Locally advanced prostate cancer: a population-based study of treatment patterns.
Study Type--Therapy (practice patterns). Level of Evidence 2b. What's known on the subject? And what does the study add? The treatment of locally advanced prostate cancer varies widely even though there is level one evidence supporting the use of multimodality therapy as compared with monotherapy. This study defines treatment patterns of locally advanced prostate cancer within the United States and identifies predicators of who receives multimodality therapy rather than monotherapy. • To identify treatment patterns and predictors of receiving multimodality therapy in patients with locally advanced prostate cancer (LAPC). • The cohort comprised patients ≥66 years with clinical stage T3 or T4 non-metastatic prostate cancer diagnosed between 1998 and 2005 identified from the Surveillance, Epidemiology and End Results (SEER) cancer registry records linked with Medicare claims. • Treatments were classified as radical prostatectomy (RP), radiation therapy (RT) and androgen deprivation therapy (ADT) received within 6 and 24 months of diagnosis. • We assessed trends over time and used multivariable logistic regression to identify predictors of multimodality treatment. • Within the first 6 months of diagnosis, 1060 of 3095 patients (34%) were treated with a combination of RT and ADT, 1486 (48%) received monotherapy (RT alone, ADT alone or RP alone), and 461 (15%) received no active treatment. • The proportion of patients who received RP increased, exceeding 10% in 2005. • Use of combined RT and ADT and use of ADT alone fluctuated throughout the study period. • In all 6% of patients received RT alone in 2005. • Multimodality therapy was less common in patients who were older, African American, unmarried, who lived in the south, and who had co-morbidities or stage T4 disease. • Treatment of LAPC varies widely, and treatment patterns shifted during the study period. • The slightly increased use of multimodality therapy since 2003 is encouraging, but further work is needed to increase combination therapy in appropriate patients and to define the role of RP.


Inhibition of prostate smooth muscle contraction and prostate stromal cell growth by the inhibitors of Rac, NSC23766 and EHT1864.
Medical therapy of lower urinary tract symptoms (LUTS) suggestive of benign prostatic hyperplasia (BPH) targets smooth muscle contraction in the prostate, or prostate growth. However, current therapeutic options are insufficient. Here, we investigated the role of Rac in the control of smooth muscle tone in human prostates and growth of prostate stromal cells. Experiments were performed using human prostate tissues from radical prostatectomy and cultured stromal cells (WPMY-1). Expression of Rac was examined by Western blot and fluorescence staining. Effects of Rac inhibitors (NSC23766 and EHT1864) on contractility were assessed in the organ bath. The effects of Rac inhibitors were assessed by pull-down, cytotoxicity using a cell counting kit, cytoskeletal organization by phalloidin staining and cell growth using an 5-ethynyl-2'-deoxyuridine assay. Expression of Rac1-3 was observed in prostate samples from each patient. Immunoreactivity for Rac1-3 was observed in the stroma, where it colocalized with the smooth muscle marker, calponin. NSC23766 and EHT1864 significantly reduced contractions of prostate strips induced by noradrenaline, phenylephrine or electrical field stimulation. NSC23766 and EHT1864 inhibited Rac activity in WPMY-1 cells. Survival of WPMY-1 cells ranged between 64 and 81% after incubation with NSC23766 (50 or 100 μM) or EHT1864 (25 μM) for 24 h. NSC23766 and EHT1864 induced cytoskeletal disorganization in WPMY-1 cells. Both inhibitors impaired the growth of WPMY-1 cells. Rac may be a link connecting the control of prostate smooth muscle tone with proliferation of smooth muscle cells. Improvements in LUTS suggestive of BPH by Rac inhibitors appears possible.


Social determinants of health and HIV Pre-Exposure Prophylaxis (PrEP) interest and use among young Black and Latinx sexual minority men.
Young Black and Latinx sexual minority men (YBLSMM) have low use of HIV pre-exposure prophylaxis (PrEP), despite high rates of new HIV diagnosis. While unmet social determinants of health (SDOH) have been associated with low uptake of preventive health services, this association is unknown for PrEP. To understand the relationship between SDOH and PrEP adoption in this population, we analyzed data from an online survey of HIV-negative YBLSMM aged 18-29 in New York City (n = 143). Participants completed a 17-item SDOH needs scale measuring basic, health/social-services, and economic needs. We used regression models to examine associations of unmet SDOH with outcomes of intention to use PrEP and current PrEP use. Of those not on PrEP (n = 114), 69 (61%) intended to use PrEP. More unmet SDOH needs overall were associated with intention to use PrEP (OR 1.4; 95% CI 1.1, 2.0), as were more unmet basic needs (OR 1.7; 95% CI 1.1, 2.5) and more unmet economic needs (OR 1.3; 95% CI 1.0, 1.7). Unmet SDOH needs were not associated with current PrEP use. Findings suggest that intention to use PrEP among YBLSMM is a likely marker of unmet SDOH needs, as YBLSMM with unmet needs may have limited resources to support moving from intention to actual use. Future research should evaluate programs engaging YBLSMM intending to use PrEP with interventions to screen for and address SDOH.


A reliable method for avoiding false negative results with Luminex single antigen beads; evidence of the prozone effect.
Luminex single antigen bead (SAB) assays have become an essential tool in monitoring the status of antibody to the Human Leucocyte Antigen (HLA) of patients both before and after transplantation. In addition SAB data is used to aid risk stratification to assess immunological risk of humoral rejection in solid organ transplantation (CTAG/BTAG guidelines) [1]. Increasingly laboratories are reporting false negative results at high antibody titre due to a prozone effect. Here we report a case study where the prozone effect led to a false negative antibody result that could have resulted in adverse outcome. We describe a method to reliably remove the prozone effect through heat inactivation and the addition of Ethylenediaminetetraacetic acid (EDTA) to the Luminex wash buffer.


Modeled cost-effectiveness of the Experience Corps Baltimore based on a pilot randomized trial.
The Experience Corps program was designed to harness the social capital of an aging society to improve outcomes for public elementary schools. The objectives of this article are (1) to model the cost-effectiveness of the Experience Corps Baltimore using data from a pilot randomized trial, including costs, older adults' health status, and quality of life and cost data from the Medical Expenditure Panel Survey, and (2) to describe the relationship between children experiencing increased expected lifetime earnings through improved educational attainment resulting from exposure to the Experience Corps Baltimore volunteers and the program's costs and cost-effectiveness. On average, each quality adjusted life year (QALY) gained by older adults in Experience Corps Baltimore costs $205,000. The lower bound of the 95% confidence interval for the cost-effectiveness is $65,000/QALY. The upper bound is undefined as 15% of the simulations indicated no QALY improvements. If 0.3% of students exposed to the Experience Corps Baltimore changed from not graduating to graduating, the increased lifetime earnings would make the incremental cost-effectiveness ratio $49,000/QALY. If an additional 0.1% changed to graduating from high school, the program would be cost-saving. Using conservative modeling assumptions and excluding benefits to teachers, principals, and the surrounding community, the Experience Corps Baltimore appears expensive for the older adults' health improvements, but requires only small long-term benefits to the target children to make the program cost-effective or cost-saving.


Effect of topical applications of a chlorhexidine/thymol-containing varnish on fissure caries assessed by laser fluorescence.
The aim of this study was to monitor the effect of an antibacterial varnish using the readings of a caries-detecting device (DIAGNOdent) in fissures of young permanent molars. The material consisted of 32 healthy patients with a mean age of 14.1 years undergoing orthodontic treatment with fixed appliances. The inclusion criteria were presence of one homologous pair of 2nd upper or lower molars with clinically intact occlusal surfaces. A split-mouth study design was used in which the fissures were treated with either an antibacterial chlorhexidine/thymol-containing varnish or a placebo varnish every 6th week. The follow-up period was 42 weeks and laser fluorescence (LF) readings were carried out every 12th week. The mean LF values increased significantly (P < 0.05) after 24, 36, and 48 weeks compared to baseline following the placebo treatments but not after treatment with the active antibacterial varnish. During the study period, micro-cavities were diagnosed in two test-treated and five placebo-treated teeth. In conclusion, the results reinforce previous findings that frequent applications of a chlorhexidine/thymol-containing dental varnish might have a protective role in fissures of young permanent molars and that this could be monitored with a chair-side caries detecting LF device.


Warping an atlas derived from serial histology to 5 high-resolution MRIs.
Previous work from our group demonstrated the use of multiple input atlases to a modified multi-atlas framework (MAGeT-Brain) to improve subject-based segmentation accuracy. Currently, segmentation of the striatum, globus pallidus and thalamus are generated from a single high-resolution and -contrast MRI atlas derived from annotated serial histological sections. Here, we warp this atlas to five high-resolution MRI templates to create five de novo atlases. The overall goal of this work is to use these newly warped atlases as input to MAGeT-Brain in an effort to consolidate and improve the workflow presented in previous manuscripts from our group, allowing for simultaneous multi-structure segmentation. The work presented details the methodology used for the creation of the atlases using a technique previously proposed, where atlas labels are modified to mimic the intensity and contrast profile of MRI to facilitate atlas-to-template nonlinear transformation estimation. Dice's Kappa metric was used to demonstrate high quality registration and segmentation accuracy of the atlases. The final atlases are available at https://github.com/CobraLab/atlases/tree/master/5-atlas-subcortical.


Rebound excitation and alternating slow wave patterns depend upon eicosanoid production in canine proximal colon.
1. We tested the hypothesis that eicosanoid production could be related to the long-duration slow waves that occur after brief periods of inhibitory neurotransmission (rebound excitation) and the alternating patterns of long- and short-duration slow waves observed in the canine proximal colon. 2. Electrical field stimulation of colonic muscles inhibited slow waves during the stimulus and a long-duration slow wave occurred after the stimulus. Indomethacin reduced the post-stimulus response without affecting the inhibitory response. 3. ATP or 2-methylthio-ATP produced post-stimulus rebound responses similar to the response to field stimulation. Indomethacin inhibited the rebound response caused by ATP or 2-methylthio-ATP. 4. Alternating patterns consisting of long- and short-duration slow waves occurred spontaneously in some colonic muscles. These patterns could also be induced with acetylcholine. 5. Indomethacin, acetylsalicylic acid and ibuprofen abolished the alternating pattern and shifted the bimodal distribution of slow wave durations toward an intermediate duration. 6. Patch clamp experiments on isolated colonic myocytes showed that indomethacin blocked L-type Ca2+ currents. The effects of indomethacin on rebound excitation and alternating slow waves were accomplished at concentrations that blocked cyclooxygenase activity without significantly inhibiting L-type Ca2+ currents. 7. The results demonstrate that rebound excitation and alternating slow wave patterns in the canine colon have similar dependence on endogenous eicosanoid production. Rebound excitation may result from reduced production of an inhibitory eicosanoid during inhibitory nerve stimulation, and the alternating pattern may result from oscillations in eicosanoid production as a function of changes in cytoplasmic Ca2+ during long and short slow waves.


Prevalence of adrenal carcinoma among incidentally discovered adrenal masses. A retrospective study from 1989 to 1994. Gruppo Piemontese Incidentalomi Surrenalici.
The incidental discovery of an adrenal mass poses the problem of distinguishing between the frequent benign masses and the infrequent malignant ones that require surgery. Univocal guidelines to approach this problem are unavailable. To perform a survey of the clinical management of incidentally discovered adrenal masses (ie, adrenal incidentalomas). A multicentric retrospective analysis of hospital medical records of adrenal incidentalomas diagnosed during a 5-year period; the medical records were scrutinized for demographic data and clinical details by means of a specifically tailored questionnaire. The major surgical and medical centers of Piedmont, a northern Italian region with approximately 4 million inhabitants. The recruitment pattern of these centers was unselected. The definition of adrenal incidentaloma was limited to patients with a physical examination and a clinical history unindicative of adrenal disease. Exclusion criteria also included hypertension of suspected endocrine origin and a history of neoplasms known to metastasize frequently in the adrenal glands. Two hundred twenty-four medical records were collected, and 210 were analyzed (14 excluded a posteriori). Most patients were in their 50s and 60s, and women were predominantly affected. The frequency of adrenocortical cancer was 13% among patients operated on. The tumor diameter was highly correlated with the risk of cancer; a cutoff at 5 cm had a sensitivity of 93% with a specificity of 64% in discriminating between benign and malignant cortical lesions. The occurrence of adrenocortical carcinoma among adrenal incidentalomas is not rare. The evaluation of the mass size is a simple and effective method for selecting patients at risk for cancer. The indication for surgery of masses larger than 5 cm, or of masses of any diameter that have suspicious imaging characteristics, limits unnecessary operations and costs.


Low-Intensity Cognitive Behavioural Therapy-Based Music Group (CBT-Music) for the Treatment of Symptoms of Anxiety and Depression: A Feasibility Study.
Music has the potential to be an effective and engaging therapeutic intervention in the treatment of mental illness. This research area remains underdeveloped. This paper reports the feasibility of an innovative low-intensity CBT-based music (CBT-Music) group targeted to symptoms of depression and anxiety. A total of 28 participants with symptoms of depression and anxiety who were attending community mental health services were recruited for the study and randomized into TAU (treatment as usual) plus low-intensity CBT-Music (treatment) or to TAU alone (control). The treatment group consisted of a 9-week music group that incorporated various components of CBT material into a musical context. Feasibility was the primary outcome. The secondary outcomes were a reduction in depression, anxiety (Hospital Anxiety and Depression Scale) and disability (WHO Disability Assessment Schedule 2.0) assessed at baseline and 10 weeks. Recruitment proved feasible, retention rates were high, and the participants reported a high level of acceptability. A randomized control study design was successfully implemented as there were no significant differences between treatment and control groups at baseline. Participants in the treatment group showed improvement in disability (p = 0.027). Despite a reduction in depression and anxiety scores, these differences were not statistically significant. A low-intensity CBT-based music group can be successfully administered to clients of community mental health services. There are indications of effectiveness in reducing disability, although there appears to be negligible effect on symptoms of anxiety and depression. This is the first report of a trial of a low-intensity CBT-based music group intervention.


Collaboration and the practice of nurse-midwifery.
In the United States there are growing examples of physician and certified nurse-midwife collaborations capitalizing on the strengths of both disciplines working in the best interest of the patient and her family. The philosophy and practice of certified nurse-midwives (CNMs), however, are not embraced universally by all physicians, and childbirth continues to be treated and reimbursed as a disease process. As Americans seek to establish a partnership with those providing their care, they will naturally embrace advanced practice nurses and reach a mutually beneficial health outcome.


Neuronal pp60c-src contains a six-amino acid insertion relative to its non-neuronal counterpart.
Neuronal cells express a pp60c-src variant that displays an altered electrophoretic mobility and a different V8 peptide pattern relative to pp60c-src expressed in tissues of non-neuronal origin. To determine whether the neuronal form of pp60c-src is encoded by a brain-specific messenger RNA, a mouse brain complementary DNA (cDNA) library was screened with a chicken c-src probe and a 3.8-kilobase c-src cDNA clone was isolated. This clone encodes a 60-kilodalton protein that differs from chicken or human pp60c-src primarily in having six extra amino acids (Arg-Lys-Val-Asp-Val-Arg) within the NH2-terminal 16 kilodaltons of the molecule. S1 nuclease protection analysis confirmed that brain c-src RNA contains an 18-nucleotide insertion at the position of the extra six amino acids. This insertion occurs at a position that corresponds to a splice junction in the chicken and human c-src genes. The isolated c-src cDNA clone encodes a protein that displays an identical V8 peptide pattern to that observed in pp60c-src isolated from tissues of neuronal origin.


Best Matching Protein Conformations and Docking Programs for a Virtual Screening Campaign Against SMO Receptor.
SMO receptor is one of the main components of the Hedgehog biochemical pathway. In the last decades compelling body of evidence demonstrated that this receptor is a pertinent target for the treatment of various types of solid tumors. Recently, the X-ray determination of the three-dimensional structure of SMO in complex with different antagonists opened up the way for the structure-based design of new antagonists for this receptor that could possibly overcome the limitations connected with the induction of acquired tumor resistance. Herein, taking advantage of three different docking software (namely Glide, PLANTS, and Vina) and of the available SMO structures we set up a retrospective virtual screening (VS) protocol. A database, made up by known SMO antagonists and compounds with no alleged activity against the receptor was created and screened against the different SMO structures. To evaluate the performance of the ranking in VS calculations different statistical metrics (EF, AUAC and BEDROC) were employed allowing to identify the best performing VS docking protocol. Results of these studies will serve as a platform for the application of structure-based VS against the pharmaceutically relevant SMO receptor.


[Clinical experience with Diane-35, currently the lowest dose antiandrogenic hormonal ovulation inhibitor, in mild to moderative androgenization in the female].
Low-dose hormonal contraceptives with specifically reduced estrogen are now the drug of choice for the prevention of internal risks. The antiandrogenic hormonal contraceptives have also had to be adapted to this situation. In a study involving 144 women, most of whom were suffering from moderately severe androgenization, Diane-35 (reduced to 0.035 mg ethinyl estradiol) was used as an antiandrogenically active hormonal contraceptive. From the sixth treatment cycle onward acne and seborrhea were significantly improved or already healed. In the 12th treatment cycle the treatment success rate was almost 90%. The side effects occurring with higher-dose hormonal contraceptives were reduced, cycle behavior was acceptable, and the incidence of metrorrhagia corresponded to that found with other micropills.


Lethal graft-vs-host disease induced by a class II MHC antigen only disparity is not mediated by cytotoxic T cells.
Treatment of C57BL/6J (B6) murine splenocytes with L-leucyl-L-leucine methyl ester (Leu-Leu-OMe) selectively removes NK cells, CTL precursors, and the capacity to cause lethal graft-vs-host disease (GVHD) in irradiated B6 X DBA/2 F1 mice. In contrast, alloantigen-induced L3T4(+) Th cell function has been shown to be relatively preserved after exposure to this agent. The present studies assessed the effects of Leu-Leu-OMe treatment of donor cells on induction of lethal GVHD in other murine strain combinations. When irradiated B6 X CBAF1 mice were infused with T and NK cell-depleted B6 bone marrow cells and 3 to 30 X 10(6) B6 spleen cells, uniformly lethal GVHD was observed. However, B6 X CBAF1 recipients of T and NK-depleted B6 bone marrow cells and similar numbers of Leu-Leu-OMe-treated B6 spleen cells demonstrated 90 to 100% long term survival. In contrast, Leu-Leu-OMe treatment of B6 donor cells had no beneficial effect on mortality rates in irradiated (B6 X B6-C-H-2bm12)F1 (B6 X bm12F1) recipients. When B6 spleen cells were stimulated in vivo or in vitro with either B6 X CBAF1 or B6 X bm12F1 stimulator cells, the capacity to generate alloantigen-specific CTL was abolished comparably by Leu-Leu-OMe treatment. Thus, the dramatic difference between the effects of Leu-Leu-OMe treatment of B6 spleen cells on the course of GVHD in B6 x CBAF1 and class II MHC only disparate B6 x bm12F1 recipients could not be explained by unique resistance of bm12-specific CTL precursors to Leu-Leu-OMe. These findings indicate that T cell effector mechanisms distinct from classic cell-mediated cytotoxicity are sufficient to generate lethal GVHD in class II MHC only disparate B6----B6 X bm12F1 mice.


Plasma pyridoxal 5'-phosphate and high-sensitivity C-reactive protein are independently associated with an increased risk of coronary artery disease.
Whether vitamin B6 exerts an independent or a synergic effect in combination with inflammation for the risk of coronary artery disease (CAD) is unclear. The purpose of this study was to investigate whether plasma pyridoxal 5'-phosphate (PLP) is dependent on or independent of the inflammation marker C-reactive protein (CRP) to associate with the risk of CAD. This was a hospital-based case-control. Patients were identified with cardiac catheterization as having at least 70% stenosis of one major coronary artery were assigned to the case group (n = 184). The control group (n = 516) was comprised of healthy individuals with normal blood biochemical values. All subjects' height, weight, blood pressure, plasma PLP, homocysteine, high-sensitivity CRP (hs-CRP), and lipid profiles were measured. Plasma PLP concentration was only negatively associated with hs-CRP level in the control group (beta = -0.001, P = 0.03) but not in the CAD or pooled groups. The magnitude of the risk of CAD for low plasma PLP (odds ratio [OR] 2.39) and high hs-CRP (OR 3.37) was very similar. Low plasma PLP concentration combined with low hs-CRP level (OR 2.34) and high plasma PLP concentration combined with high hs-CRP level (OR 3.61) were independently associated with risk for CAD. However, the combined presence of low PLP and higher hs-CRP levels enhanced the risk of CAD and the magnitude was substantially greater (OR 4.35). Plasma PLP and hs-CRP are independently associated with an increased risk of CAD, the combined presence of low PLP and high hs-CRP enhanced the risk of CAD, and the magnitude was almost double.


The sodium pertechnetate Tc 99m scan: an aid in the evaluation of gastrointestinal bleeding.
Twenty pediatric patients presenting primarily with unexplained gastrointestinal bleeding were evaluated with sodium pertechnetate Tc 99m imaging. Three patients had normal barium enemas and scans consistent with Meckel's diverticulum. These three patients and three additional patients with normal scans underwent surgical exploration. Meckel's diverticula containing gastric mucosa were found in all three patients with positive scans. No diverticula were found in the three patients with normal scans. Four other patients had scans that were considered abnormal but not felt to represent Meckel's diverticula. In one of these patients a radiographic gastrointestinent, a nonspecific terminal ilial ulcer without gastric mucosa was found at surgery. The two other patients had normal radiographic gastrointestinal studies and no further evaluation was carried out. The etiology of gastrointestinal bleeding in pediatric patients is frequently unexplained even after thorough evaluation including celiotomy. The sodium pertechnetate Tc 99m scan is a safe, simple, non-invasive procedure that can demonstrate Meckel's diverticula with greater certainty than the barium enema and can suggest suspicious areas that can then be evaluated by more definitive procedures.


Laboratory- and field-based performance-predictions in cross-country skiing and roller-skiing.
The purpose of the present study was to investigate how various laboratory- and field-based tests predict on-snow cross-country (XC) skiing and roller-skiing performance. Thirty-three national-level male XC skiers (19.0±2.5 years, maximal oxygen uptake [VO2max] 70.8±4.7 mL·min-1·kg-1) performed a 13.6-km roller-ski skating competition tracked by a global positioning system (GPS), which together with individual distance International Ski Federation (FIS) points was used to assess their performance level. On separate days, time in a 6.4-km uphill running time-trial (RUN-TT) and 1.3-km uphill roller-ski double-poling time-trial (DP-TT) was measured in the field and performance indices determined while running and roller-ski skating in the laboratory. The mean finishing times for the RUN-TT and the DP-TT showed moderate to large correlations with distance FIS points and performance in the roller-ski skating competition (r = 0.56-0.72; all p<0.05). RUN-TT was more strongly correlated with distance FIS points than DP-TT (r = 0.72 versus 0.56; p<0.05). Performance indices and VO2max in incremental running and roller-ski skating in the laboratory showed large to very large correlations with distance FIS points and roller-skiing performance (r = 0.50-0.90; all p<0.05). Performance indices and VO2max in running tended to be more strongly correlated with roller-skiing performance than corresponding values obtained while roller-ski skating (all p<0.10). The present findings suggest that both laboratory performance indices and field-based performance tests provide valid predictions of XC skiing and roller-skiing performance in a heterogeneous group of male XC skiers, with test values obtained in running tending to be more strongly correlated with XC skiing performance than those found for technique-specific modalities on roller skis. However, more sophisticated and mode-specific testing might be required for more homogenous groups of elite XC skiers.


Reduced dielectric screening and enhanced energy transfer in single- and few-layer MoS2.
We report highly efficient nonradiative energy transfer from cadmium selenide (CdSe) quantum dots to monolayer and few-layer molybdenum disulfide (MoS2). The quenching of the donor quantum dot photoluminescence increases as the MoS2 flake thickness decreases with the highest efficiency (>95%) observed for monolayer MoS2. This counterintuitive result arises from reduced dielectric screening in thin layer semiconductors having unusually large permittivity and a strong in-plane transition dipole moment, as found in MoS2. Excitonic energy transfer between a zero-dimensional emitter and a two-dimensional absorber is fundamentally interesting and enables a wide range of applications including broadband optical down-conversion, optical detection, photovoltaic sensitization, and color shifting in light-emitting devices.


Identification and signaling characterization of four urotensin II receptor subtypes in the western clawed frog, Xenopus tropicalis.
Urotensin II (UII) is involved, via the UII receptor (UTR), in many physiological and pathological processes, including vasoconstriction, locomotion, osmoregulation, immune response, and metabolic syndrome. In silico studies have revealed the presence of four or five distinct UTR (UTR1-UTR5) gene sequences in nonmammalian vertebrates. However, the functionality of these receptor subtypes and their associations to signaling pathways are unclear. In this study, full-length cDNAs encoding four distinct UTR subtypes (UTR1, UTR3, UTR4, and UTR5) were isolated from the western clawed frog (Xenopus tropicalis). In functional analyses, homologous Xenopus UII stimulation of cells expressing UTR1 or UTR5 induced intracellular calcoum mobilization and phosphorylation of extracellular signal-regulated kinase 1/2. Cells expressing UTR3 or UTR4 did not show this response. Furthermore, UII induced the phosphorylation of cyclic adenosine monophosphate (cAMP) response element binding protein (CREB) through the UII-UTR1/5 system. However, intracellular cAMP accumulation was not observed, suggesting that UII-induced CREB phosphorylation is caused by a signaling pathway different from that involving Gs protein. In contrast, the administration of UII to cells increased the phosphorylation of guanine nucleotide exchange factor-H1 (GEF-H1) and myosin light chain 2 (MLC2) in all UTR subtypes. These results define four distinct UTR functional subtypes and are consistent with the molecular evolution of UTR subtypes in vertebrates. Further understanding of signaling properties associated with UTR subtypes may help in clarifying the functional roles associated with UII-UTR interactions in nonmammalian vertebrates.


HIV-Related Cardiovascular Disease, Statins, and the REPRIEVE Trial.
HIV infection is associated with increased cardiovascular disease (CVD), and increased rates of myocardial infarction and stroke have been observed in HIV-infected individuals. After traditional risk factors that are more common among people living with HIV infection (such as smoking and diabetes) are accounted for, the excess risk for CVD persists. Recent studies suggest that increased immune activation and inflammation may contribute to excess risk for CVD in the context of HIV infection. Imaging studies in the HIV-infected population have found inflamed, noncalcified plaque that is vulnerable to rupture. Statin therapy may represent a potentially useful primary prevention strategy for CVD in HIV-infected individuals, as this class of drugs lowers lipid levels and may simultaneously reduce immune activation and inflammation. REPRIEVE (Randomized Trial to Prevent Vascular Events in HIV) is a large, multicenter study funded by the National Institutes of Health. REPRIEVE will test whether pitavastatin, a newer statin that does not have substantial interactions with antiretroviral drugs, can prevent vascular events over time among HIV-infected individuals who do not have known CVD. This study is now open to enrollment at sites throughout the United States and abroad and will hopefully provide definitive data on this important question.


Recruitment of Perisomatic Inhibition during Spontaneous Hippocampal Activity In Vitro.
It was recently shown that perisomatic GABAergic inhibitory postsynaptic potentials (IPSPs) originating from basket and chandelier cells can be recorded as population IPSPs from the hippocampal pyramidal layer using extracellular electrodes (eIPSPs). Taking advantage of this approach, we have investigated the recruitment of perisomatic inhibition during spontaneous hippocampal activity in vitro. Combining intracellular and extracellular recordings from pyramidal cells and interneurons, we confirm that inhibitory signals generated by basket cells can be recorded extracellularly, but our results suggest that, during spontaneous activity, eIPSPs are mostly confined to the CA3 rather than CA1 region. CA3 eIPSPs produced the powerful time-locked inhibition of multi-unit activity expected from perisomatic inhibition. Analysis of the temporal dynamics of spike discharges relative to eIPSPs suggests significant but moderate recruitment of excitatory and inhibitory neurons within the CA3 network on a 10 ms time scale, within which neurons recruit each other through recurrent collaterals and trigger powerful feedback inhibition. Such quantified parameters of neuronal interactions in the hippocampal network may serve as a basis for future characterisation of pathological conditions potentially affecting the interactions between excitation and inhibition in this circuit.


Genetic polymorphisms in mediators of inflammation and gastric precancerous lesions.
Chronic inflammation induced by Helicobacter pylori is a key process in gastric carcinogenesis. We hypothesized that genetic polymorphisms in important mediators of H. pylori-induced inflammation may influence the risk of developing various grades of precancerous lesions. We studied the associations between single nucleotide polymorphisms (SNPs) in cyclooxygenase 1 and 2 (PTGS1 and PTGS2), inducible nitric oxide synthase (NOS2A), interferon gamma (IFNG) and its receptor (IFNGR1), and risk of gastric precancerous lesions in a Venezuelan population characterized by high rates of H. pylori infection. We found no association of precancerous lesions with SNPs in PTGS1 and in IFNG. A nonsynonymous SNP of NOS2A (Ser608Leu) and an SNP located in the promoter of IFNGR1 (C-56T) were associated with higher risk of atrophic gastritis [odds ratio (OR)=1.37, 95% confidence interval (CI)=1.01-1.86, and OR=1.49, 95% CI=1.01-2.19, respectively]. Two SNPs of PTGS2 were associated with risk of dysplasia (OR=1.60, 95% CI=1.01-2.54, and OR=0.66, 95% CI=0.43-0.99). We conclude that genetic variability in the genes we studied does not play a major role in the early stages of gastric carcinogenesis.


Oxidant injury of cells. DNA strand-breaks activate polyadenosine diphosphate-ribose polymerase and lead to depletion of nicotinamide adenine dinucleotide.
To determine the biochemical basis of the oxidant-induced injury of cells, we have studied early changes after exposure of P388D1 murine macrophages to hydrogen peroxide. Total intracellular NAD+ levels in P388D1 cells decreased with H2O2 concentrations of 40 microM or higher. Doses of H2O2 between 0.1 and 2.5 mM led to an 80% depletion of NAD within 20 min. With doses of H2O2 of 250 microM or lower, the fall in NAD and, as shown previously, ATP, was reversible. Higher doses of H2O2 that cause ultimate lysis of the cells, induced an irreversible depletion of NAD and ATP. Poly-ADP-ribose polymerase, a nuclear enzyme associated with DNA damage and repair, which catalyzes conversion of NAD to nicotinamide and protein-bound poly-ADP-ribose, was activated by exposure of the cells to concentrations of 40 microM H2O2 or higher. Activation of poly-ADP-ribose polymerase was also observed in peripheral lymphocytes incubated in the presence of phorbol myristate acetate-stimulated polymorphonuclear neutrophils. Examination of the possibility that DNA alteration was involved was performed by measurement of thymidine incorporation and determination of DNA single-strand breaks (SSB) in cells exposed to H2O2. H2O2 at 40 microM or higher inhibited DNA synthesis, and induced SSB within less than 30 s. These results suggest that DNA damage induced within seconds after addition of oxidant may lead to stimulation of poly-ADP-ribose polymerase, and a consequent fall in NAD. Excessive stimulation of poly-ADP-ribose polymerase leads to a fall in NAD sufficient to interfere with ATP synthesis.


Smooth muscle contractility causes the gut to grow anisotropically.
The intestine is the most anisotropically shaped organ, but, when grown in culture, embryonic intestinal stem cells form star- or sphere-shaped organoids. Here, we present evidence that spontaneous tonic and phasic contractions of the circular smooth muscle of the embryonic gut cause short-timescale elongation of the organ by a purely mechanical, self-squeezing effect. We present an innovative culture set-up to achieve embryonic gut growth in culture and demonstrate by three different methods (embryological, pharmacological and microsurgical) that gut elongational growth is compromised when smooth muscle contractions are inhibited. We conclude that the cumulated short-term mechanical deformations induced by circular smooth muscle lead to long-term anisotropic growth of the gut, thus demonstrating a self-consistent way by which the function of this organ (peristalsis) directs its shape (morphogenesis). Our model correctly predicts that longitudinal smooth muscle differentiation later in embryogenesis slows down elongation, and that several mice models with defective gut smooth muscle contractility also exhibit gut growth defects. We lay out a comprehensive scheme of forces acting on the gut during embryogenesis and of their role in the morphogenesis of this organ. This knowledge will help design efficient in vitro organ growth protocols and handle gut growth pathologies such as short bowel syndrome.


Family reunion via error correction: an efficient analysis of duplex sequencing data.
Duplex sequencing is the most accurate approach for identification of sequence variants present at very low frequencies. Its power comes from pooling together multiple descendants of both strands of original DNA molecules, which allows distinguishing true nucleotide substitutions from PCR amplification and sequencing artifacts. This strategy comes at a cost-sequencing the same molecule multiple times increases dynamic range but significantly diminishes coverage, making whole genome duplex sequencing prohibitively expensive. Furthermore, every duplex experiment produces a substantial proportion of singleton reads that cannot be used in the analysis and are thrown away. In this paper we demonstrate that a significant fraction of these reads contains PCR or sequencing errors within duplex tags. Correction of such errors allows "reuniting" these reads with their respective families increasing the output of the method and making it more cost effective. We combine an error correction strategy with a number of algorithmic improvements in a new version of the duplex analysis software, Du Novo 2.0. It is written in Python, C, AWK, and Bash. It is open source and readily available through Galaxy, Bioconda, and Github: https://github.com/galaxyproject/dunovo.


The ligand-binding function of hepatic lipase modulates the development of atherosclerosis in transgenic mice.
To investigate the separate contributions of the lipolytic versus ligand-binding function of hepatic lipase (HL) to plasma lipoprotein metabolism and atherosclerosis, we compared mice expressing catalytically active wild-type HL (HL-WT) and inactive HL (HL-S145G) with no endogenous expression of mouse apoE or HL (E-KO x HL-KO, where KO is knockout). HL-WT and HL-S145G reduced plasma cholesterol (by 40 and 57%, respectively), non-high density lipoprotein cholesterol (by 48 and 61%, respectively), and apoB (by 36 and 44%, respectively) (p < 0.01), but only HL-WT decreased high density lipoprotein cholesterol (by 67%) and apoA-I (by 54%). Compared with E-KO x HL-KO mice, both active and inactive HL lowered the pro-atherogenic lipoproteins by enhancing the catabolism of autologous (125)I-apoB very low density/intermediate density lipoprotein (VLDL/IDL) (fractional catabolic rates of 2.87 +/- 0.04/day for E-KO x HL-KO, 3.77 +/- 0.03/day for E-KO x HL-WT, and 3.63 +/- 0.09/day for E-KO x HL-S145G mice) and (125)I-apoB-48 low density lipoprotein (LDL) (fractional catabolic rates of 5.67 +/- 0.34/day for E-KO x HL-KO, 18.88 +/- 1.72/day for E-KO x HL-WT, and 9.01 +/- 0.14/day for E-KO x HL-S145G mice). In contrast, the catabolism of apoE-free, (131)I-apoB-100 LDL was not increased by either HL-WT or HL-S145G. Infusion of the receptor-associated protein (RAP), which blocks LDL receptor-related protein function, decreased plasma clearance and hepatic uptake of (131)I-apoB-48 LDL induced by HL-S145G. Despite their similar effects on lowering pro-atherogenic apoB-containing lipoproteins, HL-WT enhanced atherosclerosis by up to 50%, whereas HL-S145G markedly reduced aortic atherosclerosis by up to 96% (p < 0.02) in both male and female E-KO x HL-KO mice. These data identify a major receptor pathway (LDL receptor-related protein) by which the ligand-binding function of HL alters remnant lipoprotein uptake in vivo and delineate the separate contributions of the lipolytic versus ligand-binding function of HL to plasma lipoprotein size and metabolism, identifying an anti-atherogenic role of the ligand-binding function of HL in vivo.


Risks of alcoholic energy drinks for youth.
Ingesting alcohol and energy drinks together is associated with a decreased awareness of the physical and mental impairment caused by the alcohol without reducing the actual impairment. This is of particular concern for youth who have a baseline of less mature judgment. Adding energy drinks to alcohol tends to increase the rate of absorption through its carbonation and dilution of the alcohol, and keep a person awake longer allowing ingestion of a greater volume of alcohol. At low blood alcohol levels, caffeine appears to decrease some of the impairment from the alcohol, but at higher blood alcohol levels, caffeine does not appear to have a modifying effect on either the physical or mental impairment induced by the alcohol. Obtaining this combination is made easier and more affordable for under aged persons by manufacturers of premixed alcoholic energy drink combination beverages. Awareness by medical and educational personnel and parents of this activity and its potential for harm is unknown.


Organ-wide telomeric status in diseased and disease-free prostatic tissues.
Telomere attrition occurs early in the development of prostatic adenocarcinoma. However, little is known about either telomere status in benign prostatic hyperplasia (BPH), or the spatial and organ-wide distribution of potential telomere aberrations throughout all areas of prostatic glands affected by cancer or BPH. Slot blot titration assay was used to determine telomere DNA content (TC), a proxy for telomere length, in macrodissected tissue consisting of 54 normal samples from 5 disease-free prostates, 128 BPH samples from 4 non-cancerous prostates, and 45 tumor, 73 BPH, and 4 prostatic intraepithelial neoplasia (PIN) samples from 5 cancerous prostates. Compared to TC in normal prostate samples (n = 54; TC mean = 0.98), tumor samples displayed telomere attrition (n = 45; TC mean = 0.67). TC in PIN samples was similar to tumors. TC in BPH samples from cancerous prostates was similar to TC in tumors and also displayed telomere shortening (n = 73; TC mean = 0.76), whereas BPH samples from non-cancerous prostates displayed longer telomeres (n = 128; TC mean = 1.06). In prostates affected by adenocarcinoma, areas of potential telomere attrition occurred in histologically normal tissues through the entire gland. However, three-dimensional zoning revealed a pattern of increasing TC as a function of distance from the primary (index) tumor. Spatial distributions of TC in prostate specimens indicate a complex "field effect" with varying contributions from both cancer and BPH. The observation that telomere length variations occur in fields of histologically normal tissues surrounding the tumor is of clinical importance, as it may have implications for the diagnosis and focal therapy of prostate cancer.


A Dispatch Screening Tool to Identify Patients at High Risk for COVID-19 in the Prehospital Setting.
Emergency medical services (EMS) dispatchers have made efforts to determine whether patients are high risk for coronavirus disease 2019 (COVID-19) so that appropriate personal protective equipment (PPE) can be donned. A screening tool is valuable as the healthcare community balances protection of medical personnel and conservation of PPE. There is little existing literature on the efficacy of prehospital COVID-19 screening tools. The objective of this study was to determine the positive and negative predictive value of an emergency infectious disease surveillance tool for detecting COVID-19 patients and the impact of positive screening on PPE usage. This study was a retrospective chart review of prehospital care reports and hospital electronic health records. We abstracted records for all 911 calls to an urban EMS from March 1-July 31, 2020 that had a documented positive screen for COVID-19 and/or had a positive COVID-19 test. The dispatch screen solicited information regarding travel, sick contacts, and high-risk symptoms. We reviewed charts to determine dispatch-screening results, the outcome of patients' COVID-19 testing, and documentation of crew fidelity to PPE guidelines. The sample size was 263. The rate of positive COVID-19 tests for all-comers in the state of Massachusetts was 2.0%. The dispatch screen had a sensitivity of 74.9% (confidence interval [CI], 69.21-80.03) and a specificity of 67.7% (CI, 66.91-68.50). The positive predictive value was 4.5% (CI, 4.17-4.80), and the negative predictive value was 99.3% (CI, 99.09-99.40). The most common symptom that triggered a positive screen was shortness of breath (51.5% of calls). The most common high-risk population identified was skilled nursing facility patients (19.5%), but most positive tests did not belong to a high-risk population (58.1%). The EMS personnel were documented as wearing full PPE for the patient in 55.7% of encounters, not wearing PPE in 8.0% of encounters, and not documented in 27.9% of encounters. This dispatch-screening questionnaire has a high negative predictive value but moderate sensitivity and therefore should be used with some caution to guide EMS crews in their PPE usage. Clinical judgment is still essential and may supersede screening status.


Cervical adenoid basal carcinoma associated with invasive squamous cell carcinoma: a report of rare co-existence and review of literature.
Cervical adenoid basal carcinoma (ABC) rarely can harbor associated malignancies like adenoid cystic carcinoma or squamous cell carcinoma (SCC), which express markedly different prognosis from a pure ABC, making an appropriate biopsy essential to provide a clear diagnosis and therapeutic plan. We report a 64-year-old asymptomatic lady with an abnormal cervical cytology, who underwent a conization to reveal an ABC with overlying microinvasive SCC. Doubtful resection margins led us to perform radical hysterectomy with lymph node dissection. Subsequent pathological examination showed a true invasive SCC co-existing with ABC, with invasion of the parametrium. Unlike the indolent course of many pure ABC patients, the prognosis of 11 previously reported co-existing invasive SCC with ABC patients appears to depend on the SCC component. Our case reiterates the importance of adequate biopsy with careful interpretation to cover the possibility of a co-existent malignancy. Besides, it presents an argument in favor of radical surgery for the primary treatment of suspicious associated malignancy, and supports adjuvant treatment according to the unfavorable extent of the co-existent invasive carcinoma.


RSV-induced bronchial epithelial cell PD-L1 expression inhibits CD8+ T cell nonspecific antiviral activity.
Respiratory syncytial virus (RSV) is a major cause of bronchiolitis in infants. It is also responsible for high morbidity and mortality in the elderly. Programmed death ligands (PD-Ls) on antigen-presenting cells interact with receptors on T cells to regulate immune responses. The programmed death receptor-ligand 1/programmed death receptor 1 (PD-L1-PD-1) pathway is inhibitory in chronic viral infections, but its role in acute viral infections is unclear. We hypothesized that bronchial epithelial cell (BEC) expression of PD-Ls would inhibit local effector CD8(+) T cell function. We report that RSV infection of primary human BECs strongly induces PD-L1 expression. In a co-culture system of BECs with purified CD8(+) T cells, we demonstrated that RSV-infected BECs increased CD8(+) T cell activation, proliferation, and antiviral function. Blocking PD-L1 on RSV-infected BECs co-cultured with CD8(+) T cells enhanced CD8(+) T cell IFN-γ, IL-2, and granzyme B production. It also decreased the virus load of the BECs. Based on our findings, we believe therapeutic strategies that target the PD-L1-PD-1 pathway might increase antiviral immune responses to RSV and other acute virus infections.


Susceptibility mapping as a means to visualize veins and quantify oxygen saturation.
To create an orientation-independent, 3D reconstruction of the veins in the brain using susceptibility mapping. High-resolution, high-pass filtered phase images usually used for susceptibility weighted imaging (SWI) were used as a source for local magnetic field behavior. These images were subsequently postprocessed using an inverse procedure to generate susceptibility maps of the veins. Regularization and interpolation of the data in k-space of the phase images were used to reduce reconstruction artifacts. To understand the effects of artifacts, and to fine-tune the methodology, simulations of blood vessels were performed with and without noise. With sufficient resolution, major veins in the brain could be visualized with this approach. The usual geometry-dependent phase dipole effects are removed by this processing, leaving basically images of the veins. Different sized vessels show a different level of contrast depending on their partial volume effects. Vessels that are 8 mm or 16 mm in size show quantitative values expected for normal oxygen saturation levels. Smaller vessels show smaller values due to errors in the methodology and due to partial volume effects. Larger vessels show a bias toward a reduced susceptibility approaching 90% of the expected value. Limitations of the method and artifacts related to different sources of errors are demonstrated. Susceptibility maps can successfully create venograms of the brain with varying levels of contrast-to-noise depending on the size of the vessel. Partial volume effects render this approach more useful as an imaging tool or a visualization tool, although certain larger vessels have measured susceptibilities close to expected values associated with normal blood oxygen saturation levels.


Presynaptic kainate receptors impart an associative property to hippocampal mossy fiber long-term potentiation.
Hippocampal mossy fiber synapses show an unusual form of long-term potentiation (LTP) that is independent of NMDA receptor activation and is expressed presynaptically. Using receptor antagonists, as well as receptor knockout mice, we found that presynaptic kainate receptors facilitate the induction of mossy fiber long-term potentiation (LTP), although they are not required for this form of LTP. Most importantly, these receptors impart an associativity to mossy fiber LTP such that activity in neighboring mossy fiber synapses, or even associational/commissural synapses, influences the threshold for inducing mossy fiber LTP. Such a mechanism greatly increases the computational power of this form of plasticity.


Imaging multispectral polarimetric sensor: single-pixel design, fabrication, and characterization.
A discrete-component approach was taken to establish the operational feasibility of a novel, imaging, midinfrared, multispectral, polarimetric sensor for remote-sensing application. The sensor is designed to exploit the spectral and polarimetric characteristics of the scene as discriminants. Pixelated multispectral filters and polarization filters were designed and fabricated on sapphire and Si substrates, respectively, and both were characterized. A single-pixel spectropolarimetric composite filter was characterized by use of a Fourier transform infrared spectrometer and a Pt-Si thermal-imaging camera. The experimental results show excellent agreement with theoretical predictions.


Inhibitory effect of [Asu1 . 7]-eel calcitonin on glucagon-induced glycogenolysis in perfused rat liver.
In an attempt to elucidate the mechanism by which calcitonin modulates glucose metabolism, the effect of elcatonin ([Asu1 . 7]-eel calcitonin), a potent synthetic eel calcitonin analogue, on hepatic glycogenolysis was investigated by use of perfused liver from fed rats. Elcatonin, as infused into the portal vein at concentrations between 10 mU/ml and 200 mU/ml did not affect glucose output into the hepatic venous effluent. At concentrations higher than 100 mU/ml, it inhibited the glycogenolysis stimulated by submaximal concentrations of glucagon which was perfused concurrently. This aspect of elcatonin effect was reproduced by synthetic salmon calcitonin. Though elcatonin showed a marked inhibition of the glycogenolytic activity induced by glucagon at or less than 5.7 X 10(-11) M, the inhibitory effect became undetectable when higher concentrations of glucagon were employed. Elcatonin did not inhibit the glycogenolysis induced by dibutyryl cyclic AMP at near (0.5 microM) or less than half-maximally effective (0.2 microM) concentrations. In addition, it did not inhibit the glycogenolytic activity half-maximally stimulated by alpha-adrenergic agonist (phenylephrine, 0.4 microM) or vasopressin (0.2 mU/ml). Elcatonin inhibited the cyclic AMP production of the tissue induced by glucagon infusion. These data indicate that elcatonin modulates hepatic glycogenolysis by preventing the glucagon effect at a step before cyclic AMP production and with an apparently competitive kinetics. In view of the concept that Ca++ is involved in the glycogenolytic effect of alpha-adrenergic agonist and vasopressin, the fact that elcatonin did not influence the action of these agents suggests that Ca++ fluxes are not involved in the elcatonin effect on liver.


Multimodal photoacoustic microscopy, optical coherence tomography, and fluorescence imaging of USH2A knockout rabbits.
Usher syndrome type 2A (USH2A) is a genetic disorder characterized by retinal degeneration and hearing loss. To better understand the pathogenesis and progression of this syndrome, animal models such as USH2A knockout (USH2AKO) rabbits have been developed. In this study, we employed multimodal imaging techniques, including photoacoustic microscopy (PAM), optical coherence tomography (OCT), fundus autofluorescence (FAF), fluorescein angiography (FA), and indocyanine green angiography (ICGA) imaging to evaluate the retinal changes in the USH2AKO rabbit model. Twelve New Zealand White rabbits including USH2AKO and wild type (WT) were used for the experiments. Multimodal imaging was implemented at different time points over a period of 12 months to visualize the progression of retinal changes in USH2AKO rabbits. The results demonstrate that ellipsoid zone (EZ) disruption and degeneration, key features of Usher syndrome, began at the age of 4 months old and persisted up to 12 months. The EZ degeneration areas were clearly observed on the FAF and OCT images. The FAF images revealed retinal pigment epithelium (RPE) degeneration, confirming the presence of the disease phenotype in the USH2AKO rabbits. In addition, PAM images provided high-resolution and high image contrast of the optic nerve and the retinal microvasculature, including retinal vessels, choroidal vessels, and capillaries in three-dimensions. The quantification of EZ fluorescent intensity using FAF and EZ thickness using OCT provided comprehensive quantitative data on the progression of degenerative changes over time. This multimodal imaging approach allowed for a comprehensive and non-invasive assessment of retinal structure, microvasculature, and degenerative changes in the USH2AKO rabbit model. The combination of PAM, OCT, and fluorescent imaging facilitated longitudinal monitoring of disease progression and provided valuable insights into the pathophysiology of USH2A syndrome. These findings contribute to the understanding of USH2A syndrome and may have implications for the development of diagnostic and therapeutic strategies for affected individuals. The multimodal imaging techniques employed in this study offer a promising platform for preclinical evaluation of potential treatments and may pave the way for future clinical applications in patients with Usher syndrome.


I-motif nanospheres: unusual self-assembly of long cytosine strands.
The synthesis and characterization of novel DNA structures based on tetraplex cytosine (C) arrangements, known as i-motifs or i-tetraplexes, is reported. Atomic force microscopy (AFM) investigation shows that long C-strands in mild acidic conditions form compact spherically shaped nanostructures. The DNA nanospheres are characterized by a typical uniform shape and narrow height distribution. Electrostatic force microscopy (EFM) measurements performed on the i-motif spheres clearly show their electrical polarizability. Further investigations by scanning tunneling microscopy (STM) at ultrahigh vacuum reveals that the structures exhibit an average voltage gap of 1.9 eV, which is narrower than the voltage gap previously measured for poly(dG)-poly(dC) molecules in similar conditions.


Safety of antiandrogen therapy for treating prostate cancer.
Antiandrogens are a treatment option in patients with prostate cancer, given either in combination with androgen deprivation or, in selected cases, as monotherapy. New-generation antiandrogens have been recently introduced in clinical practice (enzalutamide) or are under evaluation in clinical trials (ARN-509). This review elucidates the safety profile of antiandrogens, in particular focusing on the tolerability profile of each drug either when employed in combination with castration or as monotherapy, in hormone-naive or in castration-resistant patients. Non-steroidal antiandrogens are widely used in the management of hormone-sensitive disease in combination with luteinizing hormone-releasing hormone agonists or in patients failing front-line treatment with androgen-deprivative maneuvers. In selected patients, non-steroidal antiandrogen monotherapy appears to yield comparable results as castration. Novel non-steroidal antiandrogens have been investigated with promising results in castration-resistant prostate cancer. Beyond the safety profile specific to any individual compound, increased testosterone and 17β-estradiol levels are commonly observed during antiandrogen monotherapy, leading to gynecomastia and breast pain. The safety profile of old and novel antiandrogens should be taken into account by clinicians in decision making and in selecting the most suitable patients. Beyond patient selection, full clinical evaluation of patient co-morbidities that might affect the drug tolerability and clinical monitoring are anyway required.


Etiology and management of Seborrheic dermatitis.
Seborrheic dermatitis (SD) is a common dermatological disorder that varies greatly in severity between individuals and with time. The etiology of this disease is poorly understood. Early investigators focused on the role of Malassezia (previously Pityrosporum) yeasts in the development of SD. Some researchers have hypothesized that there is an immunological component to SD and that this disease is caused by an altered immune response to Malassezia yeasts. However, other researchers view this condition as the result of hyperproliferation. Both antifungal and anti-inflammatory preparations have been used to treat SD effectively and safely. The wide range of antifungal formulations available (creams, shampoos, oral drugs) provides safe, effective and flexible treatment options for SD.


Inorganic Phosphate (Pi) Signaling in Endothelial Cells: A Molecular Basis for Generation of Endothelial Microvesicles in Uraemic Cardiovascular Disease.
Hyperphosphataemia increases cardiovascular mortality in patients with kidney disease. Direct effects of high inorganic phosphate (Pi) concentrations have previously been demonstrated on endothelial cells (ECs), including generation of procoagulant endothelial microvesicles (MVs). However, no mechanism directly sensing elevated intracellular Pi has ever been described in mammalian cells. Here, we investigated the hypothesis that direct inhibition by Pi of the phosphoprotein phosphatase PP2A fulfils this sensing role in ECs, culminating in cytoskeleton disruption and MV generation. ECs were treated with control (1 mM [Pi]) vs. high (2.5 mM [Pi]), a condition that drives actin stress fibre depletion and MV generation demonstrated by confocal microscopy of F-actin and NanoSight Nanoparticle tracking, respectively. Immuno-blotting demonstrated that high Pi increased p-Src, p-PP2A-C and p-DAPK-1 and decreased p-TPM-3. Pi at 100 μM directly inhibited PP2A catalytic activity. Inhibition of PP2A enhanced inhibitory phosphorylation of DAPK-1, leading to hypophosphorylation of Tropomyosin-3 at S284 and MV generation. p-Src is known to perform inhibitory phosphorylation on DAPK-1 but also on PP2A-C. However, PP2A-C can itself dephosphorylate (and therefore inhibit) p-Src. The direct inhibition of PP2A-C by Pi is, therefore, amplified by the feedback loop between PP2A-C and p-Src, resulting in further PP2A-C inhibition. These data demonstrated that PP2A/Src acts as a potent sensor and amplifier of Pi signals which can further signal through DAPK-1/Tropomyosin-3 to generate cytoskeleton disruption and generation of potentially pathological MVs.


Histone Chaperone HIRA in Regulation of Transcription Factor RUNX1.
RUNX1 (Runt-related transcription factor 1) is indispensable for the generation of hemogenic endothelium. However, the regulation of RUNX1 during this developmental process is poorly understood. We investigated the role of the histone chaperone HIRA (histone cell cycle regulation-defective homolog A) from this perspective and report that HIRA significantly contributes toward the regulation of RUNX1 in the transition of differentiating mouse embryonic stem cells from hemogenic to hematopoietic stage. Direct interaction of HIRA and RUNX1 activates the downstream targets of RUNX1 implicated in generation of hematopoietic stem cells. At the molecular level, HIRA-mediated incorporation of histone H3.3 variant within the Runx1 +24 mouse conserved noncoding element is essential for the expression of Runx1 during endothelial to hematopoietic transition. An inactive chromatin at the intronic enhancer of Runx1 in absence of HIRA significantly repressed the transition of cells from hemogenic to hematopoietic fate. We expect that the HIRA-RUNX1 axis might open up a novel approach in understanding leukemogenesis in future.


Use of health information technology (HIT) to improve statin adherence and low-density lipoprotein cholesterol goal attainment in high-risk patients: proceedings from a workshop.
The workshop discussions focused on how low-density lipoprotein cholesterol (LDL-C) goal attainment can be enhanced with the use of health information technology (HIT) in different clinical settings. A gap is acknowledged in LDL-C goal attainment, but because of the passage of the American Recovery & Reinvestment Act and the Health Information Technology for Economic and Clinical Health Acts there is now reason for optimism that this gap can be narrowed. For HIT to be effectively used to achieve treatment goals, it must be implemented in a setting in which the health care team is fully committed to achieving these goals. Implementation of HIT alone has not resulted in reducing the gap. It is critical to build an effective management strategy into the HIT platform without increasing the overall work/time burden on staff. By enhancing communication between the health care team and the patient, more timely adjustments to treatment plans can be made with greater opportunity for LDL-C goal attainment and improved efficiency in the long run. Patients would be encouraged to take a more active role. Support tools are available. The National Lipid Association has developed a toolkit designed to improve patient compliance and could be modified for use in an HIT system. The importance of a collaborative approach between nongovernmental organizations such as the National Lipid Association, National Quality Forum, HIT partners, and other members of the health care industry offers the best opportunity for long-term success and the real possibility that such efforts could be applied to other chronic conditions, for example, diabetes and hypertension.


Faster rate of cognitive decline in essential tremor cases than controls: a prospective study.
Mild cognitive deficits have been reported in essential tremor (ET). However, these cognitive deficits have been assessed in cross-sectional rather than longitudinal analyses. To determine whether decline in cognitive test scores occurs at a faster rate in ET cases than controls. In a population-based study of older people (≥ 65 years) in central Spain (Neurological Disorders in Central Spain, NEDICES), non-demented ET cases and controls were followed prospectively. Participants with baseline or incident Parkinson's disease or dementia were excluded as were participants who developed incident ET. At baseline (1994-1995) and at follow-up (1997-1998), a 37-item version of the mini-mental state examination (37-MMSE) was administered. A total of 2319 participants (72.4 ± 5.8 years) included 135 prevalent ET cases and 2184 controls. At baseline, the mean 37-MMSE in cases was 28.8 ± 5.8 vs. 30.2 ± 4.8 in controls (P = 0.02). During the 3-year follow-up period, the 37-MMSE declined by 0.70 ± 3.2 points in cases vs. 0.11 ± 3.8 points in controls (P = 0.03). In analyses that adjusted for age, education, and other potential confounders, the case-control difference remained robust. In this population-based, prospective study of non-demented elders, baseline cognitive test scores were lower in ET cases than controls; moreover, during the 3-year follow-up period, these scores declined at a rate that was seven-times faster in ET cases. This study provides evidence that cognitive deficits in ET are not static, and they appear to be progressing at a faster rate than in elders without this disease.


Adaptation for participation!
To explore children's experiences with testing, acquiring and using assistive devices. Nine children (six boys, three girls, 9-12 years old, with different physical disability and activity experience, participated in semistructured interviews. The interviews were audio-taped, transcribed and analysed using Systematic text condensation. Assistive devices were reported to contribute to cope activities that the children otherwise would not have participated in. Several subjects listed the need for a shielded environment when adapting to new equipment. The children highlighted "independence in activities" and "having the opportunity to participate in activities with family and friends" as important for frequent use. Need for assistance and lack of localizations to perform the activities were listed as reasons for less frequent use. This study reveals that it is useful to map each child's opportunities for independency, appropriate locations for performing the activity and participation with friends, when considering obtaining assistive devices. Implications for Rehabilitation The use of assistive devices gives many children with physical disabilities the opportunity to participate in physical activity. Improving availability to assistive devices for physical activity should be a priority to help facilitate participation. Having opportunities to develop perceptions of competence may be essential for a child's long term participation in physical activity.


Not All Cases of Visual Snows are Benign: Mimics of Visual Snow Syndrome.
Visual snow syndrome (VSS) is a clinical disorder characterized by pan-field visual disturbance. It is a diagnosis of exclusion since its pathophysiology remains unknown. Excluding other mimics is of great significance since some serious pathologies can have secondary visual snow (VS) as an initial presentation. Delayed or incorrect diagnosis of these VSS mimics may lead to permanent vision loss or even death. The purpose of this review is to help physicians distinguish VSS mimics promptly to avoid bad outcomes. The authors performed a PubMed literature search of articles, case reports, and reviews describing VS symptoms in patients with underlying diseases other than VSS. The red flags of secondary VS symptoms were highlighted, such as new-onset or intermittent VS, unilateral or quadrant VS, and accompanied ocular or neurological deficits. There are four main categories of VSS mimics, ie, including neurological disorders, ocular pathologies, drug-related VS, and other systemic diseases. The physicians could largely exclude most etiologies based on history taking, ophthalmologic and neurologic examinations, and neuroimaging. Further research in VS should carefully define and unify the inclusion and exclusion criteria of this disorder and investigate these secondary VS conditions and their pathogenesis.


Trends in Incidence of ESKD in People With Type 1 and Type 2 Diabetes in Australia, 2002-2013.
The number of people with diabetes and end-stage kidney disease (ESKD) is increasing worldwide, but it is unknown whether this indicates an increasing risk for ESKD in people with diabetes. We examined temporal trends in the incidence of ESKD within the Australian population with diabetes from 2002 to 2013. Follow-up study using a national health care services registry. Registrants with type 1 or type 2 diabetes in Australia's National Diabetes Services Scheme (NDSS). Age, sex, indigenous status, diabetes type, and calendar year. Incidence of ESKD (dialysis or kidney transplantation) or death ascertained using the Australian and New Zealand Dialysis and Transplant Registry and the Australian national death index. NDSS registrants were followed up from 2002 or date of registration until onset of ESKD, death, or December 31, 2013. The incidence of ESKD in type 1 diabetes was calculated only in those younger than 55 years. Among 1,375,877 registrants between 2002 and 2013, a total of 9,977 experienced incident ESKD, representing an overall incidence of ESKD in people with diabetes of 10.0 (95% CI, 9.8-10.2) per 10,000 person-years. Among those with type 1 diabetes, the age-standardized annual incidence was stable during the study period. Among those with type 2 diabetes, the incidence increased in nonindigenous people (annual percentage change, 2.2%; 95% CI, 0.4%-4.1%) with the greatest increases in those younger than 50 and those older than 80 years. No significant change over time was observed in indigenous people, although the adjusted incident rate ratio for indigenous versus nonindigenous was 4.03 (95% CI, 3.68-4.41). Lack of covariates such as comorbid conditions, medication use, measures of quality of care, and baseline kidney function. The age-standardized annual incidence of ESKD increased in Australia from 2002 to 2013 for nonindigenous people with type 2 diabetes but was stable for people with type 1 diabetes. Efforts to prevent the development of ESKD, especially among indigenous Australians and those with early-onset type 2 diabetes, are warranted.


Asymmetric partner pronoun use and demand-withdraw interaction in couples coping with health problems.
Recent research links first-person plural pronoun use (we-talk) by individual romantic partners to adaptive relationship functioning and individual health outcomes. To examine a possible boundary condition of adaptive we-talk in couples coping with health problems, we correlated asymmetric couple-level we/I-ratios (more we-talk relative to I-talk by the spouse than the patient) with a concurrent pattern of directional demand-withdraw (D-W) interaction in which the spouse demands change while the patient withdraws. Couples in which a partner who abused alcohol (n = 65), smoked cigarettes despite having heart or lung disease (n = 24), or had congestive heart failure (n = 58) discussed a health-related disagreement during a video-recorded interaction task. Transcripts of these conversations provided measures of pronoun use for each partner, and trained observers coded D-W patterns from the recordings. As expected, partner asymmetry in we/I-ratio scores predicted directional demand-withdraw, such that spouses who used more we-talk (relative to I-talk) than patients tended to assume the demand role in concurrent D-W interaction. Asymmetric I-talk rather than we-talk accounted for this association, and asymmetric you-talk contributed independently as well. In contrast to previous studies of we-talk by individual partners, the present results identify dyad-level pronoun patterns that clearly do not mark beneficent processes: asymmetric partner we/I-ratios and you-talk reflect problematic demand-withdraw interaction.


[Evoked potentials in Chiari-malformation type I with syringomyelia--a case history].
The Chiari-syndrome Type I being a malformation of the posterior cranial fossa often leads to syringomyelia. The disease becomes apparent in adolescence with kyphoscoliosis, headache, vertigo, ataxy, hearing loss, partial paralysis and other neurological disorders. The onset is typically characterized by dissociated anesthesia, due to the frequent localization of the syrinx in the neighborhood of the posterior column of the spinal cord. It is reported a case of an 15-years-old-girl suffering from intensive headache, recurrent left-sided paresthesias and progredient scoliosis. Somatosensory evoked potentials of left ulnar and tibial nerves revealed a complete loss of cortical response. Diagnostic imaging showed an Chiari-malformation I with herniation of cerebellar tonsils and secondary syringomyelia of the cervical spinal cord. After surgical treatment with posterior fossa decompression, C1 laminectomy and partial excision of cerebellar tonsils the patient had a clear improvement in symptoms. Postsurgical the width of cervical syrinx decreases. Now somatosensory evoked potentials of the left ulnar and tibial nerves show amplitude-reduced cortical responses with a normal latency.


Helicobacter pylori strain-specific differences in genetic content, identified by microarray, influence host inflammatory responses.
Helicobacter pylori enhances the risk for ulcer disease and gastric cancer, yet only a minority of H. pylori-colonized individuals develop disease. We examined the ability of two H. pylori isolates to induce differential host responses in vivo or in vitro, and then used an H. pylori whole genome microarray to identify bacterial determinants related to pathogenesis. Gastric ulcer strain B128 induced more severe gastritis, proliferation, and apoptosis in gerbil mucosa than did duodenal ulcer strain G1.1, and gastric ulceration and atrophy occurred only in B128+ gerbils. In vitro, gerbil-passaged B128 derivatives significantly increased IL-8 secretion and apoptosis compared with G1.1 strains. DNA hybridization to the microarray identified several strain-specific differences in gene composition including a large deletion of the cag pathogenicity island in strain G1.1. Partial and complete disruption of the cag island in strain B128 attenuated induction of IL-8 in vitro and significantly decreased gastric inflammation in vivo. These results indicate that the ability of H. pylori to regulate epithelial cell responses related to inflammation depends on the presence of an intact cag pathogenicity island. Use of an H pylori whole genome microarray is an effective method to identify differences in gene content between H. pylori strains that induce distinct pathological outcomes in a rodent model of H. pylori infection.


Comparison of plasmonic sensing between polymer- and silica-coated gold nanorods.
Gold nanorods (AuNRs), rod-like gold nanoparticles, show strong plasmon bands in the near-infrared region, based on the longitudinal oscillation mode of surface plasmons. In this research, we have coated AuNRs with silica or poly (sodium 4-styrenesulfonate) (PSS) in order to evaluate the effects of surface modifications as a sensing probe material of AuNR. Multilayered assemblies of the PSS-coated AuNRs have been successfully fabricated on the glass substrate by electrostatic layer-by-layer adsorption, and their plasmonic band profiles have been analyzed as a function of refractive index. The profiles showed satisfactory linear responses with the refractive indices. The effect of the thickness of silica layer on the shift of plasmon band with refractive index of the surrounding media has been investigated, along with, the effect of silica coating on the thermal stability of AuNR. The thermal stability of the silica-coated AuNR has also been investigated. The two types of the above-described coating approaches have been compared.


Reducing Radiation Damage in Soft Matter with Femtosecond-Timed Single-Electron Packets.
Despite the development of a myriad of mitigation methods, radiation damage continues to be a major limiting factor in transmission electron microscopy. Intriguing results have been reported using pulsed-laser driven and chopped electron beams for modulated dose delivery, but the underlying relationships and effects remain unclear. Indeed, delivering precisely timed single-electron packets to the specimen has yet to be systematically explored, and no direct comparisons to conventional methods within a common parameter space have been made. Here, using a model linear saturated hydrocarbon (n-hexatriacontane, C36H74), we show that precisely timed delivery of each electron to the specimen, with a well-defined and uniform time between arrival, leads to a repeatable reduction in damage compared to conventional ultralow-dose methods for the same dose rate and the same accumulated dose. Using a femtosecond pulsed laser to confine the probability of electron emission to a 300 fs temporal window, we find damage to be sensitively dependent on the time between electron arrival (controlled with the laser repetition rate) and on the number of electrons per packet (controlled with the laser-pulse energy). Relative arrival times of 5, 20, and 100 μs were tested for electron packets comprised of, on average, 1, 5, and 20 electrons. In general, damage increased with decreasing time between electrons and, more substantially, with increasing electron number. Further, we find that improvements relative to conventional methods vanish once a threshold number of electrons per packet is reached. The results indicate that precise electron-by-electron dose delivery leads to a repeatable reduction in irreversible structural damage, and the systematic studies indicate this arises from control of the time between sequential electrons arriving within the same damage radius, all else being equal.


Effect of nutritional deprivation on diaphragm contractility and muscle fiber size.
The influence of nutritional deprivation on the contractile and fatigue properties of the diaphragm was studied in adult rats. Food access was restricted to one-third of normal daily intake until the body weight of nutritionally deprived (ND) animals was approximately 50% of controls (CTL). Isometric contractile properties were studied in an in vitro nerve muscle strip preparation. Both twitch (Pt) and tetanic (Po) tensions of diaphragms from the ND animals were markedly reduced compared with CTL; however, Pt/Po was higher for the ND group. The shape of the force-frequency curve (normalized to Po) was generally similar between the two groups, except at 5 and 10 pulses/s stimulation, where greater relative tensions were produced in diaphragms from the ND animals. Diaphragm fatigue was induced by repetitive stimulation at either 20 or 100 pulses/s. Endurance time (defined as the time required for tension to fall to 50% of initial) of diaphragms from ND animals was prolonged at both 20 and 100 pulses/s. Immediately after induction of fatigue, force-frequency curves for both ND and CTL diaphragms were shifted to the right. However, this rightward shift was attenuated in the ND group compared with CTL. Nutritional deprivation had no effect on the proportions of different fiber types within the diaphragm but did result in a significant decrease in the cross-sectional area of both fast-and slow-twitch fibers. This decrease in cross-sectional area was significantly greater for fast-twitch fibers. We conclude that these changes in diaphragm contractile and fatigue properties occur as a result of the influence of malnutrition on muscle fiber cross-sectional area.


Anticancer effect of Polyphyllin Ι in colorectal cancer cells through ROS-dependent autophagy and G2/M arrest mechanisms.
Polyphyllin Ι is a steroidal saponin isolated from the rhizoma of Paris polyphylla. In the present study, we aimed to investigate the anticancer effects of polyphyllin Ι in colorectal cancer and to elucidate the potential underlying molecular mechanisms. Using, CCK8 assay, flow cytometry, laser confocal microscope analysis and western blot, the anticancer effects of the polyphyllin Ι were analysed in colorectal cells. Our results indicate that polyphyllin Ι significantly decreased cell viability of HCT 116 cells and induced autophagy. Furthermore, we found that polyphyllin Ι induced autophagy in an ROS-dependent cell death and not related with PI3 K/AKT/mTOR pathway. We also provide evidence that excessive ROS triggered by polyphyllin Ι could induce G2/M phase arrest via regulating cycle proteins expression of cell cycle regulators, such as p21 and cyclinB1. In conclusion, polyphyllin Ι exhibit anticancer effect through ROS-dependent autophagy and induces G2/M arrest in colorectal cancer.


pH-dependency of basic ligand binding to alpha 1-acid glycoprotein (orosomucoid).
The binding interactions of a series of basic ligands with alpha 1-acid glycoprotein (AAG) were examined as a function of pH. The binding to AAG increased with increasing pH, and the binding data were satisfactorily fitted to a model that incorporates the effect of pH and discriminates the association constants of neutral (non-protonated) and protonated forms of ligands. It was shown that ligands in the neutral form have a markedly higher affinity for AAG than the protonated forms, resulting in a concomitant decrease in the pKa of bound ligands. The u.v.-visible difference spectra generated upon binding of a representative ligand to AAG also showed that there was a contribution to the binding arising from the deprotonation of the ligand. It is suggested that all tested ligands bind similarly to AAG and that hydrophobic interactions dominate high-affinity binding to AAG.


Serotonin signaling is associated with lower amyloid-β levels and plaques in transgenic mice and humans.
Aggregation of amyloid-β (Aβ) as toxic oligomers and amyloid plaques within the brain appears to be the pathogenic event that initiates Alzheimer's disease (AD) lesions. One therapeutic strategy has been to reduce Aβ levels to limit its accumulation. Activation of certain neurotransmitter receptors can regulate Aβ metabolism. We assessed the ability of serotonin signaling to alter brain Aβ levels and plaques in a mouse model of AD and in humans. In mice, brain interstitial fluid (ISF) Aβ levels were decreased by 25% following administration of several selective serotonin reuptake inhibitor (SSRI) antidepressant drugs. Similarly, direct infusion of serotonin into the hippocampus reduced ISF Aβ levels. Serotonin-dependent reductions in Aβ were reversed if mice were pretreated with inhibitors of the extracellular regulated kinase (ERK) signaling cascade. Chronic treatment with an SSRI, citalopram, caused a 50% reduction in brain plaque load in mice. To test whether serotonin signaling could impact Aβ plaques in humans, we retrospectively compared brain amyloid load in cognitively normal elderly participants who were exposed to antidepressant drugs within the past 5 y to participants who were not. Antidepressant-treated participants had significantly less amyloid load as quantified by positron emission tomography (PET) imaging with Pittsburgh Compound B (PIB). Cumulative time of antidepressant use within the 5-y period preceding the scan correlated with less plaque load. These data suggest that serotonin signaling was associated with less Aβ accumulation in cognitively normal individuals.


Doenjang, a fermented Korean soybean paste, inhibits lipopolysaccharide production of gut microbiota in mice.
Doenjang has been reported to exhibit antioxidant, fibrinolytic, antimutagenic, anticancer, and antiobesity effects. In our preliminary study, doenjang decreased fecal lipopolysaccharide (LPS) levels in mice. Therefore, we investigated the effect of doenjang on the composition of gut microbiota in mice. Treatment with doenjang significantly increased the number of bifidobacteria cultured in BL media, compared with mice not treated with doenjang. However, doenjang decreased the number of Enterobacteriaceae cultured in DHL media. Doenjang significantly suppressed the β-glucuronidase activity, but did not influence α-/β-glucosaminidase and α-/β-glucosidase activities. When gut microbiota in mice treated with or without doenjang was analyzed by pyrosequencing, doenjang induced a significant modulation of the populations of the dominant gut microbiota. At the phylum level, doenjang treatment resulted in a significant decrease of Firmicutes and an increase of Bacteroidetes, which led to a decrease in the Firmicutes to Bacteroidetes ratio in gut microbiota. At the family level, the number of Ruminococcaceae and Lachnospiraceae were significantly decreased, while the number of Odoribacter_f was increased in doenjang-treated mice. Of colonic tight junction proteins, occludin, ZO-1, and claudin-1 in mice, occludin alone was significantly increased by treatment with doenjang. Although treatment with doenjang seemed to suppress NF-κB activation, it was not significant. Doenjang significantly suppressed tumor necrosis factor-α expression, whereas it did not influence interleukin (IL)-1β and IL-6 expression. However, doenjang increased IL-10 expression. Based on these findings, doenjang may promote gut health by regulating gut microbiota and its LPS concentrations and suppressing harmful enzyme production.


Acute and chronic effects of triclosan on the behavior, physiology, and multigenerational characteristics of the water flea Moina macrocopa.
Triclosan, a chlorinated biphenyl ether is widely used in industrial products and cosmetics due to its antibiotic activity. Although relatively levels of triclosan have been detected in aquatic ecosystems, limited information is available regarding the acute and chronic impacts of triclosan on aquatic invertebrates, especially planktonic crustaceans. In this study, we analyzed the acute (24 h) and chronic (14 days exposure across three generations) effects of different concentrations of triclosan [1/10 of the no observed effect concentration (NOEC), the NOEC, and 1/10 of the LC50] calculated from the 24 h acute toxicity value, on the water flea Moina macrocopa. In the acute exposure experiment, the 1/10 LC50 value of triclosan significantly reduced survival, feeding rate, thoracic limb activity, heart activity, and acetylcholinesterase activity. In response to the 1/10 LC50 value, intracellular reactive oxygen species increased along with elevated levels of malondialdehyde and glutathione. Enzymatic activities of catalase, superoxide dismutase, glutathione peroxidase, and glutathione reductase were significantly increased by the 1/10 LC50 value, suggesting active protection of the antioxidant defense system against oxidative stress. Chronic exposure to the 1/10 NOEC and NOEC values revealed multigenerational adverse impacts of triclosan. The second generation was found to be the most sensitive to triclosan, as the NOEC value significantly reduced the survival rate, body length, and the number of neonates per brood, along with a delayed hatching period. Taken together, these results indicate that even sublethal levels of triclosan can have detrimental effects on the water flea population's maintenance through intergenerational toxicity.


Effect of furosemide on renal hilar lymph flow.
Furosemide is known to increase total renal blood flow. The purpose of this study was to determine the relationship between this hemodynamic change and renal hilar lymph flow. Renal blood flow was measured with an electromagnetic flowmeter placed on the left renal artery of anesthetized dogs. Lymph was collected from a cannulated hilar vessel. Urine volume loss was not replaced. In the first 10 min after furosemide (1 mg/kg i.v.), lymph flow was significantly increased and then declined toward control within 30 to 40 min. The decline in lymph flow lagged behind the decline in blood flow by about 10 min. In 11 experiments in which there was a significant increase in renal blood flow, renal hilar lymph flow also increased. In 5 experiments in which renal blood flow did not increase after furosemide, lymph flow also did not increase. In both groups, urine volume was significantly increased but the diuresis was less in the group in which renal blood flow and lymph did not increase. When hydrochlorothiazide (5 mg/kg, i.v.) was administered, neither renal blood flow nor hilar lymph flow was altered. The effect of equi-diuretic doses of furosemide and hydrochlorothiazide on renal tissue water content were compared. The amount of water present after furosemide was significantly greater than the amount present after hydrochlorothiazide. These data support the concept that changes in renal hilar lymph flow are more a consequence of changes in renal blood flow than in urine volume.


Simultaneous evaluation of molecular size and antigenic stability of PNEUMOVAX 23, a multivalent pneumococcal polysaccharide vaccine.
A technique using high performance size exclusion chromatography (HPSEC) with rate nephelometry (RN) detection has been developed to simultaneously measure the relative molecular size and antigenicity of the bacterial polysaccharide components in a multivalent pneumococcal vaccine, PNEUMOVAX 23. This assay was used to establish stability profiles for each of the 23 pneumococcal polysaccharide serotypes in this vaccine formulation, based on concurrent analyses of vaccine lots up to nine years of age. The exceptional inter-assay precision (<1% RSD) permitted detailed analysis of the data and a more accurate measure of the stability of this product that heretofore has not been available. While 21 of the 23 serotypes in the vaccine show essentially no change in molecular size over several years, serotypes 19A and 19F show changes in relative molecular size of approximately 2% per year. Similar decreases in relative molecular size for serotypes 19A and 19F stored in aqueous formulation have also been observed in other commercially available pneumococcal vaccine products. Additionally, stability profiles of relative antigenicity for nine of the 23 serotypes are reported based on information that is simultaneously obtained in the HPSEC/RN analysis. Of the nine serotypes examined, only serotypes 1, 9V and 18C demonstrate antigenic lability over time, in each case showing a decrease in antigenicity on the order of 5% to 10% per year. Overall, this method is a precise and efficient means of providing data on relative molecular size and relative antigenicity for each polysaccharide component of a multivalent vaccine product. Application of this method in stability studies of such vaccines provides critical information for evaluating time-dependent changes in these products.


Abscopal Effect after Stereotactic Body Radiotherapy with Nivolumab for Lung Metastasis of Head and Neck Cancer: A Case Report.
The abscopal effect (AE) is a phenomenon, in which radiotherapy exerts an antitumour effect on distant lesions outside the primary irradiated area. Although immune checkpoint inhibitors have been widely studied for their potential to enhance the AE and improve patient outcomes, findings in cases of head and neck cancers remain limited. We report the case of a 72-year-old man who experienced lung oligoprogression during nivolumab treatment for metastatic hypopharyngeal cancer. Stereotactic body radiotherapy (SBRT) was administered to one of the lung lesions, after which both irradiated and nonirradiated lesions regressed. Upon an 18-month follow-up period after SBRT, the patient showed no disease progression or toxicity, and continued receiving nivolumab therapy. The intent behind presenting this case report was to contribute to the accumulation of evidence regarding the AE in cases of head and neck cancer.


Effects of temporary vascular occluder poloxamer 407 gel on the endothelium.
Coronary occlusion techniques during OPCAB may lead to an endothelial damage to the target vessel. The adverse effects of these techniques are well-known, and researches have been trying to find out new materials to occlude the coronary artery without an endothelial damage. In the present study, we investigate to the endothelial damage in the rat aorta which is occluded by Poloxamer 407 gel. Forty-five rats were randomized in three groups: (1) segment of the aorta was occluded with Poloxamer 407 gel in P 407 group; (2) segment of the aorta was occluded with microvascular clamp in MV clamp group; and (3) no onclusion was available in the Control group. The rats were sacrificed of observation, and a 15mm segment of the aorta was obtained as a specimen. Integrity of the endothelial lining was observed with a scanning electron microscopy. Scanning electron microscopy revealed a statistically significant difference among the 3 groups (p<0,001) using the SPSS 13.0 test. No difference was found between the Control group and the P 407 group (p=0,059). The differences between MV clamp-Control group (p<0,001) and MV clamp-P 407 group were statistically significant (p<0,002). We suggest that Poloxamer 407 gel occlusion may be a safer and more effective method compared to the microvascular clamp occlusion.


Neuromuscular deficits after peripheral joint injury: a neurophysiological hypothesis.
In addition to biomechanical disturbances, peripheral joint injuries (PJIs) can also result in chronic neuromuscular alterations due in part to loss of mechanoreceptor-mediated afferent feedback. An emerging perspective is that PJI should be viewed as a neurophysiological dysfunction, not simply a local injury. Neurophysiological and neuroimaging studies have provided some evidence for central nervous system (CNS) reorganization at both the cortical and spinal levels after PJI. The novel hypothesis proposed is that CNS reorganization is the underlying mechanism for persisting neuromuscular deficits after injury, particularly muscle weakness. There is a lack of direct evidence to support this hypothesis, but future studies utilizing force-matching tasks with superimposed transcranial magnetic stimulation may be help clarify this notion.


Capsid proteins of cowpea mosaic virus transiently expressed in protoplasts form virus-like particles.
The coding regions for cowpea mosaic virus (CPMV) capsid proteins VP37 and VP23 were introduced separately into a transient plant expression vector containing an enhanced CaMV 358 promoter. Significant expression of either capsid protein was observed only in protoplasts transfected simultaneously with both constructs. Immunosorbent electron microscopy revealed the presence of virus-like particles in extracts of these protoplasts. An extract of protoplasts transfected with both constructs together with RNA-1 was able to initiate a new infection, showing that the two capsid proteins of CPMV can form functional particles containing RNA-1 and that the 60-kDa capsid precursor is not essential for this process.


Silver-Foil Psychrometer for Measuring Leaf Water Potential in situ.
The water potential of leaves in situ can be measured without temperature control with a miniature, single-junction psychrometer constructed from silver foil and attached to the leaf with a silver-impregnated, conductive coating. The temperature of the psychrometer has been found to stay within 0.025 degrees C of the temperature of a simulated leaf when the latter temperature was changing at a rate of 1 degrees C per minute. Leaf water potentials can be measured with a precision of +/- 1 bar, or better.


[Public health impact of adsorption of enteroviruses on ocean and river sediments].
Fixation of enteroviruses in sands, ocean sediments, and river mud constitutes a very real public health risk. The authors review the physicochemical and biological mechanisms of virus attachment to particles. Rates of adherence frequently reach 90 to 100%, especially in montmorillonites and sands. Studies devoted to microorganism adherence are mentioned. Attachment of enteroviruses to particles in suspension, to bacteria and other microorganisms--all becoming vectors--is described. Also reviewed is the manner in which these pathogenic substances are disseminated in the environment, especially at beaches, recreational areas and shellfish breeding areas. Greater vigilance to the dangers is advocated on the part of public health authorities, those responsible for environmental salubrity and for shellfish grounds.


Extracorporeal shock wave lithotripsy monotherapy of staghorn calculi with Dornier MFL 5000.
A retrospective study was conducted of the efficacy of extracorporeal shock wave lithotripsy (SWL) monotherapy for the management of 31 patients with staghorn calculi (mean size 5.2 cm2). Five patients were lost to follow-up, 10 were stone-free in the end, and 11 had effective disintegration with small residual fragments. The remaining five patients required open surgery because of insufficient stone fragmentation. According to our data, SWL monotherapy is not sufficient for achieving stone-free status in patients with staghorn calculi, but it relieves obstruction and decreases the stone bulk in the majority of them.