIN 5 and -7 were drastically decreased, with retention of desmoplakin in mutant SC. In cultured wild type keratinocytes, both KALLIKREIN 5 and -7 colocalized with ceramide metabolites following calcium-induced differentiation. Reducing the intracellular levels of glucosylceramide with a glucosylceramide synthase inhibitor resulted in decreased secretion of KALLIKREIN proteases by wild type keratinocytes, but not by smsk mutant keratinocytes. Together, these findings suggest an essential role for ABCA12 in transferring not only lipids, which are required for the formation of multilamellar structures in the stratum corneum, but also proteolytic enzymes that are required for normal desquamation. Smsk mutant mice recapitulate many of the pathological features of HI and can be used to explore novel topical therapies against a potentially lethal and debilitating neonatal disease.


Can Measured Synergy Excitations Accurately Construct Unmeasured Muscle Excitations?
Accurate prediction of muscle and joint contact forces during human movement could improve treatment planning for disorders such as osteoarthritis, stroke, Parkinson's disease, and cerebral palsy. Recent studies suggest that muscle synergies, a low-dimensional representation of a large set of muscle electromyographic (EMG) signals (henceforth called "muscle excitations"), may reduce the redundancy of muscle excitation solutions predicted by optimization methods. This study explores the feasibility of using muscle synergy information extracted from eight muscle EMG signals (henceforth called "included" muscle excitations) to accurately construct muscle excitations from up to 16 additional EMG signals (henceforth called "excluded" muscle excitations). Using treadmill walking data collected at multiple speeds from two subjects (one healthy, one poststroke), we performed muscle synergy analysis on all possible subsets of eight included muscle excitations and evaluated how well the calculated time-varying synergy excitations could construct the remaining excluded muscle excitations (henceforth called "synergy extrapolation"). We found that some, but not all, eight-muscle subsets yielded synergy excitations that achieved >90% extrapolation variance accounted for (VAF). Using the top 10% of subsets, we developed muscle selection heuristics to identify included muscle combinations whose synergy excitations achieved high extrapolation accuracy. For 3, 4, and 5 synergies, these heuristics yielded extrapolation VAF values approximately 5% lower than corresponding reconstruction VAF values for each associated eight-muscle subset. These results suggest that synergy excitations obtained from experimentally measured muscle excitations can accurately construct unmeasured muscle excitations, which could help limit muscle excitations predicted by muscle force optimizations.


Effect of Different Antioxidants on the Microtensile Bond Strength of an Adhesive System to Sodium Hypochlorite-treated Dentin.
To evaluate the effects of different antioxidant treatments on the microtensile bond strength of an adhesive system to sodium hypochlorite (NaOCl)-treated dentin. Thirty extracted third molars were sectioned 3 mm below the occlusal surface and divided into six groups according to the antioxidant treatment received: control group: distilled water; NaOCl group: 5.25% NaOCl and distilled water; proanthocyanidin (PA) group: 5.25% NaOCl, 5% PA and distilled water; 1-week storage group: 5.25% NaOCl and storage for 1 week in distilled water; Accel group: 5.25% NaOCl, Accel, and distilled water; noni group: 5.25% NaOCl, noni fruit juice, and distilled water. NaOCl, PA, Accel, noni, and distilled water were administered for 30 s, 10 min, 30 s, 10 min, and 30 s, respectively. A self-etching adhesive system (Single Bond Universal Adhesive) was applied to each specimen and a resin composite (Filtek Z550) was built up to a height of 5 mm on the dentin surface. Each specimen was serially sectioned to obtain sticks with a cross-sectional area of 1 mm2, and their microtensile bond strength was determined. Statistical differences between groups were analyzed using one-way ANOVA and Tamhane's T2 test. Microtensile bond strength in the NaOCl group was significantly lower than in all other groups. However, there were no significant differences in the bond strength between the groups treated with different antioxidants. NaOCl significantly reduced the microtensile bond strength of the adhesive system. The application of PA, Accel, and noni fruit juice to NaOCl-treated dentin significantly improved the microtensile bond strength.


Perceived barriers to preventive dental care among Libyan dentists.
To explore the barriers to providing preventive dental care to patients, as perceived by Libyan dentists working in Benghazi. A cross-sectional, questionnaire-based survey was conducted among dentists working in Benghazi, Libya. All dentists registered with the Dental Association of Benghazi and with 2 or more years of practice were invited to participate. The questionnaire collected information on participants' demographic and professional characteristics as well as the patient-, practice- and dentist-related barriers to providing preventive dental care. Scores for each type of barrier were compared by demographic and professional characteristics in bivariate and multivariate analyses. One hundred and seventy five dentists returned the questionnaires (response rate: 79%) and 166 had complete information on all the variables selected for analysis (75%). The majority were females (70%), aged between 23 and 34 years (85%), was working in the public health sector (43%), and had up to 5 years of service (46%). Patient-related barriers were scored the highest, followed by practice- and dentist-related barriers. Dentists with mixed practice reported lower scores on patient- and practice-related barriers than those in public or private practice. Respondents were generally aware of the barriers to preventive dentistry and perceived the barriers as being more related to their patients than to their practices or themselves. However, these perceptions varied by practice sector.


Long-term visual outcomes in pachychoroid spectrum diseases and its associating factors of eyes with chronic central serous chorioretinopathy.
To analyze the long-term visual outcomes of pachychoroid spectrum diseases (PSD). Retrospective study. We reviewed the medical charts of consecutive patients with PSD, including focal choroidal excavation (FCE), pachychoroid pigment epitheliopathy (PPE), central serous chorioretinopathy (CSC), and pachychoroid neovasculopathy (PNV). The patients initially visited the Tokyo University Hospital from January 2008 to March 2021. Survival analyses were performed, in which loss of vision was defined as visual acuity (VA) of 0.2 logarithm of minimal angle of resolution (logMAR) or worse, 0.5 logMAR or worse, or VA worsening by 0.3 logMAR or greater. Moreover, we further investigated factors associated with visual prognosis, particularly in the CSC group. A total of 741 eyes of 638 patients were included in this analysis. The CSC or PNV group showed significantly worse visual prognosis than the FCE&PPE group for VA to 0.2 logMAR or worse (P = 0.0117 or 0.0001, respectively) and for VA worsening by 0.3 logMAR or greater (P = 0.0283 or 0.0037, respectively). In the CSC group, unlike age, sex, or treatment history, the accumulative duration of subfoveal fluid existence ≥ 12 months (continuous or intermittent) was significantly associated with visual prognosis (P < 0.0001). Among PSD, CSC and PNV were associated with a higher risk of vision loss in the long term than FCE and PPE. The duration of subretinal fluid existence was identified as a significant factor affecting long-term visual outcomes in CSC.


Stem cell gene expression programs influence clinical outcome in human leukemia.
Xenograft studies indicate that some solid tumors and leukemias are organized as cellular hierarchies sustained by cancer stem cells (CSCs). Despite the promise of the CSC model, its relevance in humans remains uncertain. Here we show that acute myeloid leukemia (AML) follows a CSC model on the basis of sorting multiple populations from each of 16 primary human AML samples and identifying which contain leukemia stem cells (LSCs) using a sensitive xenograft assay. Analysis of gene expression from all functionally validated populations yielded an LSC-specific signature. Similarly, a hematopoietic stem cell (HSC) gene signature was established. Bioinformatic analysis identified a core transcriptional program shared by LSCs and HSCs, revealing the molecular machinery underlying 'stemness' properties. Both stem cell programs were highly significant independent predictors of patient survival and were found in existing prognostic signatures. Thus, determinants of stemness influence the clinical outcome of AML, establishing that LSCs are clinically relevant and not artifacts of xenotransplantation.


Bone mineral loss at the proximal femur in acute spinal cord injury.
This study used quantitative computed tomography to assess changes in bone mineral at the proximal femur after acute spinal cord injury (SCI). Individuals with acute SCI experienced a marked loss of bone mineral from a combination of trabecular and endocortical resorption. Targeted therapeutic interventions are thus warranted in this population. SCI is associated with a rapid loss of bone mineral and an increased rate of fragility fracture. Some 10 to 20% of these fractures occur at the proximal femur. The purpose of this study was to quantify changes to bone mineral, geometry, and measures of strength at the proximal femur in acute SCI. Quantitative computed tomography analysis was performed on 13 subjects with acute SCI at serial time points separated by a mean of 3.5 months (range, 2.6-4.8 months). Changes in bone mineral content (BMC) and volumetric bone mineral density (vBMD) were quantified for integral, trabecular, and cortical bone at the femoral neck, trochanteric, and total proximal femur regions. Changes in bone volumes, cross-sectional areas, and surrogate measures of compressive and bending strength were also determined. During the acute period of SCI, subjects experienced a 2.7-3.3%/month reduction in integral BMC (p < 0.001) and a 2.5-3.1 %/month reduction in integral vBMD (p < 0.001). Trabecular BMC decreased by 3.1-4.7 %/month (p < 0.001) and trabecular vBMD by 2.8-4.4 %/month (p < 0.001). A 3.9-4.0 %/month reduction was observed for cortical BMC (p < 0.001), while the reduction in cortical vBMD was noticeably lower (0.8-1.0 %/month; p ≤ 0.01). Changes in bone volume and cross-sectional area suggested that cortical bone loss occurred primarily through endosteal resorption. Declines in bone mineral were associated with a 4.9-5.9 %/month reduction in surrogate measures of strength. These data highlight the need for therapeutic interventions in this population that target both trabecular and endocortical bone mineral preservation.


Brief periods of hyperphagia cause renal injury in the obese Zucker rat.
Female obese (fa/fa) Zucker rats are maximally hyperphagic from the beginning of access to solid food until 20 weeks of age and die primarily from renal failure. We documented that urinary albumin excretion (UAE) rises early in obese rats during this time of greatest hyperphagia. This study was conducted to examine if this early surge of hyperphagia is critical to the initiation of glomerular damage. Three groups of six-week-old rats were used: (a) obese females fed ad libitum (AL-obese), (b) obese females pair fed to lean controls until 21 weeks and then allowed to eat ad libitum until 57 weeks (PF. AL-obese), (c) lean (Fa/Fa) Zucker rats fed ad libitum (AL-lean). Cohorts of AL-obese and PF.AL-obese rats were allowed to continue to death or 57 weeks of age, and the rest were terminated at 21 weeks for renal histology. At 21 weeks, neither PF.AL-obese nor AL-lean rats had elevated UAE or glomerular histopathology. In contrast, glomerular injury was severe in AL-obese rats. UAE increased by 10 and 29 weeks in AL- and PF.AL-obese rats, respectively. Plasma triglycerides increased prior to UAE in both PF. AL- and AL-obese rats. In obese rats fed ad libitum, hyperphagia is followed within a few weeks by hypertriglyceridemia and then by glomerular injury regardless of when ad libitum feeding is initiated. These events do not occur in lean rats or in obese rats pair fed to lean rats. Protective effects of pair feeding did not extend into the period of ad libitum feeding for PF.AL-obese rats. Hyperphagia quickly initiates glomerular injury in obese female Zucker rats.


[Changes in the Activity of Antioxidant Systems of Escherichia coli under Phosphate Starvation].
Changes in the activity of antioxidant systems in Escherichia coli during phosphate starvation have been studied. It is shown that starvation was accompanied by a decrease in the intensity of respiration, an increase in the rate of superoxide production, and a decrease in the level of ATP. Simultaneously, there was a decrease in H2O2 in the medium and a significant increase in the expression of the katG and katE genes which encode the HPI and HPII catalases, respectively. At the same time, there was no drop in the membrane potential, which may indicate the retention of normal membrane activity in starving cells. It has been shown for the first time that the transition of E. coli to phosphate starvation is accompanied by significant changes in the status of glutathione. The most important of these are associated with a decrease in the level of reduced glutathione in the medium (GSHout) and with a simultaneous increase in its content in the cytoplasm (GSHin), as well as a shift in the GSHin to oxidized glutathione form (GSSGin) ratio towards reductive values, and GSHout/GSSGout towards oxidative values. Among the mutants used in the work, the gor trxB double mutant, which is deficient in the synthesis of glutathione reductase and thioredoxin reductase, showed the most pronounced distinctive features. Compared to the parental strain, this mutant showed a multiple higher expression of katG::lacZ, the highest level of oxidized intra- and extracellular glutathione, and, accordingly, the lowest GSH/GSSG ratio in both compartments. In general, the data we obtained indicate that during phosphate starvation the interaction of the glutathione redox-system and regulons that control protection against reactive oxygen species creates conditions that allow maintaining the concentration of ROS below the toxic level. As a result, phosphate-starved E. coli cells can maintain high viability for a long period of time, which allows them to quickly resume growth after the addition of phosphate.


Induction of pluripotency in human endothelial cells resets epigenetic profile on genome scale.
Reprogramming of a limited number of human cell types has been achieved through ectopic expression of four transcription factors to yield induced pluripotent stem (iPS) cells that closely resemble human embryonic stem cells (ESCs). Here, we determined functional and epigenetic properties of iPS cells generated from human umbilical vein endothelial cells (HUVEC) by conventional method of direct reprogramming. Retroviral overexpression of four transcription factors resets HUVEC to the pluripotency. Human endothelial cell-derived iPS (endo-iPS) cells were similar to human ESCs in morphology, gene expression, in vitro and in vivo differentiation capacity. Endo-iPS cells were efficiently differentiated in vitro into endothelial cells. Using genome-wide methylation profiling we show that promoter elements of endothelial specific genes were methylated following reprogramming whereas pluripotency-related gene promoters were hypomethylated similar to levels observed in ESCs. Genome-wide methylation analysis of CpG sites located in the functional regions of over than 14,000 genes indicated that human endo-iPS cells were highly similar to human ES cells, although differences in methylation levels of 46 genes were found. Overall CpG methylation of promoter regions in the pluripotent cells was higher than in somatic. We also show that during reprogramming female human endo-iPS cells exhibited reactivation of the somatically silenced X chromosome. Our findings demonstrate that iPS cells can be generated from human endothelial cells and reprogramming resets epigenetic status of endothelial cells to pluripotency.


Role of receptor-independent low density lipoprotein transport in the maintenance of tissue cholesterol balance in the normal and WHHL rabbit.
These studies were undertaken to determine the role of receptor-independent low density lipoprotein (LDL) transport in cholesterol balance across individual tissues and the whole animal. Homologous LDL, which measures total LDL transport, and methylated heterologous LDL, which measures receptor-independent LDL uptake, were cleared from the plasma at very different rates in the NZ control rabbit (3,900 and 1,010 microliter/hr per kg, respectively) whereas in the WHHL rabbit both preparations were cleared at essentially the same rate (approximately 1,070 microliter/hr per kg). Receptor-independent LDL clearance was detected in all tissues of the NZ control rabbit and these varied from 32 (spleen) to less than 0.5 (skeletal muscle) microliter/hr per g. In contrast, receptor-dependent LDL uptake was found in only about half of these same organs. In the WHHL rabbit, the rates of receptor-independent LDL transport were the same as in the NZ control rabbit, but no receptor-dependent uptake was detected. Using these clearance values it was calculated that in the control rabbit nearly 70% of LDL-cholesterol was removed from the plasma by the liver and 89% of this was receptor-mediated. With loss of receptor activity, however, the burden of LDL degradation was shifted away from the liver so that approximately 70% of LDL-cholesterol uptake took place in the extra-hepatic tissues of the WHHL rabbit. Thus, in the normal animal, the primary function of receptor-dependent LDL transport is to promote the rapid uptake and disposal of plasma LDL by the liver. In the absence of such receptor activity, cholesterol balance across most individual organs and the whole animal remains essentially normal and is mediated by the receptor-independent process. Because of the much lower absolute clearance rates manifested by this transport mechanism, however, substantial and predictable elevations in the circulating plasma LDL-cholesterol levels are required to maintain this balance.


Oligo (p-Phenylene Vinylene)/Polyisocyanopeptide Biomimetic Composite Hydrogel-Based Three-Dimensional Cell Culture System for Anticancer and Antibacterial Therapeutics.
Cells are normally cultured in 2D environment, which is usually inconsistent with the real microenvironment in vivo, and it is rarely reported that an effective cancer cell killing process occurs in a 3D network environment. Herein, a kind of new biomimetic composite hydrogel which can achieve 3D cell culture has been prepared and constructed by assembly of polyisocyanopeptide (PIC) with cationic oligo (p-phenylene vinylene) (OPV). The polymer chains of PIC can be bound and frizzled to form a 3D network when the temperature rises above the gelation temperature, followed by encapsulating the cells into biomimetic composite hydrogel. Cells grow and proliferate well in 3D composite hydrogels with excellent cell viability. When the cells undergo cancerization or microbial infection during the 3D culture, the addition of the luminol luminescence system can cause a strong bioluminescence resonance energy transfer (BRET) process to produce highly active reactive oxygen species (ROS) in 3D culture and kill the cancer cells and pathogenic microorganism effectively. Utilizing the BRET process in 3D composite biomimetic hydrogels provides an efficient antibacterial and anticancer approach in 3D culture to overcome the light-penetration limitation.


An evidence-based and occupational perspective of interventions for persons with substance-use disorders.
An interdisciplinary evidence-based review of interventions among persons with substance-use disorders was completed in 2001 as part of American Occupational Therapy Association's (AOTA's) Evidence-Based Literature Review Project (Lieberman & Scheer, 2002). Four effective interventions for adults and adolescents with substance use were identified, including brief interventions, cognitive behavioral therapy, motivational strategies, and 12-step programs. The research studies reviewed reported outcomes primarily related to reduction in alcohol and drug use. Occupational therapy interventions grounded in current evidence-based literature are suggested. Interventions are modified to include an occupational perspective leading to outcomes consistent with the Occupational Therapy Practice Framework (American Occupational Therapy Association [AOTA], 2002). Study findings propose research questions to encourage further investigation of the effectiveness of these best practice interventions.


Decreases in smoking during treatment for methamphetamine-use disorders: preliminary evidence.
Despite high rates of smoking (70-90%) and the severely negative impact of smoking on physical and mental health, only 12% of individuals receiving stimulant-use disorder treatment also receive smoking-cessation treatment. The aim of this investigation was to examine the effect of a contingency management (CM) intervention targeting methamphetamine (MA) use on cigarette smoking. Sixty-one adults with MA-use disorders who were smokers were assigned to CM or standard psychosocial treatment. Rates of smoking-negative breath samples (carbon monoxide <3 ppm) were compared between the two groups while controlling for baseline carbon monoxide level, marijuana use, MA use, and time. This subgroup of mostly male (59%) participants included 44 participants in the CM group and 17 participants in the standard psychosocial treatment. Tobacco smoking participants who received CM targeting MA use were 140% (odds ratio: 2.395; 95% confidence interval: 1.073-5.346) more likely to submit a smoking-negative breath sample relative to standard psychosocial treatment during the treatment period, holding constant several other prespecified covariates. This study provides evidence that a behavioral treatment for MA use results in reductions in cigarette smoking in adults with MA-use disorder.


Akt activation is a common event in pediatric malignant gliomas and a potential adverse prognostic marker: a report from the Children's Oncology Group.
Aberrant activation of Akt is a common finding in adult malignant gliomas, resulting in most cases from mutations or deletions involving PTEN, which allows constitutive Akt phosphorylation. In contrast, we have previously reported that pediatric malignant gliomas, which are morphologically similar to lesions arising in adults, have a substantially lower incidence of genomic alterations of PTEN. The objective of this study was to determine whether Akt activation was also an uncommon finding in childhood malignant gliomas and whether this feature was associated with survival. To address this issue, we examined the frequency of Akt activation, determined by overexpression of the activated phosphorylated form of Akt (Se(473)) on immunohistochemical analysis, in a series of 53 childhood malignant gliomas obtained from newly diagnosed patients treated on the Children's Oncology Group ACNS0126 and 0423 studies. The relationship between Akt activation and p53 overexpression, MIB1 labeling, and tumor histology was evaluated. The association between Akt activation and survival was also assessed. Overexpression of activated Akt was observed in 42 of 53 tumors, far in excess of the frequency of PTEN mutations we have previously observed. There was no association between Akt activation and either histology, p53 overexpression, or MIB1 proliferation indices. Although tumors that lacked Akt overexpression had a trend toward more favorable event-free survival and overall survival (p = 0.06), this association reflected that non-overexpressing tumors were significantly more likely to have undergone extensive tumor removal, which was independently associated with outcome. Activation of Akt is a common finding in pediatric malignant gliomas, although it remains uncertain whether this is an independent adverse prognostic factor. In view of the frequency of Akt activation, the evaluation of molecularly targeted therapies that inhibit this pathway warrants consideration for these tumors.


Characterization of the histamine receptors in rabbit left atria.
The effects of selective histamine receptor analogs were studied in electrically paced rabbit left atria. Atrial tension was increased by histamine (an H1 and H2 agonist), 4-methylhistamine and impromidine (H2 agonists), and 2-pyridylethylamine (PEA) (an H1 agonist). The responses to histamine and impromidine were not altered by propranolol (1 x 10(-7) M) or reserpine pretreatment. However, the responses to 4-methylhistamine and PEA were significantly decreased upon pretreatment with propranolol or reserpine. Promethazine pretreatment (H1 receptor blockade) antagonized the inotropic effects of histamine and PEA but had no effect on the responses to 4-methylhistamine or impromidine. Cimetidine pretreatment (H2 receptor antagonism) competitively blocked the positive inotropic effects of histamine, 4-methylhistamine, and impromidine. These results suggest that the left atrial inotropic response is mediated through H1 and H2 receptor stimulation.


Saccharomyces cerevisiae BUB2 prevents mitotic exit in response to both spindle and kinetochore damage.
The spindle assembly checkpoint-mediated mitotic arrest depends on proteins that signal the presence of one or more unattached kinetochores and prevents the onset of anaphase in the presence of kinetochore or spindle damage. In the presence of either damage, bub2 cells initiate a preanaphase delay but do not maintain it. Inappropriate sister chromatid separation in nocodazole-treated bub2 cells is prevented when mitotic exit is blocked using a conditional tem1(c) mutant, indicating that the preanaphase failure in bub2 cells is a consequence of events downstream of TEM1 in the mitotic exit pathway. Using a conditional bub2(tsd) mutant, we demonstrate that the continuous presence of Bub2 protein is required for maintaining spindle damage-induced arrest. BUB2 is not required to maintain a DNA damage checkpoint arrest, revealing a specificity for spindle assembly checkpoint function. In a yeast two-hybrid assay and in vitro, Bub2 protein interacts with the septin protein Cdc3, which is essential for cytokinesis. These data support the view that the spindle assembly checkpoint encompasses regulation of distinct mitotic steps, including a MAD2-directed block to anaphase initiation and a BUB2-directed block to TEM1-dependent exit.


Heparin's roles in stabilizing, potentiating, and transporting LEDGF into the nucleus.
Lens epithelium-derived growth factor (LEDGF) is a 60-kDa protein that dramatically enhances cellular survival, growth, adhesiveness, and resistance to heat and oxidative stress. Full-size recombinant LEDGF is degraded during prokaryotic preparation. Heparin's capacity to stabilize recombinant LEDGF in the face of various stresses (heat, pH, proteolysis), to potentiate its growth-enhancing properties, and to enable transport of LEDGF into the nucleus of mouse lens epithelial cells has been characterized. LEDGF-cDNA was cloned in a pGEX-2T expression vector to produce a fusion protein, GST-LEDGF. Porcine heparin was used to stabilize GST-LEDGF. Heparin-Sepharose was used to characterize heparin-GST-LEDGF binding, and GST-LEDGF or heparin-GST-LEDGF was used to quantitate heparin's stabilization of LEDGF in the face of heat, pH, and proteolytic stresses. Fluorescein isothiocyanate-labeled GST-LEDGF and heparin-GST-LEDGF were incubated with cultured mouse lens epithelial cells (LECs). Fluorescence microscopy and immunostaining techniques were used to monitor heparin's potentiation of LEDGF's growth stimulation and heparin's role in the translocation of GST-LEDGF from the extracellular space into the cytoplasm and nucleus. Heparin, at concentrations as low as 7.1 mg/ml, protected GST-LEDGF from degradation and increased the yield of the full-size fusion protein in a prokaryotic system. It also protected GST-LEDGF from heat, acid-base deactivation, and proteolytic degradation with trypsin and chymotrypsin and greatly potentiated LEDGF's enhancement of mouse LEC growth in culture. It also increased nuclear uptake of exogenous GST-LEDGF and endogenous LEDGF. Heparin protected GST-LEDGF from degradation under various stress conditions and facilitated transport of GST-LEDGF into the nucleus.


Definition of target antigens for naturally occurring CD4(+) CD25(+) regulatory T cells.
The antigenic targets recognized by naturally occurring CD4(+) CD25(+) regulatory T cells (T reg cells) have been elusive. We have serologically defined a series of broadly expressed self-antigens derived from chemically induced mouse sarcomas by serological identification of antigens by recombinant expression cloning (SEREX). CD4(+) CD25(+) T cells from mice immunized with SEREX-defined self-antigens had strong suppressive activity on peptide-specific proliferation of CD4(+) CD25(-) T cells and CD8(+) T cells. The suppressive effect was observed without in vitro T cell stimulation. Foxp3 expression in these CD4(+) CD25(+) T cells from immunized mice was 5-10 times greater than CD4(+) CD25(+) T cells derived from naive mice. The suppressive effect required cellular contact and was blocked by anti-glucocorticoid-induced tumor necrosis factor receptor family-related gene antibody. In vitro suppressive activity essentially disappeared 8 wk after the last immunization. However, it was regained by in vitro restimulation with cognate self-antigen protein but not with control protein. We propose that SEREX-defined self-antigens such as those used in this study represent self-antigens that elicit naturally occurring CD4(+) CD25(+) T reg cells.


Human OX40 tunes the function of regulatory T cells in tumor and nontumor areas of hepatitis C virus-infected liver tissue.
Regulatory T cells (Tregs) can be considered as a mixed population of distinct subsets, endowed with a diverse extent and quality of adaptation to microenvironmental signals. Here, we uncovered an opposite distribution of Treg expansion, phenotype, and plasticity in different microenvironments in the same organ (liver) derived from patients with chronic hepatitis C: On the one side, cirrhotic and tumor fragments were moderately and highly infiltrated by Tregs, respectively, expressing OX40 and a T-bethigh IFN-γ- "T-helper (Th)1-suppressing" phenotype; on the other side, noncirrhotic liver specimens contained low frequencies of Tregs that expressed low levels of OX40 and highly produced interferon-gamma (IFN-γ; T-bet+IFN-γ+), thus becoming "Th1-like" cells. OX40-expressing and Th1-suppressing Tregs were enriched in the Helios-positive subset, carrying highly demethylated Treg cell-specific demethylated region that configures committed Tregs stably expressing forkhead box protein 3. OX40 ligand, mostly expressed by M2-like monocytes and macrophages, boosted OX40+ Treg proliferation and antagonized the differentiation of Th1-like Tregs. However, this signal is counteracted in noncirrhotic liver tissue (showing various levels of inflammation) by high availability of interleukin-12 and IFN-γ, ultimately leading to complete, full Th1-like Treg differentiation. Our data demonstrate that Tregs can finely adapt, or even subvert, their classical inhibitory machinery in distinct microenvironments within the same organ.


Accumulation or production of arsenobetaine in humans?
Arsenobetaine has always been referred to as a non-toxic but readily bioavailable compound and the available data would suggest that it is neither metabolised by nor accumulated in humans. Here this study investigates the urine of five volunteers on an arsenobetaine exclusive diet for twelve days and shows that arsenobetaine was consistently excreted by three of the five volunteers. From the expected elimination pattern of arsenobetaine in rodents, no significant amount of arsenobetaine should have been detectable after 5 days of the trial period. The arsenobetaine concentration found in the urine was constant after 5 days and varied between 0.2 and 12.2 microg As per L for three of the volunteers. Contrary to the established belief that arsenobetaine is neither accumulated nor generated by humans, the presented results would suggest that either accumulated arsenobetaine in the tissues is slowly released over time or that arsenobetaine is a human metabolite of dimethylarsinic acid or inorganic arsenic from the trial food, or both. Either possibility is intriguing and raises fundamental questions about human arsenic metabolism and the toxicological and environmental inertness of arsenobetaine.


Penetrating neck injuries: a guide to evaluation and management.
Introduction Penetrating neck injury is a relatively uncommon trauma presentation with the potential for significant morbidity and possible mortality. There are no international consensus guidelines on penetrating neck injury management and published reviews tend to focus on traditional zonal approaches. Recent improvements in imaging modalities have altered the way in which penetrating neck injuries are now best approached with a more conservative stance. A literature review was completed to provide clinicians with a current practice guideline for evaluation and management of penetrating neck injuries. Methods A comprehensive MEDLINE (PubMed) literature search was conducted using the search terms 'penetrating neck injury', 'penetrating neck trauma', 'management', 'guidelines' and approach. All articles in English were considered. Articles with only limited relevance to the review were subsequently discarded. All other articles which had clear relevance concerning the epidemiology, clinical features and surgical management of penetrating neck injuries were included. Results After initial resuscitation with Advanced Trauma Life Support principles, penetrating neck injury management depends on whether the patient is stable or unstable on clinical evaluation. Patients whose condition is unstable should undergo immediate operative exploration. Patients whose condition is stable who lack hard signs should undergo multidetector helical computed tomography with angiography for evaluation of the injury, regardless of the zone of injury. Conclusions The 'no zonal approach' to penetrating neck trauma is a selective approach with superior patient outcomes in comparison with traditional management principles. We present an evidence-based, algorithmic and practical guide for clinicians to use when assessing and managing penetrating neck injury.


Neurotrophic factors as pharmacological agents for the treatment of injured auditory neurons.
Mature auditory neurons degenerate in response to a loss of target-derived trophic factors. Neurotrophic factors influence the health and viability of auditory neurons. This suggests that neurotrophic factors can be used as therapeutic agents to prevent neuronal cell death and to initiate repair of damaged neuronal processes in the injured auditory system. Both in vitro and in vivo experiments have been performed to determine which of the vast array of neurotrophic factors affect mature auditory neurons and how they can be delivered to the sites of injury within the auditory system. Neurotrophin 3 was found to be a major survival factor for auditory neurons. Brain-derived neurotrophic factor is a minor survival factor for auditory neurons and nerve growth factor, although not promoting survival, does elicit the repair of neuronal processes. Fibroblast growth factor 2, transforming growth factor beta 1 and ciliary neurotrophic factor function as injury-response factors in the auditory system. Combination of different classes of growth factors has an additive effect on neuronal survival. Growth factors may be able to be delivered to sites of injury within the cochlea by either direct perfusion or gene therapy (e.g. a defective virus expressing a growth factor gene).


METHOD USING ORTHO-TOLIDINE FOR THE QUANTITATIVE DETERMINATION OF HAEMOGLOBIN IN SERUM AND URINE.
Following a study of the spectrophotometric properties of ortho-tolidine and its oxidation products, with particular attention to variation brought about by change in the hydrogen ion concentration, a method for the quantitative estimation of haemoglobin in serum and urine in which ortho-tolidine is substituted for benzidine in a peroxidase system is described. The method is designed to measure haemoglobin value within the range 0-125 mg. per 100 ml. Evidence is presented showing that it gives results equal in accuracy and reproducibility to a benzidine method in common use and for reasons stated is a more satisfactory technique for estimating the haemoglobin content of urine.


Antioxidant capacity of seed coat, dehulled bean, and whole black soybeans in relation to their distributions of total phenolics, phenolic acids, anthocyanins, and isoflavones.
Black soybeans have been used as an excellent dietary source for disease prevention and health promotion in China for hundreds of years. However, information about the distribution of health-promoting phenolic compositions in different physical parts of black soybean and the contribution of phenolic compositions to overall antioxidant capacity is limited. To elucidate the distribution of phenolic composition and their contribution to antioxidant activities in black soybean, the total and individual phenolic profiles, and antioxidant capacities of seed coat, dehulled and whole black soybean were systematically investigated. The seed coat exhibited much higher total phenolic indexes and antioxidant activities than whole and dehulled black soybean. Dehulled black soybean possessed similar levels of total phenolic content, total flavonoid content, 2-diphenyl-1-picryhydrazyl (DPPH) radical scavenging activity, ferric reducing antioxidant power (FRAP), and oxygen radical absorbance capacity (ORAC) activities as compared to whole yellow soybean. Cyanidin-3-glucoside, petunidin-3-glucoside, and peonidin-3-glucoside were detected in the seed coat but not in dehulled black soybean and yellow soybean. Among benzoic acid detected, caffeic and chlorogenic acid were the predominant phenolic acids. Whole black soybean and dehulled black soybean exhibited similar isoflavone contents in 7- O-beta-glucosides and malonylglucosides of daidzein and genistein. The seed coat possessed significantly ( p < 0.05) lower 7- O-beta-glucosides and malonylglucosides of daidzein and genistein, acetylglycitin, and total isoflavones than whole and dehulled black soybean. The contribution of phenolics in the seed coat to the antioxidant activity of black soybean parts depends on the assay methods. When measured with the DPPH and FRAP methods, the seed coat contributed 90% of the total antioxidant capacity of black soybean. However, when measured with the ORAC method, the seed coat and dehulled portion contributed approximately equally the total antioxidant capacity of black soybeans. The information generated from this study on the distribution and content of their active components is useful for the effective use of black soybeans as an ingredient for promoting health.


Early-stage visual processing and cortical amplification deficits in schizophrenia.
Patients with schizophrenia show deficits in early-stage visual processing, potentially reflecting dysfunction of the magnocellular visual pathway. The magnocellular system operates normally in a nonlinear amplification mode mediated by glutamatergic (N-methyl-D-aspartate) receptors. Investigating magnocellular dysfunction in schizophrenia therefore permits evaluation of underlying etiologic hypotheses. To evaluate magnocellular dysfunction in schizophrenia, relative to known neurochemical and neuroanatomical substrates, and to examine relationships between electrophysiological and behavioral measures of visual pathway dysfunction and relationships with higher cognitive deficits. Between-group study at an inpatient state psychiatric hospital and outpatient county psychiatric facilities. Thirty-three patients met DSM-IV criteria for schizophrenia or schizoaffective disorder, and 21 nonpsychiatric volunteers of similar ages composed the control group. (1) Magnocellular and parvocellular evoked potentials, analyzed using nonlinear (Michaelis-Menten) and linear contrast gain approaches; (2) behavioral contrast sensitivity measures; (3) white matter integrity; (4) visual and nonvisual neuropsychological measures, and (5) clinical symptom and community functioning measures. Patients generated evoked potentials that were significantly reduced in response to magnocellular-biased, but not parvocellular-biased, stimuli (P = .001). Michaelis-Menten analyses demonstrated reduced contrast gain of the magnocellular system (P = .001). Patients showed decreased contrast sensitivity to magnocellular-biased stimuli (P<.001). Evoked potential deficits were significantly related to decreased white matter integrity in the optic radiations (P<.03). Evoked potential deficits predicted impaired contrast sensitivity (P = .002), which was in turn related to deficits in complex visual processing (P< or =.04). Both evoked potential (P< or =.04) and contrast sensitivity (P = .01) measures significantly predicted community functioning. These findings confirm the existence of early-stage visual processing dysfunction in schizophrenia and provide the first evidence that such deficits are due to decreased nonlinear signal amplification, consistent with glutamatergic theories. Neuroimaging studies support the hypothesis of dysfunction within low-level visual pathways involving thalamocortical radiations. Deficits in early-stage visual processing significantly predict higher cognitive deficits.


Stress regulates endocannabinoid-CB1 receptor signaling.
The CB1 cannabinoid receptor is a G protein coupled receptor that is widely expressed throughout the brain. The endogenous ligands for the CB1 receptor (endocannabinoids) are N-arachidonylethanolamine and 2-arachidonoylglycerol; together the endocannabinoids and CB1R subserve activity dependent, retrograde inhibition of neurotransmitter release in the brain. Deficiency of CB1 receptor signaling is associated with anhedonia, anxiety, and persistence of negative memories. CB1 receptor-endocannabinoid signaling is activated by stress and functions to buffer or dampen the behavioral and endocrine effects of acute stress. Its role in regulation of neuronal responses is more complex. Chronic variable stress exposure reduces endocannabinoid-CB1 receptor signaling and it is hypothesized that the resultant deficiency in endocannabinoid signaling contributes to the negative consequences of chronic stress. On the other hand, repeated exposure to the same stress can sensitize CB1 receptor signaling, resulting in dampening of the stress response. Data are reviewed that support the hypothesis that CB1 receptor signaling is stress responsive and that maintaining robust endocannabinoid/CB1 receptor signaling provides resilience against the development of stress-related pathologies.


Microbial Dimethylsulfoniopropionate Cycling in Deep Sediment of the Mariana Trench.
Dimethylsulfoniopropionate (DMSP) and related organic sulfur compounds play key roles in global sulfur cycling. Bacteria have been found to be important DMSP producers in seawater and surface sediments of the aphotic Mariana Trench (MT). However, detailed bacterial DMSP cycling in the Mariana Trench subseafloor remains largely unknown. Here, the bacterial DMSP-cycling potential in a Mariana Trench sediment core (7.5 m in length) obtained at a 10,816-m water depth was investigated using culture-dependent and -independent methods. The DMSP content fluctuated along the sediment depth and reached the highest concentration at 15 to 18 cm below the seafloor (cmbsf). dsyB was the dominant known DMSP synthetic gene, existing in 0.36 to 1.19% of the bacteria, and was identified in the metagenome-assembled genomes (MAGs) of previously unknown bacterial DMSP synthetic groups such as Acidimicrobiia, Phycisphaerae, and Hydrogenedentia. dddP, dmdA, and dddX were the major DMSP catabolic genes. The DMSP catabolic activities of DddP and DddX retrieved from Anaerolineales MAGs were confirmed by heterologous expression, indicating that such anaerobic bacteria might participate in DMSP catabolism. Moreover, genes involved in methanethiol (MeSH) production from methylmercaptopropionate (MMPA) and dimethyl sulfide (DMS), MeSH oxidation, and DMS production were highly abundant, suggesting active conversions between different organic sulfur compounds. Finally, most culturable DMSP synthetic and catabolic isolates possessed no known DMSP synthetic and catabolic genes, and actinomycetes could be important groups involved in both DMSP synthesis and catabolism in Mariana Trench sediment. This study extends the current understanding of DMSP cycling in Mariana Trench sediment and highlights the need to uncover novel DMSP metabolic genes/pathways in extreme environments. IMPORTANCE Dimethylsulfoniopropionate (DMSP) is an abundant organosulfur molecule in the ocean and is the precursor for the climate-active volatile gas dimethyl sulfide. Previous studies focused mainly on bacterial DMSP cycling in seawater, coastal sediment, and surface trench sediment samples, but DMSP metabolism in the Mariana Trench (MT) subseafloor sediments remains unknown. Here, we describe the DMSP content and metabolic bacterial groups in the subseafloor of the MT sediment. We found that the tendency for vertical variation of the DMSP content in the MT was distinct from that of the continent shelf sediment. Although dsyB and dddP were the dominant DMSP synthetic and catabolic genes in the MT sediment, respectively, both metagenomic and culture methods revealed multiple previously unknown DMSP metabolic bacterial groups, especially anaerobic bacteria and actinomycetes. The active conversion of DMSP, DMS, and methanethiol may also occur in the MT sediments. These results provide novel insights for understanding DMSP cycling in the MT.


Isolation and deisolation of patients admitted with presumptive pulmonary tuberculosis. Can it be shortened?
To determine the ideal number of sputum acid-fast bacilli (AFB) smears and polymerase chain reaction (PCR) required for discontinuing TB isolation among patients with suspected pulmonary TB. Methods: This was a single-center, record-based retrospective study of all admitted patients diagnosed with culture-proven pulmonary TB between 2010 and 2018. The study was conducted at Prince Sultan Military Medical City (PSMMC) in Riyadh, Saudi Arabia, a large tertiary care center consisting of 1,200 beds. Data were obtained from our TB notification records. Patients with smear-positive TB were investigated. Only the first 3 sputum smears for AFB were included in the analysis. The PCR results for Mycobacterium tuberculosis (MTB) were also included in the study. The incremental yield of the second and third smears was assessed. Results: Overall, 240 patients were MTB-culture positive. A total of 126 (52.5%) patients were smear and culture positive, whereas 114 were culture positive but smear negative. Of 126 patients who were AFB smear positive, 98 (77.8%) were detected in the first specimen, 13 (10.3%) in the second specimen, and only 9 (7.1%) in the third specimen. Polymerase chain reaction for MTB was positive in 122 (96.8%) smear-positive patients. Four patients did not undergo a PCR test. Conclusion: A single Xpert MTB/resistance to rifampicin test detected all smear-positive patients, whereas the third smear did not significantly contribute to MTB isolation.


Development and Validation of the Questionnaire of Academic Stress in Secondary Education: Structure, Reliability and Nomological Validity.
This study presents the validation process of the Questionnaire on Academic Stress in Secondary Education (QASSE) designed to assess the wide variety of school sources and situations related to academic stress in adolescence, and their relationship with students' physical and psychological well-being. The participants were 860 Spanish high school students (52.9% girls) with an average age of 14.62 years (SD = 1.8). Through a cross-validation process, results supported the QASSE multifactorial structure with four first-order factors-academic overload, interaction with classmates, family pressure, and future-oriented perspective-and a second-order factor of academic stress, showing a significant and intense relationship with adolescents' psychological and physical well-being. Results also highlight the effects of the gender and educational level interaction on the students' stress, with girls showing higher levels of stress in the transition courses between educational phases (sophomore and junior years). The QASSE demonstrates good validity and reliability, showing potential for both research and educational application. The results show the high impact of the QASSE dimensions on psychological and physical well-being in adolescence, highlighting its special usefulness for designing and adjusting educational prevention and intervention actions in this area to the students' specific characteristics and needs.


Graphene-supported PtPd Bimetallic Gathered Nanocrystals for Non-enzymatic Sensing of Oxalic Acid.
A novel non-enzymatic oxalic acid (OA) sensor was developed using a nanocrystal PtPd loaded reduced graphene nanosheets (PtPdNCs/RGO)-modified electrode. PtPdNCs/RGO were successfully achieved by a facile, one-step and template-free method, in which PtPd nanoparticles with 100 nm-scale were assembled from polyhedral PtPd nanocrystals of various shapes and dispersed on the graphene nanosheets. Resulting PtPdNCs/RGO were characterized and used for PtPdNCs/RGO-modified electrodes. Electrochemical oxidation of OA on the modified electrode was investigated by cyclic voltammetry and differential pulse voltammetry (DPV). Well-defined peaks of OA oxidation could be obtained using an electrode that indicated its high electrochemical activity. The concentration of OA and the current responses could be obtained in the ranges of 0.5 - 10 and 10 - 35 mM with correlation coefficients of 0.9994 and 0.9952; the detection limit (S/N = 3) was found to be 0.05 mM. The modified electrode presented good characteristics in terms of both stability and reproducibility, promising its applicability in practical analysis.


The activation loop of PIP5K functions as a membrane sensor essential for lipid substrate processing.
Phosphatidylinositol 4-phosphate 5-kinase (PIP5K), a representative member of the phosphatidylinositol phosphate kinase (PIPK) family, is a major enzyme that biosynthesizes the signaling molecule PI(4,5)P2 (phosphatidylinositol 4,5-bisphosphate) in eukaryotic cells. The stringent specificity toward lipid substrates and the high sensitivity to the membrane environment strongly suggest a membrane-sensing mechanism, but the underlying structural basis is still largely unknown. We present a nuclear magnetic resonance (NMR) study on a peptide commensurate with a PIP5K's activation loop, which has been reported to be a determinant of lipid substrate specificity and subcellular localization of PIP5K. Although the activation loop is severely disordered in the crystal structure of PIP5K, the NMR experiments showed that the largely unstructured peptide folded into an amphipathic helix upon its association with the 1,2-dihexanoyl-sn-glycero-3-phosphocholine (DHPC) micellar surface. Systematic mutagenesis and functional assays further demonstrated the crucial roles of the amphipathic helix and its hydrophobic surface in kinase activity and membrane-sensing function, supporting a working model in which the activation loop is a critical structural module conferring a membrane-sensing mechanism on PIP5K. The activation loop, surprisingly functioning as a membrane sensor, represents a new paradigm of kinase regulation by the activation loop through protein-membrane interaction, which also lays a foundation on the regulation of PIP5K (and other PIPKs) by membrane lipids for future studies.


Sites and mechanisms of aconitase inactivation by peroxynitrite: modulation by citrate and glutathione.
Aconitases are iron-sulfur cluster-containing proteins present both in mitochondria and cytosol of cells; the cubane iron-sulfur (Fe-S) cluster in the active site is essential for catalytic activity, but it also renders aconitase highly vulnerable to reactive oxygen and nitrogen species. This study examined the sites and mechanisms of aconitase inactivation by peroxynitrite (ONOO-), a strong oxidant and nitrating agent readily formed from superoxide anion and nitric oxide generated by mitochondria. ONOO- inactivated aconitase in a dose-dependent manner (half-maximal inhibition was observed with approximately 3 microM ONOO-). Low levels of ONOO- caused the conversion of the Fe-S cluster from the [4Fe-4S]2+ form to the inactive [3Fe-4S]1+ form with the loss of labile iron, as confirmed by low-temperature EPR analysis. In the presence of the substrate, citrate, 66-fold higher concentrations of ONOO- were required for half-maximal inhibition. The protective effects of citrate corresponded to its binding to the active site. The inactivation of aconitase in the presence of citrate was due to ONOO--mediated cysteine thiol loss and tyrosine nitration in the enzyme as shown by Western blot analyses. LC/MS/MS analyses revealed that ONOO- treatment to aconitase resulted in nitration of tyrosines 151 and 472 and oxidation to sulfonic acid of cysteines 126 and 385. The latter is one of the three cysteine residues in aconitase that binds to the Fe-S cluster. All other modified tyrosine and cysteine residues were adjacent to the binding site, thus suggesting that these modifications caused conformational changes leading to active-site disruption. Aconitase cysteine thiol modifications other than oxidation to sulfonic acid, such as S-glutathionylation, also decreased aconitase activity, thus indicating that glutathionylation may be an important means of modulating aconitase activity under oxidative and nitrative stress. Taken together, these results demonstrate that the Fe-S cluster in the active site, cysteine 385 bound to the Fe-S cluster, and tyrosine and cysteine residues in the vicinity of the active site are important targets of oxidative and/or nitrative attack, which is selectively controlled by the mitochondrial matrix citrate levels. The mechanisms inherent in aconitase inactivation by ONOO- are discussed in terms of the mitochondrial matrix metabolic and thiol redox state.


The microtubule-targeted agent lisavanbulin (BAL101553) shows anti-tumor activity in lymphoma models.
Microtubules are major components of the cellular cytoskeleton, ubiquitously founded in all eukaryotic cells. They are involved in mitosis, cell motility, intracellular protein and organelle transport, and maintenance of cytoskeletal shape. Avanbulin (BAL27862) is a microtubule-targeted agent (MTA) that promotes tumor cell death by destabilization of microtubules. Due to its unique binding to the colchicine site of tubulin, differently from other MTAs, avanbulin has previously shown activity in solid tumor cell lines. Its prodrug, lisavanbulin (BAL101553), has shown early signs of clinical activity, especially in tumors with high EB1 expression. Here, we assessed the preclinical anti-tumor activity of avanbulin in diffuse large B cell lymphoma (DLBCL) and the pattern of expression of EB1 in DLBCL cell lines and clinical specimens. Avanbulin showed a potent in vitro anti-lymphoma activity, which was mainly cytotoxic with potent and rapid apoptosis induction. Median IC50 was around 10 nM in both ABC and GCB-DLBCL. Half of the cell lines tested showed an induction of apoptosis already in the first 24 h of treatment, the other half in the first 48 h. EB1 showed expression in DLBCL clinical specimens, opening the possibility for a cohort of patients that could potentially benefit from treatment with lisavanbulin. These data show the basis for further preclinical and clinical evaluation of lisavanbulin in the lymphoma field.


Changes in food sources of dietary fat in response to an intensive low-fat dietary intervention: early results from the Women's Health Initiative.
To evaluate changes in food sources of dietary fat made by participants in the Women's Health Initiative Low-Fat Dietary Modification Trial. This study compares sources of dietary fat intake, estimated by a food frequency questionnaire, between intervention and control participants at baseline, 1 year (year 1) and 2 years (year 2) after randomization. The outcome measure was intake of fat in grams per day. Results are given on consumption of fat from six food groups and the intervention effect, defined as mean change in the intervention group minus the change in controls, controlling for baseline fat intake. 5,004 intervention and 7,426 control postmenopausal women in 40 clinical centers across the United States. At baseline, the major sources of fat were added fats, such as butter, oils, and salad dressings (25%); meats (21%); and desserts (13%). From baseline to year 1, the intervention group reduced fat by 24.3 g/day compared with the control group. Reductions came primarily from added fats (9.1 g/day), meats (4.6 g/day), and desserts (3.9 g/day). White people reduced added fats more than other race/ethnicity groups did, white and Hispanic people were more likely to reduce fat intake from milk and cheese compared with other groups, and Hispanics reduced fat from mixed dishes more than did other race/ethnicity groups (P<.05 for all). These data indicate that women in the Women's Health Initiative dietary change intervention made substantial changes in food choices. These results can facilitate future low-fat interventions, and also offer clinical applications, by identifying foods that may be refractory to change.


Transcranial magnetic stimulation studies in complex regional pain syndrome type I: A review.
The sensory and motor cortical representation corresponding to the affected limb is altered in patients with complex regional pain syndrome (CRPS). Transcranial magnetic stimulation (TMS) represents a useful non-invasive approach for studying cortical physiology. If delivered repetitively, TMS can also modulate cortical excitability and induce long-lasting neuroplastic changes. In this review, we performed a systematic search of all studies using TMS to explore cortical excitability/plasticity and repetitive TMS (rTMS) for the treatment of CRPS. Literature searches were conducted using PubMed and EMBASE. We identified 8 articles matching the inclusion criteria. One hundred fourteen patients (76 females and 38 males) were included in these studies. Most of them have applied TMS in order to physiologically characterize CRPS type I. Changes in motor cortex excitability and brain mapping have been reported in CRPS-I patients. Sensory and motor hyperexcitability are in the most studies bilateral and likely involve corresponding regions within the central nervous system rather than the entire hemisphere. Conversely, sensorimotor integration and plasticity were found to be normal in CRPS-I. TMS examinations also revealed that the nature of motor dysfunction in CRPS-I patients differs from that observed in patients with functional movement disorders, limb immobilization, or idiopathic dystonia. TMS studies may thus lead to the implementation of correct rehabilitation strategies in CRPS-I patients. Two studies have begun to therapeutically use rTMS. This non-invasive brain stimulation technique could have therapeutic utility in CRPS, but further well-designed studies are needed to corroborate initial findings.


[Molecular remission of chronic myeloid leukaemia in a patient with hepatitis and a second kidney transplant].
Chronic myeloid leukemia (CML) is a myeloproliferative disorder characterized by clonal expansion of cells in the myeloid line, expressing the BCR-ABL fusion protein responsible for the oncogenic effect of CML. The current frontline therapy in CML is the BCR-ABL tyrosine kinase inhibitor, Imatinib. Although this drug has been shown to improve survival in CML patients, its role in the context of a transplant setting has not been widely described in the literature. We report on the long term molecular remission of CML in a 55 year old man with a second renal transplant who is hepatitis C virus positive, and has associated cardiovascular and immunological risk factors.


A scoping review of skills and tools oral health professionals need to engage children and parents in dietary changes to prevent childhood obesity and consumption of sugar-sweetened beverages.
Increased consumption of sugar-sweetened beverages (SSBs) has been linked to obesity. Obesity now affects one in six children in the United States. The purpose of this scoping review is to identify and review published studies that discuss skills and tools oral health professionals can use with children (under age 12) and their parents to encourage dietary changes to aid in preventing childhood obesity and reducing consumption of SSBs. Key search terms were identified and used to examine selected databases via PubMed, EMBASE, CINAHL, and Cochrane Database of Systematic Reviews. A total of 637 records were identified. After duplicates were removed and records were screened for eligibility, 33 remained. Six met established inclusion/exclusion criteria and were included in the review. Only two full-text articles included dental-office-based weight interventions. Patient response to education on healthy habits and weight maintenance in the dental setting was favorable. Literature supports oral health professionals expanding their role in health care delivery by offering nutrition and physical activity recommendations to prevent and/or reduce chronic disease. Active listening and motivational interviewing were techniques identified to promote beneficial lifestyle changes. There is limited research on behavior modification tools and skills that have been effectively implemented in the dental setting to decrease risk of obesity. Oral health professionals are uniquely positioned to address consumption of SSBs and promote positive dietary habits for improved weight management. Future studies are needed to identify effective techniques that techniques that oral health professionals can integrate into preventive patient care.


Processing of ring saturation and fragmentation products of DNA thymine in Escherichia coli.
The biological processing of thymine ring saturation and fragmentation products is summarized in Table 1. The ring saturation product, thymine glycol, is a block to in vitro DNA synthesis, whereas the ring saturation product, dihydrothymine, is not. Both these lesions are recognized in vitro by endonucleases III and VIII. Since thymine glycol is a replicative block, it is a lethal lesion in vivo. The excision repair process for removal of thymine glycols from DNA is initiated in vivo by endonuclease III and is followed by the action of either exonuclease III or endonuclease IV. Thymine glycol is very efficiently bypassed by translesion bypass in both single and double stranded DNA, however, because thymine glycol templates an adenine (A) and retains pairing characteristics, it is at best a weakly mutagenic lesion. The thymine ring fragmentation product, urea, and apurinic/apyrimidinic (AP) sites are both strong blocks to in vitro DNA synthesis. Both are substrates in vitro for endonucleases III, IV, VIII and IX as well as exonuclease III. Both are lethal lesions in single stranded and double stranded phage transfecting DNA. The excision repair of urea residues and AP sites is initiated in vivo by either exonuclease III or endonuclease IV. Neither of these noninstructive lesions are efficiently bypassed by UV-induced translesion bypass, however, when bypass occurs mutations result. beta-ureidoisobutylic acid is also a block to DNA synthesis in vitro. DNA containing this lesion is a substrate for endonucleases VIII and IX. The biological processing of this ring open thymine fragmentation product has yet to be determined. Thus, these ring saturation and fragmentation products of thymine have provided a point of departure for understanding the biological processing of modified bases with altered pairing and/or stacking properties.


Molecular variations in Klebsiella pneumoniae and Escherichia coli FimH affect function and pathogenesis in the urinary tract.
Type 1 pili mediate binding, invasion, and biofilm formation of uropathogenic Escherichia coli (UPEC) in the host urothelium during urinary tract infection (UTI) via the adhesin FimH. In this study, we characterized the molecular basis of functional differences between FimH of the UPEC isolate UTI89 and the Klebsiella pneumoniae cystitis isolate TOP52. Type 1 pili characteristically mediate mannose-sensitive hemagglutination of guinea pig erythrocytes. Although the adhesin domain of K. pneumoniae TOP52 FimH (FimH(52)) is highly homologous to that of E. coli, with an identical mannose binding pocket and surrounding hydrophobic ridge, it lacks the ability to agglutinate guinea pig erythrocytes. In addition, FimH-dependent biofilm formation in K. pneumoniae is inhibited by heptyl mannose, but not methyl mannose, suggesting the need for contacts outside of the mannose binding pocket. The binding specificity differences observed for FimH(52) resulted in significant functional differences seen in the pathogenesis of K. pneumoniae UTI compared to E. coli UTI. Infections in a murine model of UTI demonstrated that although the K. pneumoniae strain TOP52 required FimH(52) for invasion and IBC formation in the bladder, FimH(52) was not essential for early colonization. This work reveals that a limited amount of sequence variation between the FimH of E. coli and K. pneumoniae results in significant differences in function and ability to colonize the urinary tract.


Nutritional encephalomalacia in the chick: an exposure of the vulnerable period for cerebellar development and the possible need for both omega 6- and omega 3-fatty acids.
1. Cockerels (1-d-old) received over a period of 4 weeks, a balanced diet containing either safflower oil (diet S) or linseed oil (diet L) as a source of polyunsaturated fatty acids (PUFA). Body-weight, and weights of cerebrum and cerebellum increased at similar rates in the two dietary groups. The total fatty acids (FA) of the cerebellum differed from the cerebral FA by their higher PUFA and oleic acid contents and their lower stearic acid level. During the 3rd week of life there was a spurt in accretion of PUFA in the cerebellum, but not in the cerebrum. At the end of the experimental period phosphatidylethanolamine was present at twice the concentration in the cerebellum, compared with the cerebrum. 2. Diets S and L resulted in extensive mutual replacement of omega 6- and omega 3-FA in brain, without any significant change in the total PUFA. Brain oleic acid concentration was higher in the diet-L group than in the diet-S group, but saturated FA were not affected by the dietary treatments. 3. These results may be relevant to basic brain biology and to chick nutritional encephalomalacia (NE). This disease, which specifically affects the cerebellum and is readily induced by diets supplying linoleic acid but deficient in vitamin E, usually reaches its highest incidence during the 3rd week of life and may thus be related to the cerebellar PUFA spurt that occurs at that time. The fact that NE was induced by linoleic acid, while alpha-linolenic acid exerted a protective action, points to an overproduction of arachidonic-derived eicosanoids as a factor in the etiology of the cerebellar lesion and possibly a structural change due to a loss of docosahexaenoic acid and gain of arachidonic acid in the chicks given diet S.


p53 isoform profiling in glioblastoma and injured brain.
The tumor suppressor p53 has been found to be the most commonly mutated gene in human cancers; however, the frequency of p53 mutations varies from 10 to 70% across different cancer types. This variability can partly be explained by inactivating mechanisms aside from direct genomic polymorphisms. The p53 gene encodes 12 isoforms, some of which can modulate full-length p53 activity in cancer. In this study, we characterized p53 isoform expression patterns in glioblastoma, gliosis, non-tumor brain and neural progenitor cells by SDS-PAGE, immunoblot, mass spectrometry and reverse transcription-PCR. We found that the most consistently expressed isoform in glioblastoma, Δ40p53, was uniquely expressed in regenerative processes, such as those involving neural progenitor cells and gliosis compared with tumor samples. Isoform profiling of glioblastoma tissues revealed the presence of both Δ40p53 and full-length p53, neither of which were detected in non-tumor cerebral cortex. Upon xenograft propagation of tumors, p53 levels increased. The variability of overall p53 expression and relative levels of isoforms suggest fluctuations in subpopulations of cells with greater or lesser capacity for proliferation, which can change as the tumor evolves under different growth conditions.


BFACE: A Framework for Evaluating Breast Aesthetics.
Although much has been written about breast aesthetics, the literature lacks a simple yet systematic and comprehensive approach for preoperative breast assessment. With use of the mnemonic "BFACE," the breast surgeon will analyze the bony skeleton and the breast footprint, areola, conus, and envelope. The authors present a thorough review of the important parameters that define the ideal breast, and several techniques for perceiving asymmetries more clearly. Strategic surgical planning is enabled by accurate perception.


Potentiation of pentazocine antinociception by tripelennamine in the rat.
The effect of tripelennamine on pentazocine antinociception in rats was investigated utilizing a low temperature (51.5 degrees C) hot-plate technique. Tripelennamine (10 and 20 mg/kg i.p.) showed some antinociceptive activity, which was not antagonized by naloxone. Pentazocine antinociception was potentiated by simultaneous administration of a large dose (20 mg/kg) but not a small dose (5 mg/kg) of tripelennamine. Potentiation was not observed when tripelennamine was administered 2 hr before the injection of pentazocine and chronic administration of tripelennamine for 14 days did not alter pentazocine antinociceptive activity. After administration of pentazocine and tripelennamine, levels of pentazocine under concentration-time curves in the brain and plasma were slightly and significantly larger, respectively, than the levels obtained by the administration of pentazocine alone. After the administration of tripelennamine and pentazocine, the brain tripelennamine concentration at 1/4 hr was about 2.6 times that after the administration of tripelennamine alone. The results suggest that the effect of tripelennamine on pentazocine antinociception is additive; very little was through a mechanism of inhibition of pentazocine metabolism.


The Effects of Water Immersion during First Stage of Labor on Postpartum Systemic Inflammatory Response.
The systemic inflammatory response is a cascade of physiologic reactions that arise in response to trauma, infection, burn, or any kind of injury. This study aimed to determine the effects of water immersion during the first stage of labor on the systemic inflammatory indices in the postpartum period. In this retrospective study, 125 healthy multiparous women with uncomplicated pregnancies between 37 and 41 weeks of gestation who elected for immersion in water during the first stage of labor were compared with multiparous uncomplicated term women who had conventional vaginal births on land (n=125). Age, parity, body mass index (BMI), gestational age, duration of labor, birth weight, Apgar scores, neonatal intensive care unit admissions, and ante- and postpartum whole blood parameters were noted. Antepartum and postpartum neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), platelet-to-lymphocyte ratio (PLR), and mean platelet volume (MPV) were calculated for all patients as systemic inflammatory indices. Demographic characteristics and birth outcomes of both groups were similar except BMI, which was statistically significantly higher in the water immersion group. There were no statistical differences in antepartum NLR, MLR, PLR, and MPV between the 2 groups. However, postpartum NLR, MLR, PLR, and MPV were statistically significantly lower in the water immersion group compared to the controls. Water immersion during the first stage of labor might decrease systemic inflammatory indices in the early postpartum period.


Esophagogastric junction morphology predicts susceptibility to exercise-induced reflux.
Although strenuous exercise has been reported to increase gastroesophageal reflux, there are few data exploring the mechanism behind this relationship. The aim of this study was to use vigorous exercise as a provocation for strain-induced reflux and examine the correlation between endoscopically assessed EGJ integrity and exercise-induced reflux. Ten controls and 10 GERD patients were studied for a 2-day period using the wireless Bravo pH monitoring system. The subjects were randomly assigned to perform 60 min of exercise on day 1 or 2 consuming the same diet on both days. Exercise consisted of 30 min of running and 30 min of 5 resistance exercises. Subjects underwent endoscopy to grade the EGJ "flap valve" and manometry to measure basal LES pressure. Nineteen subjects completed the 2-day study with 100% data capture during exercise. Median acid exposure was increased more than threefold for both controls and GERD patients during exercise when compared to nonexercise periods. In addition, a strong correlation existed between EGJ grade and % time pH < 4 during exercise while there was not a significant correlation between LES pressure and EGJ grade. These findings were present even after exclusion of hiatus hernia patients (flap valve grade 4). Exercise caused a threefold increase in esophageal acid exposure in both controls and GERD patients. The degree of exercise-induced reflux is strongly correlated with EGJ morphology and this supports the hypothesis that anatomical integrity of the EGJ is of cardinal importance in preventing strain-induced reflux.


Paternal occupation and birth defects: findings from the National Birth Defects Prevention Study.
Several epidemiological studies have suggested that certain paternal occupations may be associated with an increased prevalence of birth defects in offspring. Using data from the National Birth Defects Prevention Study, the authors investigated the association between paternal occupation and birth defects in a case-control study of cases comprising over 60 different types of birth defects (n=9998) and non-malformed controls (n=4066) with dates of delivery between 1997 and 2004. Using paternal occupational histories reported by mothers via telephone interview, jobs were systematically classified into 63 groups based on shared exposure profiles within occupation and industry. Data were analysed using bayesian logistic regression with a hierarchical prior for dependent shrinkage to stabilise estimation with sparse data. Several occupations were associated with an increased prevalence of various birth defect categories, including mathematical, physical and computer scientists; artists; photographers and photo processors; food service workers; landscapers and groundskeepers; hairdressers and cosmetologists; office and administrative support workers; sawmill workers; petroleum and gas workers; chemical workers; printers; material moving equipment operators; and motor vehicle operators. Findings from this study might be used to identify specific occupations worthy of further investigation and to generate hypotheses about chemical or physical exposures common to such occupations.


Advances in Imaging of Inflammation, Fibrosis, and Cancer in the Gastrointestinal Tract.
Gastrointestinal disease is prevalent and broad, manifesting itself in a variety of ways, including inflammation, fibrosis, infection, and cancer. However, historically, diagnostic technologies have exhibited limitations, especially with regard to diagnostic uncertainty. Despite development of newly emerging technologies such as optoacoustic imaging, many recent advancements have focused on improving upon pre-existing modalities such as ultrasound, computed tomography, magnetic resonance imaging, and endoscopy. These advancements include utilization of machine learning models, biomarkers, new technological applications such as diffusion weighted imaging, and new techniques such as transrectal ultrasound. This review discusses assessment of disease processes using imaging strategies for the detection and monitoring of inflammation, fibrosis, and cancer in the context of gastrointestinal disease. Specifically, we include ulcerative colitis, Crohn's disease, diverticulitis, celiac disease, graft vs. host disease, intestinal fibrosis, colorectal stricture, gastric cancer, and colorectal cancer. We address some of the most recent and promising advancements for improvement of gastrointestinal imaging, including unique discussions of such advancements with regard to imaging of fibrosis and differentiation between similar disease processes.


Integrating nutrition outcomes into agriculture development for impact at scale: Highlights from the Canadian International Food Security Research Fund.
The Canadian International Food Security Research Fund programme supported research and scaling up of nutrition- and gender-sensitive agriculture innovations from 2009 to 2018. Women and girls were identified as agents of change and were targeted as the main programme beneficiaries. Projects were implemented in 25 countries through multistakeholder partnerships among universities, research institutions, public and private sectors, and civil society groups, reaching over 78 million people, mainly women and children. Approaches specific to nutrition included growing more nutritious crops, improving dietary diversity, value added processing, food fortification, and nutrition education. Scale-up for impact was achieved through a number of pathways that started with evidence through rigorous research, followed by a combination of elements such as understanding local and regional contexts to identify specific bottlenecks and opportunities for the deployment and adoption of successful innovations, selecting politically effective or influential partners to lead the scaling up process, and investing in long-term local capacity and leadership building. Overall, the knowledge generated in the programme indicate that well-designed nutrition-sensitive agriculture and food-based interventions can have meaningful impacts on pathways that will lead to better health and well-being of women and children through improving household and individual access to nutrient-rich foods. Longer intervention times are needed to demonstrate changes in health indicators such as reduced stunting. This overview paper summarises the programme and showcases examples from studies that demonstrate the impact pathway for nutrition interventions that encompass efficacy and effectiveness studies, value-added processing, cost effectiveness of interventions, and bringing a proven intervention to scale.


Prevalence of degenerative vertebral disc changes in elite female Crossfit athletes - a cross-sectional study.
Crossfit athletes consistently recruit or transfer high levels of repetitive forces through the spine, and MRI has documented a higher rate of intervertebral disc degeneration in athletes compared with matched controls. The aim of this study was to evaluate early degenerative spinal disc changes in elite female CrossFit athletes quantified by 3.0 Tesla magnetic resonance imaging (MRI) matched with female none-athletes. In a cross-sectional single-center study 19 asymptomatic adult participants, nine German female elite Crossfit athletes and ten female participants underwent spinal MRI (3.0T). Demographic data, spinal clinical examination results and sport-specific performance parameters were collected prior to the MRI. The primary outcome was the prevalence of degenerative spinal disc changes. The secondary outcome was the grade of degeneration using Pfirrmann grading. A total of 437 discs underwent spinal MRI (3.0T). The prevalence of early degenerative disc disease was not increased. Pfirrmann degenerative grade did not show significant differences among groups. Asymptomatic female elite Crossfit athletes do not show an increased prevalence of degenerative disc disease. Compared to a sex-matched control group, high training volume in Crossfit does not correlate to a higher incidence of degenerative disc changes in young females.


Monoclonal antibody to chicken fetal antigen on Marek's disease lymphoblastoid cell line MDCC-MSB1.
A monoclonal antibody (2H3) to chicken fetal antigen (CFA) expressed on the cell surface of the Marek's disease lymphoblastoid cell line MDCC-MSB1 was generated. 2H3 reacted specifically with various cells from chicken embryos, especially with fetal red blood cells, fetal bursa-derived lymphocytes, fetal liver cells, and embryo fibroblasts but not with fetal peripheral blood lymphocytes. 2H3 reacted also with all lymphoblastoid cell line cells tested: Marek's disease, avian leukosis, and reticuloendotheliosis line cells. On the basis of 2H3 specificity, CFA detected by 2H3 seemed to be similar to chicken fetal red blood cell antigen previously reported, but not to chicken alpha-fetoprotein. A transient increase of reactivities with 2H3 was observed in lymphocytes prepared from thymus, spleen, and bursa of chickens inoculated with Marek's disease virus or herpesvirus of turkeys from 7 to 21 days postinoculation. The average percentage of CFA-positive cells in lymphoid cells from Marek's disease virus-infected chickens at the peaks was higher than that of the cells in Marek's disease tumor cells from 146- and 156-day-old chickens in the field. The results of sodium dodecyl sulfate-polyacrylamide gel electrophoresis and Western blotting analysis revealed that the monoclonal 2H3 is recognized a Mr 50,000 oncodevelopmental cell surface antigen present on MDCC-MSB1 cells. The possible differences between CFA detected by 2H3 and chicken fetal red blood cell antigen expressed on normal chicken fetal erythrocytes are discussed.


Light deprivation soon after frontal brain trauma accelerates recovery from attentional deficits and promotes functional normalization of basal ganglia.
Light deprivation significantly accelerates recovery from attention deficits (neglect) after cortical ablation in rats. We hypothesized that light deprivation would improve recovery after traumatic contusive brain injury (TBI) and do so by enhancing dopaminergic function in the ipsilateral basal ganglia. Adult rats received left frontal contusion injury and were placed into darkness or standard light/dark cycling for 48 hours. Neurologic evaluation included attentional and sensorimotor tasks. Amphetamine-induced production of the immediate early gene protein product Fos was quantified to determine neuronal dopaminergic response in caudate-putamen (striatum). Unilateral frontal TBI produced severe contralateral deficits in all tasks. Postoperative light deprivation resulted in improved recovery from attentional but not sensorimotor deficits. Five days after injury, ipsilateral striatal Fos expression was reduced by 51% in TBI rats experiencing normal light cycling (p < 0.006). In contrast, postoperative light deprivation normalized striatal Fos expression. By 6 weeks, all TBI rats demonstrated nearly full recovery and striatal Fos expression was symmetrical between the two striata. Postoperative light deprivation may improve recovery from TBI-induced attention deficits by normalizing basal ganglia function.


A nanographene disk rotating a single molecule gear on a Cu(111) surface.
On Cu(111) surface and in interaction with a single hexa-tert-butylphenylbenzene molecule-gear, the rotation of a graphene nanodisk was studied using the large-scale atomic/molecular massively parallel simulator molecular dynamics simulator. To ensure a transmission of rotation to the molecule-gear, the graphene nanodisk is functionalized on its circumference bytert-butylphenyl chemical groups. The rotational motion can be categorized underdriving, driving and overdriving regimes calculating the locking coefficient of this mechanical machinery as a function of external torque applied to the nanodisk. The rotational friction with the surface of both the phononic and electronic contributions is investigated. For small size graphene nanodisks, the phononic friction is the main contribution. Electronic friction dominates for the larger disks putting constrains on the experimental way of achieving the transfer of rotation from a graphene nanodisk to a single molecule-gear.


A carboxyl-terminal sequence in the lutropin beta subunit contributes to the sorting of lutropin to the regulated pathway.
Although synthesized in the same pituitary gonadotropes, the secretion profiles of lutropin (LH) and follitropin (FSH) differ. LH is secreted through a regulated pathway and associated with a bolus release at mid-estrous cycle. In contrast, the majority of FSH is secreted constitutively with an incremental increase until ovulation. Both share an identicalalpha subunit, and thus thebeta subunit contains determinants for sorting into the regulated pathway. Previously, we demonstrated that a hydrophobic carboxyl-terminal heptapeptide of the LHbeta subunit (Leu-Ser-Gly-Leu-Leu-Phe-Leu), not found in the FSHbeta subunit, influences the intracellular behavior of the LH dimer. To test the hypothesis that the peptide contributes to differential sorting, we monitored the fates of LH and LHDeltaT (LHbeta subunit lacking the carboxyl-terminal seven amino acids) dimers in the rat somatotrope-derived GH(3) cell line in which both the regulated and constitutive secretory pathways operate. Pulse-chase labeling demonstrated that the LHDeltaT dimer was diverted to the constitutive pathway, resulting in a significant decrease in the corresponding intracellular pool. Forskolin stimulated LH dimer release 3-fold, which was accompanied by a parallel decrease of intracellular LH; only marginal forskolin stimulation of LHDeltaT was seen. Immunofluorescence after cycloheximide treatment demonstrated decreased retention of LHDeltaT compared with LH, consistent with increased constitutive secretion of LHDeltaT. We also demonstrated that fusing the heptapeptide to the carboxyl terminus of the FSHbeta subunit resulted in an increased regulated secretion of this FSH analog compared with wild-type FSH. These data are the first to identify a novel structural determinant responsible for the sorting of a member of the glycoprotein hormone family into the regulated secretory pathway.


Can posterior dynamic stabilization reduce the risk of adjacent segment deterioration?
The aim of this study was to systematically review the relevant literature to develop a benchmark for the incidence of adjacent segment degeneration (ASDeg) and adjacent segment disease (ASDis) following the posterior dynamic stabilization (PDS) procedure and to investigate whether conclusions can be made with regard to the isolated PDS procedure in reducing the risk of ASDeg and ASDis compared with fusion, and with regard to the role of additional PDS devices implanted adjacent to fusion in protecting from ASDeg and ASDis caused by the neighboring fusion. We retrieved electronic databases of Medline, Ovid and Cochrane Central Registry of Controlled Trials, combined with a supplemental hand search. Thirty-one articles met our inclusion criteria. The pooled incidence of ASDeg and ASDis following PDS procedure was 16.4% and 5.5% respectively. Data from comparative studies showed a significantly lower incidence of ASDeg and nonsignificantly lower incidence of ASDis following PDS than following fusion surgery. Further, the additional PDS devices implanted adjacent to fusion could significantly reduce the risk of ASDeg and nonsignificantly decrease that of ASDis caused by fusion. These results suggested relative success of the PDS procedure in protecting against ASDeg and ASDis.


Review on the Antibacterial Mechanism of Plant-Derived Compounds against Multidrug-Resistant Bacteria (MDR).
Microbial resistance has progressed rapidly and is becoming the leading cause of death globally. The spread of antibiotic-resistant microorganisms has been a significant threat to the successful therapy against microbial infections. Scientists have become more concerned about the possibility of a return to the pre-antibiotic era. Thus, searching for alternatives to fight microorganisms has become a necessity. Some bacteria are naturally resistant to antibiotics, while others acquire resistance mainly by the misuse of antibiotics and the emergence of new resistant variants through mutation. Since ancient times, plants represent the leading source of drugs and alternative medicine for fighting against diseases. Plants are rich sources of valuable secondary metabolites, such as alkaloids, quinones, tannins, terpenoids, flavonoids, and polyphenols. Many studies focus on plant secondary metabolites as a potential source for antibiotic discovery. They have the required structural properties and can act by different mechanisms. This review analyses the antibiotic resistance strategies produced by multidrug-resistant bacteria and explores the phytochemicals from different classes with documented antimicrobial action against resistant bacteria, either alone or in combination with traditional antibiotics.


Research progress on proteasome subunits in regulating occurrence and development of hepatocellular carcinoma.
Proteasome is the eukaryotic organelle responsible for degradation of short-lived proteins and involved in maintaining cellular protein homeostasis. It has been reported that during the occurrence and development of hepatocellular carcinoma (HCC), the regulatory particle subunits of proteasome regulate a series of tumor-related proteins, and proliferation, survival-associated signaling molecules, including PTEN gene, P53, Bcl-2, Bcl-2 interacting mediator of cell death (Bim), cyclin-dependent kinase 4(CDK4), transforming growth factor β receptor (TGFBR), E2F1, growth factor receptor-bound protein 2 (GRB2) . Meanwhile, these subunits regulate some tumor-associated pathway protein, such as signal transducer and activator of transcription 3 (STAT3) and protein kinase B (AKT), inducing their malfunction to promote the occurrence, proliferation, invasion and metastasis of HCC. The core particle subunits are more to perform the degradation of HCC-related proteins, so inhibitors targeting the core particle show a good anti-tumor effect. This review summarizes the current research progress on the regulation and mechanism of proteasome subunits in promoting the occurrence and development .


Perspective: Integrating research into surgical residency education: lessons learned from orthopaedic surgery.
Orthopaedic research has advanced tremendously in parallel with accelerated progress in medical science. Possession of a fundamental understanding of basic and clinical science has become more essential than previously for orthopaedic surgeons to be able to translate advances in research into clinical practice. The number of medical graduates with prior education in scientific research who choose to pursue careers in orthopaedic surgery is small. Therefore, it is important that a core of research education be included during residency training to ensure the continued advancement of the clinical practice of orthopaedics. The authors examine some of the challenges to a comprehensive research experience during residency, including deficient priority, inadequate institutional infrastructure, financial strain on residency budgets, restricted time, and an insufficient number of mentors to encourage and guide residents to become clinician-scientists. They also present some strategies to overcome these challenges, including development and expansion of residency programs with clinician-scientist pathways, promotion of financial sources, and enhancement of opportunities for residents to interact with mentors who can serve as role models. Successful integration of research education into residency programs will stimulate future orthopaedic surgeons to develop the critical skills to lead musculoskeletal research, comprehend related discoveries, and translate them into patient care. Lessons learned from incorporating research training within orthopaedic residency programs will have broad application across medical specialties-in both primary and subspecialty patient care.


[Energy expenditure of workers at modern animal-breeding complexes].
The energy expenditure of workers at modern cattle-breeding farm complexes was studied during their working time and during 24 h. It was found that during the working period the energy expenditure fluctuated from 9.2 to 25.9 kJ/min, while daily energy expenditure comprised 11.6-13.8 MJ.


Enzymatic properties and anticancer activity of L-lysine α-oxidase from Trichoderma cf. aureoviride Rifai BKMF-4268D.
L-Lysine α-oxidase (LO) from a novel Trichoderma strain: Trichoderma cf. aureoviride Rifai shows favorable biochemical and kinetic properties (Km for L-lysine of 17.9 µmol/l, optimum pH 8.0, high stability) and significant antiproliferative activity both in vitro and in vivo. The molecular weight of LO was determined to be 115-116 kDa; the active dimer consists of two identical 57-58 kDa subunits. LO shows considerable cytotoxicity against the following tumor cell lines: K562, LS174T, HT29, SCOV3, PC3, and MCF7, with the inhibition concentration (IC50) ranging from 3.0×10 to 7.8×10 U/ml (3.2×10 to 8.2×10 mg/ml). Two human colon cancer xenografts HCT116 and LS174T and breast adenocarcinoma T47D implanted subcutaneously into Balb/c nude mice showed high sensitivity to LO with a T/C of 12, 37, and 36%, respectively (P<0.05). The antitumor efficacy of LO was observed in the absence of pronounced morbidity or toxicity in vivo. Taken together, these data suggest that LO may be considered as an effective anticancer agent for the treatment of solid tumors in vivo. This study presents promising data on the possible application of LO in clinical oncology for patients with colorectal cancer.


Characteristics of phase-aberrated nondiffraction-limited laser beams.
To simulate nondiffraction-limited laser beams numerically, one needs to understand their nature better. For a phase aberration the correlation length of which is much less than the width of the beam, one can show that the far-field irradiance distribution can be written as the sum of two beams. One beam is the attenuated diffraction-limited beam; the other is a much wider beam the exact shape of which is closely related to the power spectrum of the phase fluctuations. Computer simulations of random phase aberrations are shown to agree well with the analytic predictions. Attempts at simulation of nondiffraction-limited beams for nonlinear wave propagation problems are discussed.