Transduction efficiency and immune response associated with the administration of AAV8 vector into dog skeletal muscle.
Recombinant adeno-associated virus (rAAV)-mediated gene transfer is an attractive approach to the treatment of Duchenne muscular dystrophy (DMD). We investigated the muscle transduction profiles and immune responses associated with the administration of rAAV2 and rAAV8 in normal and canine X-linked muscular dystrophy in Japan (CXMD(J)) dogs. rAAV2 or rAAV8 encoding the lacZ gene was injected into the skeletal muscles of normal dogs. Two weeks after the injection, we detected a larger number of beta-galactosidase-positive fibers in rAAV8-transduced canine skeletal muscle than in rAAV2-transduced muscle. Although immunohistochemical analysis using anti-CD4 and anti-CD8 antibodies revealed less T-cell response to rAAV8 than to rAAV2, beta-galactosidase expression in rAAV8-injected muscle lasted for <4 weeks with intramuscular transduction. Canine bone marrow-derived dendritic cells (DCs) were activated by both rAAV2 and rAAV8, implying that innate immunity might be involved in both cases. Intravenous administration of rAAV8-lacZ into the hind limb in normal dogs and rAAV8-microdystrophin into the hind limb in CXMD(J) dogs resulted in improved transgene expression in the skeletal muscles lasting over a period of 8 weeks, but with a declining trend. The limb perfusion transduction protocol with adequate immune modulation would further enhance the rAAV8-mediated transduction strategy and lead to therapeutic benefits in DMD gene therapy.


Childhood Obesity and the Food Environment: A Population-Based Sample of Public School Children in New York City.
This study aimed to examine the relationship between proximity to healthy and unhealthy food outlets around children's homes and their weight outcomes. A total of 3,507,542 student-year observations of height and weight data from the 2009-2013 annual FitnessGram assessment of New York City public school students were used. BMI z scores were calculated, student obesity or obesity/overweight was determined using Centers for Disease Control and Prevention growth charts, and these data were combined with the locations of four food outlet types (fast-food restaurants, wait-service restaurants, corner stores, and supermarkets) to calculate distance to the nearest outlet. Associations between weight status outcomes and distance to these food outlet types were examined using neighborhood (census tract) fixed effects. Living farther than 0.025 mile (about half of a city block) from the nearest fast-food restaurant was associated with lower obesity and obesity/overweight risk and lower BMI z scores. Results ranged from 2.5% to 4.4% decreased obesity. Beyond this distance, there were generally no impacts of the food environment and little to no impact of other food outlet types. Proximity to fast-food restaurants was inversely related to childhood obesity, but no relationships beyond that were seen. These findings can help better inform policies focused on food access, which could, in turn, reduce childhood obesity.


Playing our part in antibiotic awareness.
Nicky Mansell, one of the recent graduate representatives on BVA Council, discusses antimicrobial resistance and responsible use of antibiotics.


Modification of trypsin-solubilized cytochrome b5, apocytochrome b5, and liposome-bound cytochrome b5 by diethylpyrocarbonate.
The interactions of diethylpyrocarbonate (DEP) with the various forms of cytochrome b5 were studied to gain a better understanding of the factors that influence the extent of modification of the axial histidines of cytochrome b5. Very low concentrations of DEP were able to decrease the heme binding capacity of apocytochrome b5. Moreover, it was shown that two additional histidines, presumed to be the axial ligands (His 39 and 63), were modified in the apo but not the holo form of a given preparation of cytochrome b5. Trypsin-solubilized bovine cytochrome b5 was resistant to the effects of DEP. A 200-fold molar excess of DEP displaced only 15% of the heme in the trypsin-solubilized protein in contrast to an 84% displacement of the heme in the detergent-solubilized protein. However, detergent-solubilized cytochrome b5 which had been incorporated into phospholipid vesicles exhibited the same reactivity with DEP as did the trypsin-solubilized protein. This is attributed to the fact that the two resistant preparations of cytochrome b5 are monomeric in their respective environments while detergent-solubilized cytochrome b5 is known to exist as an octamer in aqueous solutions. Our studies suggest that dissociation of the octamer to the monomer results in a conformational change that decreases the reactivity of the axial ligands of the hydrophilic heme-containing domain of cytochrome b5. Examination of the cytochrome b5 molecule by computer graphics indicates that a tunnel leads from the surface of the molecule to axial histidine 63 and that axial histidine 39 is buried.


Superficial inferior epigastric artery (SIEA) free flap using perforator vessels as a recipient site: clinical implications in autologous breast reconstruction.
Breast reconstruction with autogenous tissue is a well-established technique, but there are some limitations related to donor-site morbidity. Among available techniques, the superficial inferior epigastric artery (SIEA) flap is the least invasive procedure because it does not require harvesting or incision of the rectus muscle or the abdominal fascia. Besides adequate flap choice, the proper selection of the recipient vessels is an important factor. Thus, the internal mammary perforator branches (IMPBs) have been an attractive option regarding recipient pedicle morbidity. The investigators reported the use of the free SIEA flap with the IMPBs as a recipient site to reconstruct radical mastectomy. Five patients with invasive ductal carcinoma underwent modified radical mastectomy and reconstruction. The IMPBs were selected as the recipient site and a free SIEA flap was used. The donor defect was closed directly without synthetic mesh. Satisfactory breast shape was achieved, and no complications were observed. For selected patients, the SIEA flap and IMPBs may constitute a new alternative for immediate breast reconstruction, because of the possibility of large tissue transfer with minimal donor and recipient area morbidity. The SIEA pedicle size and the quality of IMPB vessels should be carefully evaluated.


Screening primary care patients for hereditary hemochromatosis with transferrin saturation and serum ferritin level: systematic review for the American College of Physicians.
Therapeutic phlebotomy for hereditary hemochromatosis is relatively safe and presumably efficacious when offered before cirrhosis develops, so screening primary care patients is of substantial interest. To conduct a systematic review of the evidence on 1) the prevalence of the disease in primary care, 2) the risk for morbid or fatal complications for untreated patients, 3) the diagnostic usefulness of transferrin saturation and serum ferritin level in identifying early disease, 4) the efficacy of early treatment, and 5) whether the benefits of screening outweigh the risks. MEDLINE search from 1966 through April 2004, complemented by reference review of identified original studies and review articles published in English. PubMed Clinical Queries filters search of prognosis, diagnosis, etiology, or treatment were used depending on the question. Two authors reviewed all titles and abstracts. Two investigators independently reviewed extracted data. The prevalence of hereditary hemochromatosis was 1 in 169 patients to 1 in 556 patients (n = 3 studies). Uncontrolled, prospective studies of genetic homozygous patients did not consistently identify a link to overt hereditary hemochromatosis. A serum ferritin level less than 1000 microg/L was predictive of absence of cirrhosis. Six studies demonstrated reduced survival in patients with cirrhosis. Diagnostic studies varied with respect to case definition. No blinded, independent comparisons of screening tests with the gold standard (biopsy or results of quantitative phlebotomy) or randomized, controlled trials of phlebotomy were identified. Cost-effectiveness analysis was limited by lack of prospective data on the natural history of the disease. Varied case definition and lack of prospective cohort studies or randomized trials. The available evidence does not demonstrate that benefits outweigh the risks and costs of screening for hemochromatosis.


Combination Therapy using Co-encapsulated Resveratrol and Paclitaxel in Liposomes for Drug Resistance Reversal in Breast Cancer Cells in vivo.
Multidrug resistance (MDR) is a major impediment to cancer treatment. A promising strategy for treating MDR is the joint delivery of combined anticancer agents to tumor cells in a single nanocarrier. Here, for the first time, Resveratrol (Res) was co-encapsulated with paclitaxel (PTX) in a PEGylated liposome to construct a carrier-delivered form of combination therapy for drug-resistant tumors. The composite liposome had an average diameter of 50 nm with encapsulated efficiencies of above 50%. The studies demonstrated that the composite liposome could generate potent cytotoxicity against the drug-resistant MCF-7/Adr tumor cells in vitro and enhance the bioavailability and the tumor-retention of the drugs in vivo. Moreover, systemic therapy with the composite liposome effectively inhibited drug-resistant tumor in mice (p < 0.01), without any notable increase in the toxicity. These results suggested that the co-delivery of Res and a cytotoxic agent in a nanocarrier may potentially improve the treatment of drug-resistant tumors.


A case of professional exclusion in 1870. The formation of the first black medical society.
In the last half of the 19th century, medicine was becoming organized. In Washington, DC, in 1870, the attempt by black physicians to join the local medical society met with fierce and successful resistance. Ultimately, a separate, racially integrated medical society was formed. One hundred years ago, it became the still-vital Medico-Chirurgical Society of the District of Columbia, the local branch of the National Medical Society.


Gill microsomal (Na+,K+)-ATPase from the blue crab Callinectes danae: Interactions at cationic sites.
Euryhaline crustaceans tolerate exposure to a wide range of dilute media, using compensatory, ion regulatory mechanisms. However, data on molecular interactions occurring at cationic sites on the crustacean gill (Na+,K+)-ATPase, a key enzyme in this hyperosmoregulatory process, are unavailable. We report that Na+ binding at the activating site leads to cooperative, heterotropic interactions that are insensitive to K+. The binding of K+ ions to their high affinity sites displaces Na+ ions from their sites. The increase in Na+ ion concentrations increases heterotropic interactions with the K+ ions, with no changes in K0.5 for K+ ion activation at the extracellular sites. Differently from mammalian (Na+,K+)-ATPases, that from C. danae exhibits additional NH4+ ion binding sites that synergistically activate the enzyme at saturating concentrations of Na+ and K+ ions. NH4+ binding is cooperative, and heterotropic NH4+ ion interactions are insensitive to Na+ ions, but Na+ ions displace NH4+ ions from their sites. NH4+ ions also displace Na+ ions from their sites. Mg2+ ions modulate enzyme stimulation by NH4+ ions, displacing NH4+ ion from its sites. These interactions may modulate NH4+ ion excretion and Na+ ion uptake by the gill epithelium in euryhaline crustaceans that confront hyposmotic media.


The challenges of physicians' participation in hospital accreditation programs: a qualitative study in Iran.
Due to the increasing pressure on hospitals to enhance the quality of services, the participation of physicians in accreditation programs has become more important than ever. The present study was conducted to describe challenges of physicians' participation in hospital accreditation programs in Iran using a qualitative approach. We conducted interviews with 11 managers, 9 physicians and 8 experts in the field of hospital accreditation. Interviewees were selected through purposive snowball sampling. In-depth unstructured and semi-structured interviews were conducted for data collection. The data obtained were analyzed in ATLAS.ti using the conceptual framework method. The results of this study extracted 3 main themes including: cultural, organizational and behavioral factors. Also, this study found 12 sub-themes and 57 items. Sub-themes in the cultural domain were motivation, patient demand, mutual trust and evaluation system. The organizational domain consisted of seven sub-themes, including high workload, understanding the role of quality management unit, unrealistic accreditation, nature of accreditation, empowerment of physicians in the field of quality, effective communication, resource constraint. Sub-themes in the behavioral dimension were ambiguity in the role and uncertainty about how to participate in accreditation program. Physicians' participation in accreditation programs can be increased through culture building and proper training about accreditation activities in the medical community.


Sensory Reweighting for Upright Stance in Soccer Players: A Comparison of High and Low Exposure to Soccer Heading.
The purpose of this study was to compare sensory reweighting for upright stance between soccer players who report higher soccer heading exposure to those who report lower soccer heading exposure. Thirty participants completed a self-reported questionnaire to estimate the number of soccer headers experienced over the previous year and were divided into "low exposure" and "high exposure" groups based on their responses. Sensory reweighting for upright stance was assessed by simultaneously perturbing visual, vestibular, and proprioceptive systems. The visual stimulus was a sinusoidal translation of the visual scene at 0.2 Hz, the vestibular stimulus was ±1mA binaural monopolar galvanic vestibular stimulation (GVS) at 0.36 Hz, and the proprioceptive stimulus was Achilles tendon vibration at 0.28 Hz. The visual stimulus was presented at two amplitudes (0.2 m, 0.8 m). Center of mass (COM) gain/phase to each modality, total power, 95% area and velocity were compared between low exposure (N = 15, six males, 21.5 ± 1.9 years, 27.7 ± 31.6 headers) and high exposure groups (N = 15, 10 males, 22.1 ± 3.5years, 734.9 ± 877.7 headers). Without vibration, COM 95% area (F = 5.861, p = 0.022*, partial η2 = 0.173), velocity (F = 14.198, p = 0.001, partial η2 = 0.336), and total power (F = 13.491, p = 0.001, partial η2 = 0.325) for the "high exposure" group were higher than for the "low exposure" group, and postural sway lagged the vestibular stimulus in the "high exposure" group rather than leading it as in the "low exposure" group (F = 4.765, p = 0.038, partial η2 = 0.145). There were no differences in sensory reweighting and no differences in COM gain/phase between groups. These findings lend empirical evidence to a detrimental effect of soccer heading exposure on balance control during upright stance.


The relation between serum inflammatory marker levels and serous retinal detachment in macular edema secondary to retinal vein occlusion.
To assess blood-derived inflammatory markers in macular edema (ME) secondary to retinal vein occlusion (RVO) with and without serous retinal detachment (SRD). Treatment-naive patients with ME secondary to RVO were divided into two groups according to the existence of SRD in optical coherence tomography (OCT) images; group 1 consisted of 60 patients with SRD, and group 2 consisted of 60 patients without SRD. Age and gender-matched 60 patients formed group 3 as healthy controls. Neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and systemic inflammation index (SII) were calculated from blood samples to assess the differences in the levels of blood-derived inflammatory markers and the presence of SRD. The PLR, NLR, and SII values were higher in groups 1 and 2 than in group 3 (p<0.05, each comparison). The NLR and SII values were also significantly elevated in group 1 compared to group 2 (p = 0.000 and p = 0.000, respectively). The optimal cutoff value to estimate SRD in patients with ME secondary to RVO for NLR was 2.08 with 66.7% sensitivity and 65% specificity; for SII was 530.93 with 68.3% sensitivity and specificity. SII is a reliable and cost-effective tool for predicting SRD, an inflammatory OCT biomarker in ME secondary to RVO.


Paired analysis of thromboxane and prostacyclin metabolites in urine from healthy mothers and their children.
Eicosanoids have been implicated in the adaptation of the fetal to the neonatal circulation, but biochemical support for an activation of their synthesis in relation to birth has not been presented. We addressed this by assessing in pairs the excretion of two metabolites of thromboxane A2, 11-dehydro-TxB2 (dTx) and 2,3-dinor-TxB2 (Tx-M), and one metabolite of prostacyclin, 2,3-dinor-6-keto-PGF1 a (PGI-M), in the first voided urine from 13 healthy term neonates and in the immediate pre-delivery urine from their respective mothers. The excretion of dTx was higher (p less than 0.01) in the neonates than in their mothers (7430 and 1330 pg/mg creatinine, respectively), and so was the excretion of Tx-M (3730 and 900 pg/mg creatinine, respectively, p less than 0.001). Also the excretion of PGI-M was higher (p less than 0.05) in the neonates than in their mothers (2550 vs. 1510 pg/mg creatinine). Amniotic fluid contained detectable levels of both Tx-M and PGI-M. These data indicate that activation of platelets takes place in the neonate after separation of the fetal and maternal vascular circuits. The possible physiological implication of such activation requires further studies.


Osteoporosis.
This article will review the pathogenesis of osteoporosis and the potential for prevention of the disorder, paying particular attention to estrogens. In addition, it will attempt to provide some rationale for identifying those who may be at risk from the disorder at a time when effective preventive therapy can be instituted, while also reviewing the results of treatment programs for the established disorder.


The Genetics of Breast Cancer: What the Surgical Oncologist Needs to Know.
This article summarizes the impact of germline predisposition to breast cancer on the surgical management of breast cancer and breast cancer risk. Surgical implications of germline predisposition to breast cancer are now more nuanced due to the application of increasingly more complicated next-generation sequencing-based tests. The rapid pace of change will continue to challenge paradigms for genetic cancer risk assessment, which can influence the medical and surgical management of breast cancer risk as well as strategies for screening and for risk reduction.


How to be early flowering: an evolutionary perspective.
In wild and cultivated annual plant species, flowering time is an important life-history trait that coordinates the life cycle with local environmental conditions. Extensive studies on the genetic basis of flowering time in the model species Arabidopsis thaliana have revealed a complex genetic network that can detect environmental and internal signals. Based on this knowledge and on known pleiotropic effects associated with flowering time genes, we suggest that a natural shift towards an early-flowering life cycle might involve only particular functional regions in a limited number of genes. Our predictions are supported by genetic theories of adaptation and by recent data about genes associated with natural variation. We analyse the extent to which these predictions can also apply to crop species.


Intrathecal thiotepa: reappraisal of an established therapy.
Intrathecal thiotepa is recommended as a treatment of leptomeningeal metastases (LM) in children, although published data to support this approach are limited. The authors sought to determine the efficacy of intrathecal thiotepa for pediatric LM. The authors reviewed all children treated with intrathecal thiotepa for LM at two tertiary children's hospitals, assessing outcome by cerebrospinal fluid cytology, neuroimaging, neurologic examination, and overall survival rate. Fifteen children with LM evidenced by malignant cells in the cerebrospinal fluid (mean age 7.3 years; five medulloblastoma, one anaplastic astrocytoma, one glioblastoma, one retinoblastoma, one neuroblastoma, two rhabdomyosarcoma, one non-Hodgkin lymphoma, two acute lymphoblastic leukemia, and one acute myelogenous leukemia) were treated with intrathecal thiotepa at 5 to 11.5 mg/m2 per dose for two to seven doses. Five children received concomitant craniospinal irradiation; 12 received simultaneous systemic or other intrathecal chemotherapy, or both. Four children experienced clearance of malignant cells from the spinal fluid, but this response was sustained in only two. All four children with cytologic response received concurrent radiotherapy, chemotherapy, or both. No patients showed partial or complete response on neuroimaging. Only one child had improvement on the neurologic examination; six were unchanged and eight had worsening neurologic signs. Median survival was 15.1 weeks, with a 1-year overall survival rate of 26.7% (standard error 11.4%). The unfavorable outcomes observed suggest that intrathecal thiotepa adds little to combination therapy for pediatric LM.


Dual tracer single breath studies of gas transport in the lung.
We studied the ratio of the expired He and SF6 concentrations (He/SF6) after 1 litre inspirations of a gas mixture containing 5% of He and SF6. Five subjects aged 49 to 60 yrs. performed the maneuvers with both inspiration and expiration at 0.2--0.41/s or 1.5--2.01/s. In all subjects separation of the tracer gases was observed, the He/SF6 falling early to a minimum of 0.80 +/- 0.01 (mean +/- 1 SE), and increasing gradually during expiration to a maximum of 1.08 +/- 0.01. The slope of the SF6 alveolar plateau was 1.45 +/- 0.09 times that for He. Computer simulations of simultaneous convection and diffusion in an axisymmetrical series lung model predicted a pattern of He/SF6 early in expiration which corresponded qualitatively to that observed experimentally. However, the model did not predict a rising He/SF6 ratio late in expiration. This was simulated only by incorporation of parallel inhomogeneity with sequential emptying into the model analysis. Consideration of Taylor type dispersion and airway asymmetry did not influence the simulations significantly. The results suggest that differing slopes of the alveolar plateau of two tracer gases may be due to diffusion dependent concentration differences among lung units ventilated in parallel rather than due to stratification alone.


Comparison of liquid-liquid extraction with headspace methods for the characterization of volatile fractions of commercial hydrolats from typically Mediterranean species.
Chemical composition of volatile fractions of nine commercial hydrolats and corresponding essential oils obtained using an industrial process were studied. The hydrolat volatile fractions were reported for the first time. A comparative study of those obtained, on the one hand, by liquid-liquid extraction (LLE) and, on the other hand, using five solid-phase microextraction (SPME) fibers and also purge-and-trap-automatic thermal desorption (P&T-ATD) was conducted with analysis performed by GC and GC/MS. The use of various techniques has resulted in a change of chromatographic profile of the hydrolat volatile fractions. Quantitative differences were established between chemical compositions of headspace and those obtained by a conventional method (LLE). Statistical analyses were carried out to summarize the results.


Antibodies to the E2 protein of GB virus C/hepatitis G virus: low prevalence in Asian countries.
Epidemiological investigations of GB virus C (GBV-C)/hepatitis G virus (HGV), an infectious agent discovered in 1995/1996, are facilitated by a recently developed immunoassay for the detection of antibodies to the viral envelope 2 protein (anti-E2). We used this assay to establish GBV-C/HGV prevalence in seven European, African, and Asian countries. A total of 1579 serum samples from healthy adults lacking prior exposure to known parenteral risk factors was screened. Anti-E2 positivity ranged from 13.6% (Italy) to 7.7% (Mauritius) in the European and African countries investigated. Anti-E2 prevalence was exceedingly low in the Philippines and Sri Lanka. This observation might be attributable to socio-economical and demographic factors.


Prognostic value and predictive biomarkers of phenotypes of tumour-associated macrophages in colorectal cancer.
The roles of different subtypes of tumour-associated macrophages (TAMs) in predicting the prognosis of colorectal cancer (CRC) remain controversial. In this study, different subtypes of TAMs were investigated as prognostic and predictive biomarkers for CRC. Expressions of CD68, CD86 and CD163 were investigated by immunohistochemistry (IHC) and immunofluorescence (IF), and the correlation between the expression of CD86 and CD163 was calculated in colorectal cancer tissues from 64 CRC patients. The results showed that high expressions of CD86+ and CD68+ CD86+ TAMs as well as low expression of CD163+ and CD68+ CD163+ TAMs were significantly associated with favourable overall survival (OS). The level of CD86 protein expression showed a negative correlation with CD163 protein expression. In addition, CD86 protein expression remarkably negatively correlated with tumour differentiation and tumour node metastasis (TNM) stage, while CD163 protein expression significantly positively correlated with tumour differentiation and tumour size. As an independent risk factor, high expression of CD86 TAMs had prominently favourable prognostic efficacy, while high expression of CD68+ CD163+ TAMs had significantly poor prognostic efficacy. These results indicate that CD86+ and CD68+ CD163+ TAMs as prognostic and predictive biomarkers for CRC.


Protective effect of the multitarget compound DPH-4 on human SSAO/VAP-1-expressing hCMEC/D3 cells under oxygen-glucose deprivation conditions: an in vitro experimental model of cerebral ischaemia.
Stroke and Alzheimer's disease (AD) are related pathologies in which the cerebrovascular system is involved. Plasma levels of semicarbazide-sensitive amine oxidase/vascular adhesion protein 1 (SSAO/VAP-1, also known as Primary Amine Oxidase -PrAO) are increased in both stroke and AD patients and contribute to the vascular damage. During inflammation, its enzymatic activity mediates leukocyte recruitment to the injured tissue, inducing damage in the blood-brain barrier (BBB) and neuronal tissue. We hypothesized that by altering cerebrovascular function, SSAO/VAP-1 might play a role in the stroke-AD transition. Therefore, we evaluated the protective effect of the novel multitarget-directed ligand DPH-4, initially designed for AD therapy, on the BBB. A human microvascular brain endothelial cell line expressing human SSAO/VAP-1 was generated, as the expression of SSAO/VAP-1 is lost in cultured cells. To simulate ischaemic damage, these cells were subjected to oxygen and glucose deprivation (OGD) and re-oxygenation conditions. The protective role of DPH-4 was then evaluated in the presence of methylamine, an SSAO substrate, and/or β-amyloid (Aβ). Under our conditions, DPH-4 protected brain endothelial cells from OGD and re-oxygenation-induced damage, and also decreased SSAO-dependent leukocyte adhesion. DPH-4 was also effective at preventing the damage induced by OGD and re-oxygenation in the presence of Aβ as a model of AD pathology. From these results, we concluded that the multitarget compound DPH-4 might be of therapeutic benefit to delay the onset and/or progression of the neurological pathologies associated with stroke and AD, which appear to be linked.


Lipidomics as an emerging tool to predict endometrial receptivity.
From the first histologic dating methods to the new "-omics" technologies, there has been a lot of effort put into understanding and characterizing receptive endometrium. The development of new diagnostic approaches to using biologic fluids has opened up a new field of investigation in noninvasive endometrial diagnosis techniques. Moreover, improvements in the field of mass spectrometry and nuclear magnetic resonance have made the precise detection of lipids possible; these organic molecules are involved in important functions such as modulating energy reserves, forming structural features, and promoting regulatory functions. Developments in endometrial receptivity diagnosis using lipidomics are discussed in this review paper. In summary, the results currently available indicate that prostaglandins E(2) and F(2α) are particularly abundant during the window of implantation and that they might serve to nurse the blastocyst at the time of embryo implantation; they may also serve as important biomarkers to define the receptive phase of the endometrium. The importance of understanding the mechanisms that influence the production of these individual prostaglandins in the endometrium is clinically relevant because it may shed light on the sequence of events that leads to successful embryo implantation.


A correlational and factor analysis of anticipatory and consummatory measures of sexual behavior in the male rat.
This study investigated the relationship among measures of anticipatory and consummatory sexual behavior displayed by male rats in the bilevel chambers designed by Mendelson and Gorzalka (1987). Normative data from a standard test of sexual behavior were gathered from 80 intact, sexually experienced male Long-Evans rats and subjected to multiple correlational and factor analyses. The correlational analysis confirmed that several consummatory measures of copulation were related significantly, whereas the anticipatory measure, level changing, was statistically independent of consummatory measures. Factor analysis using orthogonal rotations revealed five factors that accounted for 95% of the intersubject variance for all measures: Copulatory Rate, Initiation, Hit Rate, Mount Count, and Anticipation. These results indicate that at least five conceptual mechanisms are required in any theoretical description of male sexual behavior in the bilevel chamber. In particular, the extraction of separate anticipation and initiation factors indicates that these aspects of male sexual behavior are distinct. The use of bilevel chambers thus may facilitate the identification of potential neurochemical or endocrine mechanisms associated with different aspects of male sexual motivation. In addition, several statistical techniques are discussed with the aim of reducing the elevated experiment-wise error that can occur when related measures of sexual behavior are analyzed independently.


Using EEM-PARAFAC to identify and trace the pollution sources of surface water with receptor models in Taihu Lake Basin, China.
The identification and apportionment of the multiple pollution sources are essential and crucial for improving the effectiveness of surface water resources management. In this study, the surface water samples were collected from Taihu Lake Basin, and the optimal water quality parameters for the receptor models were selected firstly with multivariate statistical analyses. In order to identify the potential pollution sources in surface water, dissolved organic matter (DOM) was analyzed with the excitation-emission matrix coupled with parallel factor analysis (EEM-PARAFAC). Through the Pearson correlation analysis of water quality parameters and DOM components, the pollution sources were further verified, i.e., agricultural activities, domestic sewage, phytoplankton growth/terrestrial input and industrial sources. In addition, principal component analysis (PCA) combined with the absolute principal component score-multiple linear regression (APCS-MLR) and positive matrix factorization (PMF) models were employed to quantify pollution sources. Compared with PCA-APCS-MLR model, PMF model resulted in higher performance on evaluation statistics and lower proportion of unexplained variability, thus showed more realistic and robust representation. The results of PMF showed that agricultural activities (42.08%) and domestic sewage (21.16%) were identified as the dominant pollution sources of surface water in the study area. This study highlights the effectiveness of EEM-PARAFAC in identifying the pollution sources, and the applicability of PMF in apportioning the contributions of each potential pollution source in surface water.


Degenerative spondylolisthesis: a prospective cross-sectional cohort study on the role of weakened anterior abdominal musculature on causation.
Degenerative spondylolisthesis (DS) is a degenerative condition of the spine which, unlike others, is more common in a female population. Previous studies have highlighted possible causative factors such as facet tropism and pregnancy as reasons for this. This study sets out to assess the possible link between abdominal musculature and DS. A prospective cross-sectional cohort study in a single surgeon practice assessed all patients aged over 50 years attending for degenerative lumbar spinal complaints. Patient demographics, as well as the number of pregnancies, children, abdominal surgical procedures, were recorded. We found 205 patients that met our inclusion criteria (98 Males/107 Females). Women with multiple pregnancies (p = 0.036) and abdominal surgeries (p = 0.021) were more likely to develop DS. Males with ventral hernias were more likely to have developed DS (p = 0.004). This study highlights the important role that the abdominal musculature plays in stabilization of the spine and highlights its potential role as a factor in the development of DS. These slides can be retrieved under Electronic Supplementary Material.


[Proton-pump inhibitors treatment. Does your patient really need it?]
Proton-pump inhibitors (PPI) are frequently prescribed for wide gastrointestinal disorders. The indications are well established, although a high rate of misuse has been reported. Observation cross-sectional study conducted a tertiary hospital. Adult patients who attended the emergency department were eligible. The appropriate indication was evaluated. Also, the prescription period, dosage and the prescribing clinician were reviewed. 300 patients were included. The indication was adequate in 142 patients (47.3%). The main indication was the primary prophylaxis for NSAIDs/ASA-induced enteropathy (n=95 patients, 31.7%). Polypharmacy was the main misuse indication (n=82 patients, 27.3%). The median prescription duration was 31 months (IQR 9-72), ranging from one month to 360 months. The duration was lower in those with correct indication (42.3 vs 59.6 months, P=.02). The primary care physician was the main responsible for prescription (n=165 patients, 55%), followed by gastroenterologist (n=38 patients, 12.7%) without significant differences in appropriateness by speciality. Studies like this raise awareness about the PPI overuse and misuse. Deprescribing should be considered as essential to reduce iatrogenic risk and redundant health expenditure.


Determination of synthetic opioids in oral fluid samples using fabric phase sorptive extraction and gas chromatography-mass spectrometry.
New psychoactive substances (NPS) continue to emerge in the drug market every year, becoming a global threat to public health and safety. These compounds are mostly synthetic cannabinoids and designer cathinones. However, synthetic opioids have appeared on the recreational drug markets in recent years, particularly fentanyl and its derivatives ("fentanyls"). Fentanyl and its analogs are related to harmful intoxications and an increase in opioid-related mortality in many countries, such as in the United States and Europe in the last years. Taking the drug related global crisis into consideration, this work developed and validated an effective and sensitive method based on fabric phase sorptive extraction (FPSE) followed by gas chromatography-mass spectrometry (GC-MS) for the simultaneous determination of 11 fentanyl analogs in oral fluid samples. The extraction was carried out using a sol-gel Carbowax 20 M sorbent immobilized on 100% cellulose fabric substrate and using ethyl acetate as the desorption solvent. The limits of detection (LODs) and quantification (LOQs) ranged from 1 to 15 ng mL-1 and 5 to 50 ng mL-1, respectively. Intra-day and inter-day precision were found within 8.2% and 8.6%, respectively, while accuracy ranged from -5.5 to 9.1%, in accordance with the established criteria. The absolute recovery values were in the range of 94.5%-109.1%. The validated method demonstrated its great potential to detect and quantify fentanyl analogs in possible forensic work and off-site analysis in road traffic cases.


The lower the better? Reviewing the evidence for more aggressive cholesterol reduction and goal attainment.
There is considerable evidence that more aggressive lowering of low-density lipoprotein (LDL) cholesterol is associated with increased benefits in reducing atherosclerotic disease burden, supporting the notion of 'the lower, the better.' However, achievement of currently recommended goals has proven difficult with lipid-lowering agents at the commonly used doses. Current options for achieving greater LDL cholesterol reductions include use of high doses of the most effective of the available statins and use of high or moderate statin doses in combination with agents that work in a complementary manner (e.g. bile acid sequestrants or niacin). Near-term options may include statins with increased LDL cholesterol-lowering effectiveness and better-tolerated secondary agents that can be combined with statin therapy. Rosuvastatin (Crestor, AstraZeneca) is a new statin that may prove to be of considerable utility in achieving greater LDL cholesterol reductions than are currently possible with existing statins. Recent phase III clinical trials have shown that this agent produces significantly greater LDL cholesterol reductions than atorvastatin, simvastatin, or pravastatin in patients with primary hypercholesterolemia and significantly greater reductions than the maximal dose of atorvastatin in patients with familial hypercholesterolemia.


Energetics of abiogenic chemical systems.
After recalling the energy consumption necessary to produce the main categories of biochemicals from the equilibrium state of an hydrogenated atmosphere, the primary processes by which energy can be absorbed in a mixture of methane and ammonia in the presence of aqueous solutions are defined. From the very first excitations, unsaturated products are formed. In fact, this formation of atmospheric precursors is the primordial state of a photochemically induced redox dismutation. The evolution of solutions obtained from the dissolution of these atmospheric precursors in aqueous media is described from experimental data and analysed on energetic grounds. The relaxation of energy accumulated in such solutions involves non enzymic archetypes of the main categories of metabolic processes; in particular some unsaturated atmospheric precursors must be looked upon as primordial representatives of biochemical dehydrating agents. Absorption of light energy in the solutions obtained from the evolution of precursors happens near the visible range and should govern their further evolution. In fact, biochemicals which were previously detected as products of model experiments are not present in these solutions. They were probably obtained during analytical procedures from products of the evolution of atmospheric precursors which are unstable against decreases of pH. Cyclic autocatalytic effects must be involved in the further evolution of the models of the first aqueous solutions. Their possible role in the appearance of optical dissymmetry is emphasized on theoretical grounds.


Gene regulation of intracellular adhesion molecule-1 (ICAM-1): A molecule with multiple functions.
Intracellular adhesion molecule 1 (ICAM-1) is one of the most extensively studied inducible cell adhesion molecules which is responsible for several immune functions like T cell activation, extravasation, inflammation, etc. The molecule is constitutively expressed over the cell surface and is regulated up / down in response to inflammatory mediators like cellular stress, proinflammatory cytokines, viral infection. These stimuli modulate the expression of ICAM-1 primarily through regulating the ICAM-1 gene transcription. On account of the presence of various binding sites for NF-κB, AP-1, SP-1, and many other transcription factors, the architecture of the ICAM-1 promoter become complex. Transcription factors in union with other transcription factors, coactivators, and suppressors promote their assembly in a stereospecific manner on ICAM-1 promoter which mediates ICAM-1 regulation in response to different stimuli. Along with transcriptional regulation, epigenetic modifications also play a pivotal role in controlling ICAM-1 expression on different cell types. In this review, we summarize the regulation of ICAM-1 expression both at the transcriptional as well as post-transcriptional level with an emphasis on transcription factors and signaling pathways involved.


The milk ejection reflex in the pig.
1. The milk ejection reflex in response to suckling was studied in conscious sows by continuous recording of intramammary pressure, radioimmunoassay of plasma concentrations of neurohypophysial hormones, and observation of the behaviour of the sows and piglets.2. A regular pattern of nursing, suckling and milk ejection was observed. The mean duration of the suckling period was 6.3 min. Over 144 suckling periods, 113 milk ejections were recorded. Each milk ejection was characterized by a sudden rise in intramammary pressure reaching 20-49 mmHg, and lasting 8-41 sec. Milk ejections occurred only once per suckling period, at a mean interval of 44.3 min.3. Each milk ejection occurred with a mean latency of 2.4 min from the onset of a period of initial massage of the udders by the piglets, and was coincident with a period of quiet suckling when the piglets were consuming milk. The onset of nursing was signalled by the sows grunting in a rhythmic manner. In most cases, the frequency of grunts, at first low, increased suddenly 23 sec before milk ejection.4. During eighteen suckling periods leading to milk ejection, neurohypophysial hormone assays performed on serial blood samples showed an increase in plasma concentration of oxytocin up to 30 sec before milk ejection. The concentration of lysine-vasopressin did not rise above basal levels.5. In 21.4% of the suckling periods, no rise in intramammary pressure was observed. In these ;incomplete sucklings', the sow usually failed to grunt rapidly, and the piglets obtained no milk. For three of these periods, hormone assay showed no increase in oxytocin or vasopressin concentrations in blood.6. Oxytocin given intravenously produced variations in intramammary pressure which depended on the dose and the rate of injection. Rapid injections of 25-50 m-u. oxytocin, caused milk ejections similar to those induced by suckling. When oxytocin was administered at different rates, the faster the injection, the shorter the latency and the higher the amplitude of the response. Plasma concentrations of oxytocin after injection of 25 m-u. were similar to those observed during reflex milk ejection.7. Trains of electrical pulses were applied to the posterior pituitary of four anaesthetized sows. At frequencies of stimulation above 10 Hz, a rise in intramammary pressure and an increase in plasma oxytocin and vasopressin concentrations were observed. At frequencies of stimulation of 30-50 Hz, the response of the mammary gland and the time course of the variations in oxytocin plasma concentrations were similar to those observed during natural reflex milk ejection.8. It is concluded that reflex milk ejections during suckling in the pig are caused by the intermittent and spurt-like release of about 25 m-u. oxytocin, without concomitant vasopressin release. It is postulated that the release of oxytocin is probably precipitated by a brief and massive activation of oxytocin-secreting neurones in the hypothalamus. Central mechanisms controlling the intermittent release of oxytocin are discussed.


Localization of Rab proteins to peroxisomes: a proteomics and immunofluorescence study.
A proteomics screen was initiated to identify Rab proteins regulating transport to and away from peroxisomes. Mass spectrometry-based protein correlation profiling of rat liver organelles and immunofluorescence analysis of the peroxisome candidate Rab proteins revealed Rab6, Rab10, Rab14 and Rab18 to associate with the peroxisomal membrane. While Rab14 localized to peroxisomes predominantly in its dominant-active form, other Rab proteins associated with peroxisomes in both their GTP- and GDP-bound state. In summary, our data suggest that Rab6, Rab10, Rab14 and Rab18 associate with the peroxisomal compartment and similar as previously shown for Rab8, Rab18 in its GDP-bound state favors peroxisome proliferation.


Nicotinic receptor modulation of the default mode network.
Previous neuroimaging studies of cognition involving nicotinic acetylcholine receptor (nAChR) agonist administration have repeatedly found enhanced task-induced deactivation of regions of the default mode network (DMN), a group of brain systems that is more active at rest and mediates task-independent thought processes. This effect may be related to pro-cognitive nAChR agonist effects OBJECTIVES: The present study sought to test whether nAChR modulation of the DMN is bi-directional, i.e., whether a nAChR antagonist would reduce task-induced deactivation. Eighteen healthy non-smokers underwent functional magnetic resonance imaging while performing a letter N-back task. Scans were performed after nicotine administration (7 mg/24 h, transdermally), after administration of the nAChR antagonist mecamylamine (7.5 mg, p.o.), and after double placebo, in counterbalanced sequence. Blood-oxygen-level-dependent (BOLD) signal was analyzed within ventromedial prefrontal cortex (vmPFC) and posterior cingulate cortex (PCC) regions of interest-central hubs of the DMN in which consistent nAChR agonist-induced changes had previously been identified. Nicotine enhanced hit rate in both the 0-back and 2-back condition, while mecamylamine slowed reaction time in the 2-back condition. Mecamylamine reduced task-induced deactivation of vmPFC and PCC. Nicotine had no significant effects on the BOLD signal. The finding that nAChR tone reduction by mecamylamine weakened task-induced DMN deactivation indicates that a constant tone of nAChR activation helps regulate DMN activity in healthy individuals. This suggests that low nAChR tone may play a causal role in DMN dysregulation seen in conditions such as mild cognitive impairment or Alzheimer's disease.


Partial blockade of neurotensin-induced hypotension in rats by nephrectomy captopril and saralasin. Possible mechanisms.
We have assessed the influence of acute bilateral nephrectomy, of captopril and saralasin, on the hypotensive activity of neurotensin (NT) and of various hypotensive drugs in pentobarbital-anesthetized rats. The results show that the hypotensive activity of NT and of compound 48/80 (C48/80), in contrast to that of histamine, of 5-hydroxytryptamine and of hexamethonium, is markedly reduced, especially for NT, in nephrectomized as compared to sham operated rats. The pretreatment of rats with captopril (10 mg kg-1, i.v.) or with saralasin (20 micrograms kg-1 min-1, i.v.) was found to inhibit significantly the hypotensive activity of NT and of C48/80. Adrenalectomy restored partially the hypotensive activity of NT in nephrectomized rats. The potent vasopressin antagonist [d(CH2)5 Tyr(Me)AVP] did not alter the refractoriness of nephrectomized rats to the hypotensive activity of NT. Neither nephrectomy nor saralasin were found to interfere with the ability of NT or of C48/80 to evoke an increase of plasma histamine level or of the hematocrit. The results were interpreted as an indication that NT produces part of its hypotensive effect in anesthetized rats by reducing the activity of the renin angiotensin system. The results also suggest that part of the refractoriness of nephrectomized rats to the hypotensive activity of NT could be due to the release of catecholamines from adrenal glands by NT. Endogenous vasopressin does not appear to contribute to the refractoriness of nephrectomized rats to the hypotensive action of NT.


Detection of root mat associated Agrobacterium strains from plant material and other sample types by post-enrichment TaqMan PCR.
The development of a fluorogenic, 5' nuclease, TaqMan PCR assay for the detection of Ri-plasmids from root mat inducing Agrobacterium biovar 1 strains. A TaqMan probe and primer set were designed within the T-DNA sequence of a known root mat inducing Agrobacterium strain. One hundred and ten Agrobacterium and closely related bacteria were tested using this novel PCR and compared with results from a conventional PCR which detects Ti and Ri-plasmids. The Agrobacterium selective media, Medium 1A was modified into broth form for use as an enrichment of the pathogen from samples prior to the TaqMan PCR. The root mat pathogen was detected successfully from a range of sample types using the enriched fluorogenic PCR assay, negating the need for complex DNA extraction procedures and post-PCR processing techniques such as gel electrophoresis. The technique is therefore a rapid and cost-effective detection method. This is the first known report of a fluorogenic, 5' nuclease, TaqMan assay designed to detect an Agrobacterium plant pathogen. The method can be used as a model system for the detection of other Agrobacterium pathogens.


Digitally-Enabled Remote Care for Cancer Patients: Here to Stay.
Digital Technology has become a pervasive, even ubiquitous part of our daily lives, affecting almost every aspect of our lives. Although the uptake of digital technology in health care has lagged behind other sectors, today, digital health is already becoming a cornerstone of developed health systems all over the world. Hence, the question is not whether we should adopt digital technology in health care, but how to do it most effectively. Digitally enabled remote care, or telemedicine has been available for many years but large-scale adoption has been slow. COVID-19 has caused a quantum leap in this area and particularly in the area of chronic disease and cancer care. The objective of this article is to briefly review the literature on the use of digitally enabled remote health care, in general and in cancer care specifically, with a focus on nursing practice, and to define the questions that need to be asked to guide effective implementation. Review of the literature and the experience of the authors. There is increasing uptake of digitally enabled remote care. A growing body of evidence suggests that care delivered via telemedicine can be both safe and effective, in some cases with better outcomes than conventional face-to-face care. However, tele-oncology has not yet become standard practice. Digital health solutions need to be integrated into the patient pathway and in health care team practices for optimal supportive care in oncology in line with appropriate guidelines. Training education and formative evaluation are required to guide effective implementation. Formulating the right questions to ask is a critical starting point. There is very little debate today about the centrality of the role of the oncology nurse in coordinating care, guiding the patient, and providing ongoing support. Mobile technology provides an opportunity for monitoring and support through a minimally burdensome, maximally accessible approach. Moreover, smartphones and applications allow for repeated evaluation of adherence and symptoms in real time, ideally enhancing care for patients. However, even with the growing acceptance of "nursing telepractice", there are challenges and barriers to overcome to mainstream digital health into oncology nursing practice. Telemedicine services go much further than simply digitizing traditionally analogue health care processes and services, they fundamentally reorganize processes, procedures, and services. Thus, in addition to training and education, nursing tele-oncology demands a service transformation.


Field application of a biofilm reactor based BOD prototype in Taihu Lake, China.
A tubular biofilm reactor (BFR) based online biochemical oxygen demand prototype was applied in Taihu Lake, China. Municipal tap water was used instead of conventional phosphate buffer as blank solution to avoid phosphate pollution. The background organic compounds in municipal tap water were taken into account and they were validated to result in negative deviation to accuracy. The microbial endogenous respiration was experimentally validated to be sensitive to salt ionic strength, and municipal tap water as blank was thought to generate positive deviation to accuracy. The system was continuously operated over 2 months without man intervention, and the automated monitoring data agreed well with that of the conventional BOD5 methods. The BFR resisted the frequent measurements with samples of high turbidity, and the BOD monitoring data indicated the index of biodegradable organic compounds of Taihu Lake was accorded with the second class described in the environmental quality standard of surface water. Analyzed together with permanganate index on site, Taihu Lake was revealed to be of good capacity of self cleaning. Importantly, field application study of new BOD method made it more objective in evaluating its applicability, and could provide practical information and useful improvements in the process of commercializing.


Muscle function, physical performance and body composition changes in men with prostate cancer undergoing androgen deprivation therapy.
Prostate cancer (PCa) is the most common visceral malignancy in men with androgen deprivation therapy (ADT) the preferred therapy to suppress testosterone production and hence tumor growth. Despite its effectiveness in lowering testosterone, ADT is associated with side effects including loss of muscle mass, diminished muscle strength, decrements in physical performance, earlier fatigue and declining quality of life. This review reports a survey of the literature with a focus on changes in muscle strength, physical function and body composition, due to short-term and long-term ADT. Studies in these areas are sparse, especially well-controlled, prospective randomized trials. Cross-sectional and longitudinal data (up to 2 years) for men with PCa treated with ADT as well as patients with PCa not receiving ADT and age-matched healthy men are presented when available. Based on limited longitudinal data, the adverse effects of ADT on muscle function, physical performance and body composition occur shortly after the onset of ADT and tend to persist and worsen over time. Exercise training is a safe and effective intervention for mitigating these changes and initial guidelines for exercise program design for men with PCa have been published by the American College of Sports Medicine. Disparities in study duration, types of studies and other patient-specific variables such as time since diagnosis, cancer stage and comorbidities may all affect an understanding of the influence of ADT on health, physical performance and mortality.


Neurotrauma.
Traumatic brain injury remains a major cause of morbidity and mortality throughout the world, affecting young and old alike. Pathologic data have been developed through observations of human autopsies and developing animal models to investigate mechanisms, although animal models do not represent the polypathology of human brain injury and there are likely to be significant differences in the anatomic basis of injury and cellular responses between species. Traumatic brain injury can be defined pathologically as either focal or diffuse, and can be considered to be either primary, directly related to the force associated with the neurotrauma, or secondary, developing as a downstream consequence of the neurotrauma. While neuropathology has traditionally focused on severe head injury, there is increasing recognition of the long-term consequences of traumatic brain injury, particularly repetitive mild traumatic brain injury, and a possible long-term association with chronic traumatic encephalopathy.


A PTPN11 gene mutation (Y63C) causing Noonan syndrome is not associated with short stature in general population.
Human growth is a highly complicated process, but it is obviously influenced by a genetic factor. Recent genome-wide linkage analyses suggested some genetic regions underlying stature variations. However, any specific genes underlying stature variations have not been identified. Noonan syndrome (NS) is an autosomal dominant disorder clinically characterized by short stature, minor facial anomalies, and congenital heart defects. Recently, PTPN11 (protein-tyrosine phosphatase, nonreceptor-type 11) has been identified as a major responsible gene for NS, causing about half of the affected individuals. We herein report a large family demonstrating NS caused by one of the common PTPN11 mutations, c.188 A > G (Y63C). In this family, the patients were apparently healthy, but heterozygosity of the c.188 A > G (Y63C) mutation was related to growth impairment. This finding suggested that PTPN11 genetic variants contribute to adult height in the general population. However, c.188 A > G (Y63C) was not identified in 96 short individuals from the general population of 2,281 healthy adults. Thus, it is unlikely that PTPN11 is one of the genes underlying stature variations in the general population.


Changing health behaviour outcomes in asthmatic patients: a pilot intervention study.
Starting from a prior study, in which cognitive and coping variables proved to be related to well-being, the use of medical resources and the absence from work in asthmatic patients, the authors constructed a cognitive-educational (a combination of health education and rational emotive behaviour modification) intervention programme aiming at altering coping behaviour in asthmatic patients in order to influence emotional distress and use of medical resources. The effects of the programme were assessed by means of a pre-test-post-test control group design. The programme was offered to ten patients and their partners. Both before and after the intervention cognitive attitudes (optimism, locus of control, and shame or stigma), coping behaviour in attack situations (minimizing the seriousness of the attack, rational action and reacting emotionally), coping in daily life (maintaining a restrictive life-style, focussing on asthma and hiding asthma), emotional distress (anxiety, anger, and depression), and the use of medication were measured in the experimental and control group. It was found that patients who received the programme became less preoccupied with their asthma and reported significantly less emotional distress (anxiety and anger) in daily life. In addition, they used less maintenance medication (corticosteroids). The authors wish to stress the importance of using medical variables such as the number of attacks as covariates in this type of research.


Computational simulation and target prediction studies of solubility optimization of decitabine through supercritical solvent.
Computational analysis of drug solubility was carried out using machine learning approach. The solubility of Decitabine as model drug in supercritical CO2 was studied as function of pressure and temperature to assess the feasibility of that for production of nanomedicine to enhance the solubility. The data was collected for solubility optimization of Decitabine at the temperature 308-338 K, and pressure 120-400 bar used as the inputs to the machine learning models. A dataset of 32 data points and two inputs (P and T) have been applied to optimize the solubility. The only output is Y = solubility, which is Decitabine mole fraction solubility in the solvent. The developed models are three models including Kernel Ridge Regression (KRR), Decision tree Regression (DTR), and Gaussian process (GPR), which are used for the first time as a novel model. These models are optimized using their hyper-parameters tuning and then assessed using standard metrics, which shows R2-score, KRR, DTR, and GPR equal to 0.806, 0.891, and 0.998. Also, the MAE metric shows 1.08E-04, 7.40E-05, and 9.73E-06 error rates in the same order. The other metric is MAPE, in which the KRR error rate is 4.64E-01, DTR shows an error rate equal to 1.63E-01, and GPR as the best mode illustrates 5.06E-02. Finally, analysis using the best model (GPR) reveals that increasing both inputs results in an increase in the solubility of Decitabine. The optimal values are (P = 400, T = 3.38E + 02, Y = 1.07E-03).


Sexual dysfunction in women partners of men with erectile dysfunction.
We evaluated 113 female partners of men with erectile dysfunction (ED) attending a sexual dysfunction clinic in order to define sexual dysfunction among these women. In all, 51 (45%) women denied having any sexual dysfunction. The other 62 (55%) responded to questions classifying their complaint(s) according to the international classification of female sexual dysfunction (FSD) in the following topics (40/62, 65%, reported having more than one problem): decreased sexual desire (n=35, 56%), sexual aversion (none), arousal (n=23, 37%) and orgasmic disorders (n=39, 63%), dyspareunia (n=19, 31%), vaginismus (n=3, 5%), and noncoital sexual pain (none). Many female partners of men with ED report having some form of sexual disorder, mostly orgasmic problems and decreased sexual desire. Therefore, for optimal outcome of ED treatment, evaluation and treatment of male and FSD should be addressed as one unit within the context of the couple, and be incorporated into one clinic of sexual medicine.


Evaluation of persons with suspected lumbosacral and cervical radiculopathy: Electrodiagnostic assessment and implications for treatment and outcomes (Part II).
The electrodiagnostic (EDX) examination with needle electromyography (EMG) is the most important means of testing for radiculopathy. This test has modest sensitivity but high specificity and complements imaging of the spine. In this second of a two-part review, the implications of electrodiagnostic findings for diagnosis and clinical management of persons with radiculopathy are reviewed. An EMG confirmed lumbosacral radiculopathy is associated with better clinical outcomes for persons undergoing aggressive conservative management. A positive EMG test portends a better clinical response to epidural corticosteroid injections. If a person undergoes spine surgery, a positive pre-operative EMG for radiculopathy is also associated with better outcomes.


The cellular apoptosis susceptibility CAS/CSE1L gene protects ovarian cancer cells from death by suppressing RASSF1C.
The cellular apoptosis susceptibility gene CAS/CSE1L is overexpressed in cancer, although it was originally identified as a gene that renders cells vulnerable to apoptotic stimuli. CAS/CSE1L has roles in the nucleocytoplasmic recycling of importin-α and in the regulation of gene expression, cell migration, and secretion. We identified CAS/CSE1L as a survival factor for ovarian cancer cells in vitro and in vivo. In 3/3 ovarian cancer cell lines, CAS/CSE1L was down-modulated by the unorthodox proapoptotic signaling of the MET receptor. CAS/CSE1L knockdown with RNA interference committed the ovarian cancer cells to death, but not immortalized normal cells and breast and colon cancer cells. In 70 and 95% of these latter cells, respectively, CAS/CSE1L was localized in the cytoplasm, while it accumulated in the nucleus in >90% of ovarian cancer cells. Nuclear localization depended on AKT, which was constitutively active in ovarian cancer cells. In the nucleus, CAS/CSE1L regulated the expression of the proapoptotic Ras-association domain family 1 gene products RASSF1C and RASSF1A, which mediated death signals evoked by depletion of CAS/CSE1L. Our data show that CAS/CSE1L protects ovarian cancer cells from death through transcriptional suppression of a proapoptotic gene and suggest that the localization of CAS/CSE1L dictates its function.


Die recovery technique.
A separating disk is used to make proximal cuts and cuts on the underside surface of the cast. The dies can be recovered without damage to the margins.


An added value for the hemoglobin content in reticulocytes (CHr) and the mean corpuscular volume (MCV) in the diagnosis of iron deficiency in postpartum anemic women.
To evaluate the use of reticulocyte hemoglobin content (CHr) and mean corpuscular volume (MCV) to identify truly iron-deficient women with postpartum anemia (PPA), in order to reduce unnecessary iron supplementation. Three hundred women with more than 500 mL of blood loss or clinical signs of anemia were divided in a control (Hb ≥ 10.5 g/dL, N = 150) and postpartum anemia group (PPA, Hb < 10.5 g/dL; N = 150). PPA women were given ferrous fumarate for a period of 4 weeks. Efficacy of the treatment was evaluated by comparing Hb, CHr, and MCV at baseline (T(0)) and after 4 weeks (T(4)). Using standard iron deficiency cut off values for MCV (80 fL) and CHr (28 pg) at T(0), we divided the PPA group of both parameters into two subgroups, one suggestive for iron deficiency and one suggestive for noniron deficiency. Irrespective of the parameter or the subdivision, delta Hb concentrations (T(4) -T(0)) showed a similar increase in all PPA subgroups investigated. Both parameters in the PPA subgroups below their respective cut off value showed a significant improvement toward normalization, while the MCV and CHr in the PPA subgroups above their respective cut off value did not show any significant increase. Our data suggest that the etiology of the anemia in postpartum anemic women is not always iron deficiency. Using a combination of Hb, MCV and CHr, we increased the stringency to identify truly iron-deficient postpartum anemic women, thereby reducing unnecessary iron supplementation in those women with sufficient iron stores.


An assessment of a property analyzer model in predicting adaptation patterns of simple and complex figures.
Selective adaptation patterns of simple contours and geometrical illusions under monocular stimulation were studied with five subjects. A strict property analyzer model predicted that adaptation patterns would mirror figural contours of both types of forms. The results supported this hypothesis: the geometrical illusions generated adaptation patterns reflecting their physical stimulus properties rather than the illusory percept resulting from contextual juxtaposition. The results are discussed with respect to a model of feature extraction which assumes that property analyzers possess a sensitivity bandwidth.


Some observations on the blink reflex in posttraumatic coma.
Blink reflex studies were carried out on 51 comatose patients with signs of brain stem impairment due to head injury. Twenty-five patients were studied in acute coma on day 1 or 2 after trauma. Twenty-six patients were studied in prolonged coma during days 3-12 after brain injury. Brain stem involvement was divided clinically and by CT scan into secondary lesions due to supratentorial mass displacement and primary lesions due to direct violence to the brain stem. Further, the comatose states were separated by behavioural and EEG signs of sleep into "sleep' and more "alert' states. The blink reflexes were recorded after mechanical and electrical stimulation. Mechanical stimulation appeared to be more effective in evoking late responses than the electrical stimulus. The elicitability of the late responses was also dependent on the time of stimulation. During "sleep', usually accompanied by a spindle-EEG, the late responses were totally absent after both mechanical and electrical stimulation in acute coma. In more "alert' states, usually accompanied by high voltage delta waves in the EEG, the late responses, especially direct R2, could be frequently elicited by mechanical stimulation. These differences decreased during prolonged coma. All patients with signs of secondary brain stem involvement who had at least one late component in the acute stage of coma recovered well. So did all patients, with one exception, with primary brain stem injuries. Early recovery of the blink reflexes in cases of primary brain stem injury was a further favourable sign. Consistent absence of R2 (and R1) in prolonged coma indicated a bad outcome. The presence of all components in prolonged coma was of less prognostic significance than in the acute stage.


Emotional dissonance and exhaustion among healthcare professionals: the role of the perceived quality of care.
The aim of this exploratory study was to analyze the association between emotional dissonance and emotional exhaustion among healthcare professionals, and the mediating role of the perceived quality of care in this relationship. Self-report questionnaires were administered to 724 healthcare workers. The measurement model was tested and the mediation hypothesis was verified through hierarchical multiple regression analyses. Bootstrapping was used to construct confidence intervals to evaluate the mediation effects. Emotional dissonance was significantly related to emotional exhaustion, and the perceived quality of care was negatively related to emotional exhaustion. The perceived quality of care had a partial mediating effect on the relationship between emotional dissonance and emotional exhaustion. Emotional dissonance had a significant effect on emotional exhaustion, and the perceived quality of care was a mediating factor in this relationship among healthcare professionals. The management of the perceived quality of care may be helpful in the prevention of burnout and distress in the workplace. Int J Occup Med Environ Health. 2019;32(6):841-51.


Combined treatment of a solid tumour by local hyperthermia and actionomycin D.
(BALB/c X C57BL/6)F1 mice bearing an SV-40 fibrosarcoma in the limb were injected with 0.045, 0.09 and 0.18 microgram/g body wt actinomycin D into the tumour. Similar animals were also treated with local hyperthermia (39.7 degrees, 42.3 degrees and 43.6 degrees C intratumour temperature for 30 min). The marked increase in median survival time following the combination of drug and local hyperthermia indicates that the combined treatment has a synergistic effect in the control of solid tumours. The median survival time of animals receiving the two treatments in immediate succession was higher than in animals with 30 min between treatments. This has important implications for the therapy of human cancer.


Continent urinary diversion with a urachal remnant.
The Mitrofanoff procedure, first described in 1980, has been widely adopted for pediatric continent urinary diversion to increase patient independence and continence, decrease morbidity and infections, and preserve renal function. Although this principle employs the appendix primarily, numerous other tissue conduits have been described. We report a unique use of a urachal remnant as a continent conduit resulting in less morbidity by maintaining the integrity of the native urinary bladder, while maintaining patient continence and allowing easy and successful catheterization.


Serotonergic terminals in the neural sheath of the blowfly nervous system: electron microscopical immunocytochemistry and 5,7-dihydroxytryptamine labelling.
With serotonin immunocytochemistry we have demonstrated an extensive plexus of immunoreactive varicose fibres in the neural sheath of the nervous system of the blowfly, Calliphora. These fibres are located in the neural sheath of the following regions: the maxillary-labial and labrofrontal nerves of the cerebral ganglia, the cervical connective, the dorsal surface of the thoracicoabdominal ganglia, two pairs of prothoracic nerves and the median abdominal nerve. We identified the serotonin-immunoreactive neural processes in the electron microscope by means of the peroxidase-antiperoxidase method. Immunoreactivity was seen in large granular vesicles (ca 100 nm), on membranes of smaller (ca 60 nm) and larger (ca 100 nm) agranular vesicles, along the inner surface of the axolemma, along neurotubules and outer membranes of mitochondria. By conventional electron microscopy we found numerous varicose neural processes in the neural sheath of some of the above regions. These varicosities are of at least two types. One type corresponds to the serotonin-immunoreactive profiles. A second type contains large granular vesicles (ca 200 nm) of variable electron density. 5,7-Dihydroxytryptamine injected into the head capsule labelled varicosities in the neural sheath, corresponding to the ones identified with serotonin immunocytochemistry. The electron-dense labelling was seen in flattened vesicles within these varicosities. We propose that the serotonin-immunoreactive fibers in the neural sheath constitute neurohemal regions for the release of serotonin into the circulation. The finding of another morphological type of varicose fibers in the neural sheath suggests the presence of further putative neurohormones in these regions.


Evaluation of flexural strength of Zirconia using three different connector designs: An in vitro study.
The aim of this study is to evaluate the flexural strength of zirconia using three different connector designs under vertical and oblique loads. Invitro - analytical study. For simulating zirconia fixed partial prosthesis, a specimen with three octagonal cylinders connected with each other was designed. Each face of the octagon was 3.75 mm ± 0.1 mm, and the total width was 9 mm ± 0.1 mm with a standard connector area of 10 mm2 at cross-section. Three different connector designs, i.e., round, oval, and triangular were milled. Universal testing machine was used to test flexural strength with vertical and oblique forces. Intergroup comparison of flexural strength was made using Descriptive statistics (1) one-way ANOVA, Bonferroni's post hoc test (2) Kruskal-Wallis test. The confidence interval was set at 95%, P < 0.05 was considered statistically significant for both the tests. The highest flexural strength was observed in the triangle connector with vertical forces and lowest with oblique forces. Triangle connector design proved to be better than round and oval connectors on the application of vertical loads. Round connector design proved to be better than triangle and oval connector on application of oblique loads.


Synthesis and cytotoxic activities of 1-benzylidine substituted beta-carboline derivatives.
A series of new beta-carboline derivatives, bearing a benzylidine substituent at position-1, has been prepared and evaluated in vitro against a panel of human cell lines. The N(2)-benzylated beta-carbolinium bromates represented the most interesting cytotoxic activities. In particular, compounds 19 were found to be the most potent compounds with IC(50) values lower than 5 microM against 10 strains human tumor cell lines. These results confirmed that the N(2)-benzyl substituent on the beta-carboline ring played an important role in the modulation of the cytotoxic activities and suggested that further development of such compounds may be interest.


Dopamine D1 receptors in the gills of Chinese crab Eriocheir sinensis.
Our investigations indicate the existence of binding sites for [3H]SCH23390 on crude membrane preparations in the anterior and posterior gills of the Chinese crab, Eriocheir sinensis acclimated to freshwater (FW) or seawater (SW). Maximum specific binding in the posterior gills is always higher than in the anterior gills, independent of saline acclimation. Kd values are similar in the two regions, suggesting the same affinity of both types of gills for the ligand, either from FW or from SW crabs.


Engagement with three or more healthy lifestyle behaviours is associated with improved quality of life over 7.5 years in people with multiple sclerosis.
People with multiple sclerosis (pwMS) report reduced quality of life (QoL). Engagement with healthy lifestyle behaviours, including consuming a healthy diet, regular physical activity, and adequate vitamin D exposure, is associated with higher QoL. We aim to assess whether individual lifestyle behaviours are more beneficial to QoL than others, and whether there are additive benefits to QoL by engaging in multiple healthy behaviours concurrently. Data from pwMS who completed an online survey at baseline, and at 2.5-, 5- and 7.5-year follow-up, were analysed. Behaviours assessed were consumption of a no-meat/dairy-plus-omega-3 supplementation diet, meditation practice, physical activity, non-smoking, and vitamin D exposure. Mental QoL (mQoL) and physical QoL (pQoL) were assessed by the Multiple Sclerosis Quality of Life (MSQOL-54) questionaire. Linear regression analyses were performed to assess associations of individual behaviours at baseline and follow-up time points with QoL, as well as between number of behaviours and QoL. At baseline, healthy diet and regular physical activity were associated with higher mQoL (5.3/100 and 4.0/100) and higher pQoL (7.8/100 and 6.7/100). Prospectively, diet was positively associated with mQoL, and physical activity with both mQoL and pQoL. At baseline, engagement with ≥3 behaviours was positively associated with mQoL and pQoL, with additive positive associations for each additional behaviour. Prospectively, engagement with ≥3 behaviours was positively associated with mQoL and pQoL, with strongest associations observed with engagement with five behaviours. Consumption of a healthy diet, and regular physical activity, are both potential interventions to improve QoL. Engagement with multiple lifestyle behaviours may provide additional benefits and should be encouraged and supported for multiple sclerosis management.


Determination of metabolite and nucleotide concentrations in proliferating lymphocytes by 1H-NMR of acid extracts.
Nuclear magnetic resonance (NMR) studies of extracts have proven to be a powerful window onto the intracellular machinery of cells and tissues. The major advantages of in vitro 1H-NMR, namely chemical preservation, simultaneous detection, identification, and quantitation of compounds, and sensitivity to a large variety of classes of compounds, are employed in this study to characterize the metabolic course of mitogen-stimulated proliferation of human peripheral lymphocytes. A reliable method to quantitate amino acids, metabolic intermediates, soluble membrane lipid precursors, and purine, pyridine and pyrimidine nucleotides is presented, using samples as small as 30 mg wet weight. A total of 53 substances were detected in lymphocytes and other blood cells. During the course of lymphocyte culture, changes in intracellular concentrations of lactate, taurine, inositol and nucleotides, including NAD, IMP and high-energy phosphates, were especially marked. 1H-NMR compares favorably to 31P-NMR and to HPLC, and is especially attractive in light of expectations for future in vivo application.


The new kisspeptin derivative - kissorphin (KSO) - attenuates acute hyperlocomotion and sensitization induced by ethanol and morphine in mice.
Kissorphin (KSO) is a new peptide derived from kisspeptin-10. This peptide possesses neuropeptide FF (NPFF)-like biological activity in vitro; NPFF, in many cases, inhibits opioid and ethanol effects in rodents. Therefore, the current study explored the influence of KSO on acute ethanol- and morphine-induced hyperactivity, and on the development and expression of locomotor sensitization induced by these drugs. In the present study, sensitization to locomotor effects was induced by repeated exposure to ethanol (2.4 g/kg, intraperitoneally [i.p.], 1 × 4 days) or morphine (10 mg/kg, subcutaneously [s.c.], 1 × 7 days). We found that KSO (1-10 nmol/300 μL, intravenously [i.v.]) did not have an impact on locomotor activity of naïve mice. However, it reduced both acute ethanol- (10 nmol/300 μL) and morphine-induced hyperactivity (3 and 10 nmol/300 μL). Pretreatment of animals with KSO (10 nmol/300 μL), before every ethanol or morphine injection during development of sensitization or before the ethanol or morphine challenge, attenuated the development, as well as the expression of locomotor sensitization to both substances. Moreover, prior administration of the NPFF receptor antagonist RF9 (10 nmol/300 μL, i.v.) inhibited the ability of KSO (10 nmol/300 μL) to reduce the expression of ethanol and morphine sensitization. KSO given alone, at all used doses, did not influence the motor coordination measured via the rotarod test. The results from this study show that KSO effectively attenuated acute and repeated effects of ethanol and morphine. Thus, KSO possesses NPFF-like anti-opioid activity in these behavioral studies.


Discovery of highly potent renin inhibitors potentially interacting with the S3' subsite of renin.
To exploit the S3' subsite of renin active site for renin inhibitor design, 42 aliskiren derivatives with modified P2' portion were designed, synthesized and biologically evaluated. Some highly potent renin inhibitors (IC₅₀ < 3 nM) were identified, among which compounds 38 (IC₅₀ = 0.9 nM) and 39 (IC₅₀ = 0.7 nM) were over 2.5-fold more potent than aliskiren (IC₅₀ = 2.3 nM). SAR analysis indicated that incorporation of polar hydrophilic moieties into the P2' portion of renin inhibitors generally enhanced the potency. Consistently with this, molecular modeling study revealed that the triazole part of 39 could provide additional interactions to the S3' subsite of renin active site. Moreover, in vivo evaluation in the double transgenic mouse hypertension model demonstrated that 39 produced greater reduction of the mean arterial blood pressure than ariskiren at the doses of 17.0 and 34.0 μmol/kg, respectively. Taken together, the S3' subsite of renin active site merits further consideration for renin inhibitor design.


Satisfactory Outcomes of All-Poly Fixed Bearing Unicompartmental Knee Arthroplasty for Avascular Osteonecrosis Versus Osteoarthritis: A Comparative Study With 10 to 22 Years of Follow-up.
While good mid-term results for treating spontaneous knee osteonecrosis (SPONK) with unicompartmental knee arthroplasty (UKA) have been reported, concerns remain about implant survival at long-term. This study aimed to compare outcomes and survivorship of UKA for SPONK vs osteoarthritis at a minimum of 10 years. This case-control study included medial UKA for femoral SPONK operated between 1996 and 2010 with a minimum 10-year follow-up (n = 47). Each case was matched with a medial UKA for osteoarthritis based on body mass index (BMI), gender, and age. Knee Society Score (KSS), complications and radiological (loosening) data were collected at the last follow-up. Kaplan-Meier survivorship analysis was performed using revision implant removal as endpoint. The mean follow-up was 13.2 years (range 10 to 21 years). Mean age and BMI were 72.9 ± 8.4 years and 25.5 ± 3.6 Kg/m2 in SPONK group. At last follow-up, knee and function KSS were 89.5 ± 12 and 79 ± 18 in SPONK group vs 90 ± 15 (P = .85) and 81.7 ± 17 (P = .47) in control group. Complications and radiological results showed no significant differences. The survival rate free from any revision was 85.1% at last follow-up in SPONK group and 93.6% in control group (P = .23). The leading cause for revision was aseptic tibial loosening (57.1%) in SPONK group. The 15-year survival estimate was 83% in SPONK group. Satisfactory clinical outcomes at long-term after UKA for femoral SPONK were observed, similar to those after UKA for osteoarthritis, despite a higher risk of tibial loosening in the SPONK group. No symptomatic femoral loosening leading to a revision was observed. IV.


Evaluation of lead-based echodensities on transesophageal echocardiogram in patients with cardiac implantable electronic devices.
Transesophageal echocardiography (TEE) is recommended to rule out endocarditis in patients with cardiac implantable electronic devices (CIED). A lead-based echodensity (LBE), however, is often found on TEE in patients with a CIED and may not represent an infection. We sought to evaluate the predictors, characteristics, and clinical significance of LBEs seen on TEE in patients with a CIED. Patients with a CIED were retrospectively identified from a database using International Classification of Diseases (ICD)-9/ICD-10 codes and were cross-matched with Current Procedural Terminology codes for a TEE. Clinical and follow-up data were collected. A blinded echo board-certified cardiologist reviewed all TEEs. Out of the 231 patients in the cohort, 191 had TEE performed for a noninfection-related indication while 40 TEEs were part of an endocarditis workup. A total of 50 LBEs were identified, and a majority were in the noninfection cohort. Systemic anticoagulant use in the noninfection cohort was associated with a decreased odds of having LBE on TEE (odds ratio [OR] of 0.23 [95% confidence interval [CI]: 0.06-0.60, p = .003]). Lead dwell time in the noninfection cohort was associated with an increased odds of having LBE on TEE (OR 1.21 (95% CI: 1.04-1.39, p = .009]). In our cohort of patients who had TEE for noninfection indications we found that systemic anticoagulant use is associated with fewer LBEs on TEEs, suggesting possible thrombin fibrin composition of LBE.


Treadmill Exercise Promotes Microglial β-Amyloid Clearance and Prevents Cognitive Decline in APP/PS1 Mice.
Growing evidence has demonstrated that treadmill exercise is beneficial to increase β-amyloid (Aβ) clearance and protect against Alzheimer's disease (AD). However, the underlying mechanisms remain to be elucidated. Recently, microglia dysfunction leading to Aβ clearance impairment is proved an important mechanism for later Aβ deposition and AD pathogenesis. The present study aimed to confirm the effect of exercise on Aβ deposition and to investigate the role of microglia in exercise-induced Aβ reduction. In the present study, 3-month-old male APPswe/PS1dE9 (APP/PS1) mice and C57BL/6 wild-type mice were randomly divided into sedentary (SED) or exercise (EX) group, twelve mice in each group. Mice in exercise groups were subjected to ran on a treadmill for 3 months, 5 days/week. Afterwards, the spatial learning and memory, hippocampal fibrillar Aβ deposits and microglial functions were determined by Morris water maze task, methoxy-X04 staining as well as in vivo and in vitro assays, respectively. The results showed that 3 months of treadmill exercise largely prevented spatial learning and memory decline and alleviated hippocampal methoxy-X04-positive fibrillar Aβ deposits in APP/PS1 mice. Moreover, treadmill exercise partly restored microglial Aβ degradation and clearance in the hippocampus, which was impaired in APP/PS1 mice. However, the impaired microglial Aβ phagocytosis in APP/PS1 mice was not altered after 3 months of treadmill exercise intervention. These findings demonstrate that 3 months of treadmill exercise alleviates hippocampal Aβ deposition and restores spatial learning and memory in APP/PS1 mice, partly by promoting microglial Aβ degradation and clearance.


Management of Oligoprogression in Patients with Metastatic NSCLC Harboring ALK Rearrangements.
Personalized treatment based on driver molecular alterations, such as ALK rearrangement, has revolutionized the therapeutic management of advanced oncogene-addicted NSCLC patients. Multiple effective ALK tyrosine kinase inhibitors (TKIs), with the amelioration of the activity at central nervous system level, are now available, leading to substantial prognosis improvement. The exposure to TKIs triggers resistance mechanisms and the sequential administration of other TKIs and chemotherapy is, for the most part, not targeted. In this context, extending the benefit deriving from precision medicine is paramount, above all, when disease progression occurs in a limited number of sites. Retrospective data indicate that, in oligoprogressive disease, targeted therapy beyond progression combined with definitive local treatment of the progressing site(s) is an effective alternative. In these cases, a multidisciplinary approach becomes essential for an integrated treatment strategy, depending on the site of disease progression, in order to improve not only survival, but also quality of life. In this review we provide an updated and comprehensive overview of the main treatment strategies in cases of ALK rearranged oligoprogression, including systemic treatment as well as local therapy, and report a real-world clinical story, with the final aim of identifying the most promising management for this subset of patients.


Radiation induced contrast enhancement after proton beam therapy in patients with low grade glioma - How safe are protons?
The optimal treatment strategy for low-grade glioma (LGG) is still a matter of controversy. Considering that the prognosis is typically favorable, the prevention of late sequelae is of particular importance. Proton beam therapy (PRT) has the potential to further reduce the burden of treatment related side effects. We set out to evaluate the clinical outcome of proton irradiation with a particular focus on morphologic features on magnetic resonance imaging (MRI). We assessed prospectively 110 patients who received radiotherapy with protons for histologically proven LGG. Clinical and radiological information were analyzed resulting in more than 1200 available MRI examinations with a median follow-up of 39 months. Newly diagnosed contrast-enhancing lesions on MRI were delineated and correlated with parameters of the corresponding treatment plan. A voxel-based dose-matched paired analysis of the linear energy transfer (LET) inside vs outside lesions was performed. Proton beam irradiation of patients with low-grade glioma results in overall survival (OS) of 90% after seven years. Median progression free survival had not yet been reached with surviving fraction of 54% after seven years. The incidence of temporary or clinically silent radiation induced contrast enhancement was significantly higher than previously assumed, however, symptomatic radiation necrosis was only detected in one patient. These radiation-induced contrast-enhancing lesions were almost exclusively seen at the distal beam end of the proton beam. In 22 out of 23 patients, the average LET of voxels inside contrast-enhancing lesions was significantly increased, compared to dose-matched voxels outside the lesions. Symptomatic radiation necrosis following PRT was as rare as conventional photon-based treatment series suggest. However, the increased incidence of asymptomatic radiation-induced brain injuries with an increased average LET observed in this cohort provides strong clinical evidence to support the hypothesis that the relative biological effectiveness of protons is variable and different to the fixed factor of 1.1 currently used worldwide.


Assessment of unloaded polymeric nanocapsules with different coatings in female rats: Influence on toxicological and behavioral parameters.
The unloaded polymeric nanocapsules (NCs) present incredible characteristics as drug carriers. However, the toxicity caused by NCs with different coatings is still a challenge for contemporary toxicology. Allied to this, preclinical studies are performed in males, disregarding possible gender-dependent toxicity. Thus, the aim of present study was to evaluate the influence of different NCs coatings on toxicological and behavioral parameters in female rats. The physicochemical characterization of NCs with different surface coatings: NC1 (Polysorbate 80), NC2 (PEG), NC3 (Eudragit®RS 100) and NC4 (Chitosan) were performed. Female rats were treated with saline, NC1, NC2, NC3 or NC4 daily for 14 days, p.o. After 24 h of last treatment, animals were submitted to behavioral tests. Only after behavioral tests, female rats were euthanized, organs were removed and weighted. After, histopathological, biochemical and oxidative stress analysis were performed. All NCs-coatings did not cause alterations in behavioral tests. For markers of hepatic, renal damage and lipid profile, the different coatings showed a low toxicity. NCs did not alter weight of organs and histopathological analysis. Also, all NCs-coatings did not modify redox balance in organs studied, only NC2 induced a increase of FRAP levels in intestine. This study demonstrated that the different NCs-coatings did not cause behavioral changes and showed a low toxicity in female rats.


Differential effects of morphine and naltrexone on the in vitro LH secretion from male and female carp pituitary gland.
The in vitro effects of morphine (10(-10), 10(-8), 10(-6) or 10(-5) M) or/and naltrexone (10(-6) or 10(-8) M) on LH release from male and female carp (Cyprinus carpio L.) dispersed pituitary cells (obtained from fish at the time of late gonad recrudescence) were investigated. Morphine alone at the lowest tested concentration (10(-10) M) increased LH secretion from the cells of males. On the contrary, in female cell incubations the highest concentrations of morphine (10(-6) or 10(-5) M) significantly lowered LH levels. Naltrexone alone (at both tested concentrations) had no influence on LH secretion, neither in males nor in females. However in the incubations of female cells it antagonised the influence of morphine at 10(-10) or 10(-8) M. In male cell incubations naltrexone abolished the stimulatory action of morphine at 10(-10) M. The results suggest that in the in vitro culture of carp pituitary cells LH secretion is modulated by the opioids which affect the release of this gonadotropin through the typical opioid receptors and that the mu type of these receptors is involved in this process. The effects of opioid agonist and antagonist depend on the stage of gonadal maturity and the sex of fish i.e. the actual level of sex steroids.


Endoscopic submucosal dissection with the Nestis® jet injector system with a bifunctional catheter: first prospective clinical trial (NCT: 2012-A00272-41).
The Enki-2 water jet system (Nestis SAS®, Lyon, France) with dual injection and dissection capability significantly reduced ESD procedure time and perforation rates in animal studies. The study aim was to evaluate its efficacy and safety in patients with superficial neoplastic lesions. A prospective study including 18 patients with esophageal, gastric and rectal superficial neoplasms treated by ESD using Enki-2 was designed. Eighteen lesions (6 esophageal, 3 gastric, 9 rectal, mean diameter 43.5 mm) in 17 patients (10 men, mean age 65.9) were included. The mean procedure time was 65.6 min. One patient needed clipping for an incomplete muscle tear during procedure; there were neither delayed bleedings nor perforation. The "en bloc" resection rate was 100 %, the R0 resection rate was 88.9 % (16/18 lesions), and the curative resection rate was 77.8 %. The 3-month disease-free rate was 92.3 % (12/13 patients, 13/14 lesions, 1 patient lost to follow-up). The 12-month disease-free rate was 69.2 % (9/13 patients, 10/14 lesions, 4 patients lost to follow-up). ESD with Enki-2 water jet system is effective and safe for superficial neoplastic digestive lesions.


Approaches to antiviral chemotherapy.
Most of the drugs used today in the treatment of viral infections in man are purine-pyrimidine antimetabolites that interfere with viral replication. Work at Southern Research Institute has identified a number of compounds of this type with promising antiviral activity in both cell culture and rodent test systems. By far the most active and selective agents are carbocyclic nucleoside analogs in which the oxygen of the furanose ring is replaced by a methylene group. The effects of this change on the metabolism and antiviral activity of these compounds is discussed below.


The association between clinician-based common terminology criteria for adverse events (CTCAE) and patient-reported outcomes (PRO): a systematic review.
Symptomatic adverse events (AEs) are monitored by clinicians as part of all US-based clinical trials in cancer via the U.S. National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE) for the purposes of ensuring patient safety. Recently, there has been a charge toward capturing the patient perspective for those AEs amenable to patient self-reporting via patient-reported outcomes (PRO). The aim of this review was to summarize the empirically reported association between analogous CTCAE and PRO ratings. A systematic literature search was conducted using PubMed, EMBASE, Web of Science, and Cochrane databases through July 2015. From a total of 5658 articles retrieved, 28 studies met the inclusion criteria. Across studies, patients were of mixed cancer types, including anal, breast, cervical, chronic myeloid leukemia, endometrial, hematological, lung, ovarian, pelvic, pharyngeal, prostate, and rectal. Given this mixture, the AEs captured were variable, with many common across studies (e.g., dyspnea, fatigue, nausea, neuropathy, pain, vomiting), as well as several that were disease-specific (e.g., erectile dysfunction, hemoptysis). Overall, the quantified association between CTCAE and PRO ratings fell in the fair to moderate range and had a large variation across the majority of studies (n = 21). The range of measures used and symptoms captured varied greatly across the reviewed studies. Regardless of concordance metric employed, reported agreement between CTCAE and PRO ratings was moderate at best. To assist with reconciliation and interpretation of these differences toward ultimately improving patient care, an important next step is to explore approaches to integrate PROs with clinician reporting of AEs.


Key mendelian variants.
Genetic comparison of the effects of mutant and wild-type alleles is a powerful way to define gene function. But those few disease-causing variants that provide qualitatively different insights into the disease mechanisms of more common sporadic diseases have the greatest translational value.


[Antiulcerous efficacy of reamberin at the background of the stress ulcerogenic factor action].
The effect of reamberin on morphofunctional changes in the small intestine mucous membrane due to stress ulcerogenesis was studied. Normalization of the lipid modifications in the tissue structure, evident of the drug antiulcerous properties, was observed.