Randomised trial evaluating chemotherapy alone or chemotherapy and a novel monoclonal antibody for canine T-cell lymphoma: A multicentre US study.
Canine peripheral nodal T-cell lymphoma is considered chemotherapy resistant and carries a relatively poor prognosis. Prospective evaluations reporting the impact of chemotherapy on progression-free survival (PFS) and overall survival time for dogs with T-cell lymphoma are lacking. This study examined the impact of L-CHOP (L-asparaginase, doxorubicin, cyclophosphamide, vincristine, prednisone) chemotherapy or L-CHOP in combination with AT-005, a US Department of Agriculture-licensed caninised monoclonal antibody, on PFS and response rates in dogs with clinical intermediate- and high-grade peripheral nodal T-cell lymphoma. A prospective, randomised, placebo-controlled, investigator- and owner-blinded, multicentre study was completed. All dogs received a 19-week L-CHOP chemotherapy protocol with randomisation (1:1) into placebo or AT-005 groups. Response was evaluated via the Veterinary Cooperative Oncology Group criteria for canine lymphoma. Forty-nine dogs were enrolled (25 received placebo and 24 received AT-005). Most demographic factors were similar between the two groups, with the exception that more dogs with stage IV and V disease were treated with AT-005 (34% vs. 8%; p = 0.03). Median PFS was 103 days (95% confidence interval [CI], 56-118) in the placebo group versus 64 days (95% CI, 36-118) in the AT-005 group. The overall response rate (ORR) for all dogs was 98% (48 of 49); complete response rate in the placebo group (64%) was not different from the AT-005 group (67%). To the best of the authors' knowledge, this is the first prospective study to document that treatment with L-CHOP chemotherapy, with or without AT-005, may result in a high ORR, but relatively brief PFS in dogs with clinical intermediate- and high-grade T-cell lymphoma.


Identification of biomarkers for the accurate and sensitive diagnosis of three bacterial pneumonia pathogens using in silico approaches.
Pneumonia ranks as one of the main infectious sources of mortality among kids under 5 years of age, killing 2500 a day; late research has additionally demonstrated that mortality is higher in the elderly. A few biomarkers, which up to this point have been distinguished for its determination lack specificity, as these biomarkers fail to build up a differentiation between pneumonia and other related diseases, for example, pulmonary tuberculosis and Human Immunodeficiency Infection (HIV). There is an inclusive global consensus of an improved comprehension of the utilization of new biomarkers, which are delivered in light of pneumonia infection for precision identification to defeat these previously mentioned constraints. Antimicrobial peptides (AMPs) have been demonstrated to be promising remedial specialists against numerous illnesses. This research work sought to identify AMPs as biomarkers for three bacterial pneumonia pathogens such as Streptococcus pneumoniae, Klebsiella pneumoniae, Acinetobacter baumannii using in silico technology. Hidden Markov Models (HMMER) was used to identify putative anti-bacterial pneumonia AMPs against the identified receptor proteins of Streptococcus pneumoniae, Klebsiella pneumoniae, and Acinetobacter baumannii. The physicochemical parameters of these putative AMPs were computed and their 3-D structures were predicted using I-TASSER. These AMPs were subsequently subjected to docking interaction analysis against the identified bacterial pneumonia pathogen proteins using PATCHDOCK. The in silico results showed 18 antibacterial AMPs which were ranked based on their E values with significant physicochemical parameters in conformity with known experimentally validated AMPs. The AMPs also bound the pneumonia receptors of their respective pathogens sensitively at the extracellular regions. The propensity of these AMPs to bind pneumonia pathogens proteins justifies that they would be potential applicant biomarkers for the recognizable detection of these bacterial pathogens in a point-of-care POC pneumonia diagnostics. The high sensitivity, accuracy, and specificity of the AMPs likewise justify the utilization of HMMER in the design and discovery of AMPs for disease diagnostics and therapeutics.


Antioxidant pretreatment for male partner before ART for male factor subfertility: a randomized controlled trial.
Does oral antioxidant pretreatment for the male partner improve clinical pregnancy rate in couples undergoing ART for male factor subfertility? There was no significant difference in clinical pregnancy rate following oral antioxidant pretreatment for male partner in couples undergoing ART for male factor subfertility compared to no pretreatment. Damage to sperm mediated by reactive oxygen species (ROS) contributes significantly to male factor infertility. The ROS-related injury reduces fertilization potential and adversely affects the sperm DNA integrity. Antioxidants act as free radical scavengers to protect spermatozoa against ROS induced damage. During ART, use of sperms which have been exposed to ROS-mediated damage may affect the treatment outcome. Pretreatment with antioxidants may reduce the ROS-mediated sperm DNA damage. Currently, antioxidants are commonly prescribed to men who require ART for male factor subfertility but there is ambiguity regarding their role. This was an open label, randomized controlled trial conducted at a tertiary level infertility clinic between February 2013 and October 2019. The trial included 200 subfertile couples who were undergoing ART treatment for male factor subfertility. Couples were randomized into treatment arm (n = 100) and control arm (n = 100). In the treatment arm, the male partner received oral antioxidants (Vitamin C, Vitamin E and Zinc) for 3 months just prior to the ART cycle. In the control arm, no antioxidant was given to the male partner. The primary outcome was clinical pregnancy rate, while live birth rate (LBR), miscarriage rate and changes in semen parameters were the secondary outcomes. Out of 200 women randomized, 135 underwent embryo transfer as per protocol. Following intention to treat analysis, no significant difference was noted in clinical pregnancy (36/100, 36% vs 26/100, 26%; odds ratio (OR) 1.60, 95% CI 0.87 to 2.93) and LBR (25/100, 25% vs 22/100, 22%; OR 1.18, 95% CI 0.61 to 2.27) between antioxidant and no pretreatment arms. The clinical pregnancy rate per embryo transfer was significantly higher following antioxidant pretreatment (35/64, 54.7% vs 26/71, 36.6%; OR 2.09, 95% CI 1.05 to 4.16) compared to no pretreatment. There was no significant difference in LBR per embryo transfer (25/64, 39.1%, vs 22/71, 31.0%; OR 1.43, 95% CI 0.70 to 2.91) after antioxidant pretreatment versus no pretreatment. The semen parameters of sperm concentration (median, interquartile range, IQR) (18.2, 8.6 to 37.5 vs 20.5, 8.0 to 52.5, million/ml; P = 0.97), motility (median, IQR) (34, 20 to 45 vs 31, 18 to 45%; P = 0.38) and morphology (mean ± SD) (2.0 ± 1.4 vs 2.2 ± 1.5%; P = 0.69) did not show any significant improvement after intake of antioxidant compared to no treatment, respectively. The objective assessment of sperm DNA damage was not carried out before and after the antioxidant pretreatment. Since the clinicians were aware of the group allotment, performance bias cannot be ruled out. The current study did not show any significant difference in clinical pregnancy and LBR following antioxidant pretreatment for the male partner in couples undergoing ART for male subfertility. The findings need further validation in a larger placebo-controlled randomized trial. This trial has been funded by Fluid Research grant of Christian Medical College, Vellore (internal funding). The authors have no conflicts of interest to declare. CTRI/2013/02/003431. 26 February 2013. 11 February 2013.


Developmental spontaneous activity promotes formation of sensory domains, frequency tuning and proper gain in central auditory circuits.
Neurons that process sensory information exhibit bursts of electrical activity during development, providing early training to circuits that will later encode similar features of the external world. In the mammalian auditory system, this intrinsically generated activity emerges from the cochlea prior to hearing onset, but its role in maturation of auditory circuitry remains poorly understood. We show that selective suppression of cochlear supporting cell spontaneous activity disrupts patterned burst firing of central auditory neurons without affecting cell survival or acoustic thresholds. However, neurons in the inferior colliculus of these mice exhibit enhanced acoustic sensitivity and broader frequency tuning, resulting in wider isofrequency laminae. Despite this enhanced neural responsiveness, total tone-responsive regions in the auditory cortex are substantially smaller. Thus, disruption of pre-hearing cochlear activity causes profound changes in neural encoding of sound, with important implications for restoration of hearing in individuals who experience reduced activity during this critical developmental period.


Families' opinions about caring for patients with psychiatric disorders after involuntary hospitalization in Japan.
It is imperative to know families' opinions about where patients should live after discharge from involuntary hospitalization in the era of community mental health. Questionnaires were sent (March-May 2011) to 808 guardians of patients who were involuntarily hospitalized in Japan (response rate = 54.2%). The final sample size was 365 family members. Whether families wanted to live with the patient after discharge from the hospital was the primary outcome variable. The associations of the demographic characteristics of the patients and families with the outcome variable were tested using logistic regression analysis. Approximately, 19% of the family guardians wanted to live with the patient after discharge from the hospital. Their wish to cohabit was positively associated with being a female (vs male) patient, having three or more cohabitants in the home and having lived together before hospitalization, after adjusting for the other covariates. Long-term hospitalization (10 years or longer) and siblings were significantly associated with the families not wanting to cohabit, after adjusting for the other covariates. It is important to know families' opinions about patients' living situations after discharge from involuntary hospitalization to provide them with an effective support system.


Ectopic stapes: a case report with embryologic correlations.
A case report of unilateral congenital stapes misplacement revealed by computed tomography is presented. In addition to this malformation, the malleus was synostosed to the middle ear roof. This kind of stapes ectopia has not been described previously. We have analyzed the malformative pattern in the light of normal and teratologic development of the stapes. In a teratologic model in which retinoic acid is administered to pregnant mice, we have observed an ectopic stapes primordium independent of the otic capsule. We discuss the possible pathogenesis of this abnormality in terms of the genetic events of middle ear development, which can be perturbed by retinoic acid administration.


Enhanced long-term dietary change and adherence in a nutrigenomics-guided lifestyle intervention compared to a population-based (GLB/DPP) lifestyle intervention for weight management: results from the NOW randomised controlled trial.
Adherence to nutritional guidelines for chronic disease prevention and management remains a challenge in clinical practice. Innovative strategies are needed to help optimise dietary behaviour change. The objective of this study was to determine if a nutrigenomics-guided lifestyle intervention programme could be used to motivate greater dietary adherence and change in dietary intake short-term, moderate-term and long-term compared to the gold-standard population-based weight management intervention (Group Lifestyle Balance (GLB)/Diabetes Prevention Programme (DPP)). The Nutrigenomics, Overweight/Obesity, and Weight Management (NOW) randomised controlled trial is a pragmatic, parallel-group, superiority clinical trial (n=140), which was conducted at the East Elgin Family Health Team (EEFHT). GLB weight management groups were prerandomised 1:1 to receive either the standard GLB programme or a modified GLB+nutrigenomics (GLB+NGx) programme. Three 24-hour recalls were collected at baseline, 3, 6 and 12 months using the validated multiple pass method. Research assistants collecting the three 24-hour recalls were blinded to the participants' group assignments. Statistical analyses included split plot analyses of variance (ANOVAs), two-way ANOVAs, binary logistic regression, χ2 and Fisher's exact tests. Using the Theory of Planned Behaviour as guidance, key confounding factors of behaviour change were considered in the analyses. This study was registered with clinicaltrials.gov (NCT03015012). Only the GLB+NGx group significantly reduced their total fat intake from baseline to 12-month follow-up (from 36.0%±4.8% kcal to 30.2%±8.7% kcal, p=0.02). Long-term dietary adherence to total fat and saturated fat guidelines was also significantly (p<0.05) greater in the GLB+NGx group compared to the standard GLB group. Weight management interventions guided by nutrigenomics can motivate long-term improvements in dietary fat intake above and beyond gold-standard population-based interventions.


Methods for RPE Sheet Construction Using iPS-CM in Conjunction with Natural Scaffold of Corneal Lenticule Derived from SMILE.
In vitro generation of a functional retinal pigment epithelium (RPE) monolayer sheet is useful and promising for RPE cell therapy. Here, we outline a method to construct engineered RPE sheets treated by induced pluripotent stem cell-conditioned medium (iPS-CM) in conjunction with femtosecond laser intrastromal lenticule (FLI-lenticule) scaffold to aid in enhanced RPE characteristics and cilium assembly. Such a strategy to construct RPE sheets is a promising avenue for developing RPE cell therapy, disease models, and drug screening tools.


Environmental xenobiotics and nuclear receptors--interactions, effects and in vitro assessment.
A group of intracellular nuclear receptors is a protein superfamily including arylhydrocarbon AhR, estrogen ER, androgen AR, thyroid TR and retinoid receptors RAR/RXR as well as molecules with unknown function known as orphan receptors. These proteins play an important role in a wide range of physiological as well as toxicological processes acting as transcription factors (ligand-dependent signalling macromolecules modulating expression of various genes in a positive or negative manner). A large number of environmental pollutants and other xenobiotics negatively affect signaling pathways, in which nuclear receptors are involved, and these modulations were related to important in vivo toxic effects such as immunosuppression, carcinogenesis, reproduction or developmental toxicity, and embryotoxicity. Presented review summarizes current knowledge on major nuclear receptors (AhR, ER, AR, RAR/RXR, TR) and their relationship to known in vivo toxic effects. Special attention is focused on priority organic environmental contaminants and experimental approaches for determination and studies of specific toxicity mechanisms.


Revisiting metatropic dysplasia: presentation of a series of 19 novel patients and review of the literature.
Metatropic dysplasia (MD-OMIM: 156530 and 250600) is a rare chondrodysplasia characterized by short limbs with limitation and enlargement of joints and usually severe kyphoscoliosis, first described in 1893. Up until now, 81 other patients have been reported. The phenotypic variability of MD has led to a classification based on radiological anomalies dividing into three different types: a lethal autosomal recessive form, an autosomal recessive non-lethal form and a non-lethal autosomal dominant form with less severe radiographs manifestations and a better clinical outcome. Here, we report on clinical and radiological features of 19 novel MD patients. We describe new radiological features, including precocious calcification of hyoid and cricoid cartilage, irregular and squared-off calcaneal bones and severe hypoplasia of the anterior portion of first cervical vertebrae. In addition, the observation of an overlap between the autosomal recessive non-lethal form and the non-lethal autosomal dominant form, the rarity of sibship recurrences and the observation of vertical transmissions of MD in the literature argue in favor of an autosomal dominant mode of inheritance for all MD types. This hypothesis is reinforced by the use of the statistical single ascertainment method that rejects the hypothesis of an autosomal recessive mode of inheritance responsible for MD. Therefore, we propose that recurrence in sibs is due to gonadal mosaicism.


Evaluation of aroma active compounds in Tuber fruiting bodies by gas chromatography-olfactometry in combination with aroma reconstitution and omission test.
The aroma active compounds of three Tuber fruiting bodies (i.e., Tuber himalayense, Tuber indicum, and Tuber sinense) were firstly systematically evaluated by instrumental gas chromatography-olfactometry combining with quantitative analysis, aroma reconstitution, and omission tests. Twelve aroma active compounds were characterized by aroma extract dilution analysis, and 3-(methylthio) propanal, 3-methylbutanal, and 1-octen-3-ol with the highest flavor dilution (FD) factor (i.e., 1,024-2,048) were suggested as key contributors to the aroma. Odor activity value (OAV) was employed to determine the relative contribution of each compound to the aroma, and the compound with the highest FD factor also had the highest OAV (i.e., 10,234-242,951). Then, the synthetic blends of odorants (aroma reconstitution) were prepared with OAV larger than 15, and their aromas were very similar to the originals. Omission tests were carried out to verify the significance of 3-(methylthio) propanal, 1-octen-3-ol, and 3-methylbutanal as key compounds in the aroma of tested Tuber fruiting bodies.


Comparisons of physical activity and understanding of the importance of exercise according to dialysis modality in maintenance dialysis patients.
Data regarding the status of physical activity or understanding of the importance of exercise, such as barriers of exercise or enablers of exercise, in dialysis patients were insufficient. This study aimed to evaluate the status of physical activity and the understanding of the importance of exercise in Korean dialysis patients. The study participants were recruited from 27 hospitals or dialysis centers (n = 1611). Physical activity was evaluated using the Korean version of the International Physical Activity Questionnaire-Short Form. High physical activity was defined as ≥ 600 metabolic equivalent of task (MET). Knowledge about the importance of exercise, enabler for regular exercise, benefits of exercise, and barrier to exercise was evaluated. Health-related quality of life (HRQoL) was assessed by the Kidney Disease Quality of Life version 1.3. The number of participants in the hemodialysis (HD) and peritoneal dialysis (PD) groups was 1247 and 364, respectively. The intensity of physical activity did not differ between the two modalities. The time of physical activity was longer in HD patients than in PD patients, which resulted in greater MET values and the number of high physical activity. There were 762 (61.1%) HD patients and 281 (77.2%) PD patients who heard of the importance of exercise (P < 0.001). In both HD and PD patients, dialysis staff played the most significant role as educators on the importance of exercise and enablers of exercise. The most important barriers to exercise were poor motivation and fatigue in both modalities. HD patients exhibited greater differences in HRQoL scales across two physical activity levels, compared to PD patients. Our study showed that the barrier to exercise and the enablers of exercise were poor motivation/fatigue and encouragement from dialysis staff, respectively.


Noninvasive evaluation of global left ventricular function with use of cine nuclear magnetic resonance.
Previous reports have validated the accuracy of nuclear magnetic resonance (NMR) imaging for quantitating ventricular volumes and myocardial mass. In this study, a new rapid NMR imaging method, cine NMR imaging, was used to compare left ventricular volumes determined from the transverse plane and short-axis plane in healthy volunteers and patients with dilated cardiomyopathy. With use of the short-axis plane, left ventricular mass at end-systole and end-diastole were determined and left ventricular systolic wall thickening at three different levels was assessed. For validation in the current study, cine NMR imaging and two-dimensional echocardiographic measurements of left ventricular volumes were correlated. Left ventricular volumes of the normal volunteers (end-systolic volume = 34 +/- 3.8 ml, end-diastolic volume = 90.4 +/- 7.2 ml) and patients with cardiomyopathy (end-systolic volume = 173 +/- 28.3 ml, end-diastolic volume = 219.5 +/- 29.6 ml) obtained in the transverse plane were nearly identical to those obtained in the short-axis plane (normal volunteers, end-systolic volume = 30.3 +/- 3.5 ml, end-diastolic volume = 84.7 +/- 7.0 ml and patients with cardiomyopathy, end-systolic volume = 179.1 +/- 27.8 ml, end-diastolic volume = 227 +/- 30.9 ml) and correlated highly (r = 0.91) with volumes obtained by two-dimensional echocardiography. Assessment of left ventricular mass over a broad range using cine NMR imaging in a short-axis plane was identical at end-systole (normal volunteers, 117 +/- 10 g; patients with cardiomyopathy, 202 +/- 20 g) and end-diastole (normal volunteers, 115 +/- 10 g; patients with cardiomyopathy, 194 +/- 21 g).(ABSTRACT TRUNCATED AT 250 WORDS)


A minimal WLE2 element is not sufficient to direct apical localization in the absence of RNAs containing the full length wingless 3'UTR.
The mRNAs encoded by the Drosophila Wnt-1 homologue, wingless, are localized to a small region of the apical cytoplasm in early embryonic epithelial cells. This requires the activity of cis-acting sequences within the 3' untranslated region called wingless localization elements (WLEs). One of these, WLE2, was identified initially as a cis-acting sequence that directed apical localization of in vivo expressed mRNAs in four to five hour Drosophila embryos. To determine the precise activity of WLE2 during wingless apical localization, we performed an in-depth mutagenesis of this sequence. Using both direct-injection and in vivo transgenes we determined that WLE2, by itself, is not sufficient to direct binding of trans-acting factors that mediate apical RNA transport in embryonic cells. Rather, RNAs containing only WLE2 are transported apically only in the presence of a second RNA containing other cis-acting localization sequences of the wingless 3' untranslated region. This co-requirement for WLE2 and additional wingless 3'UTR sequences is likely a required function during apical localization, as mutations within WLE2 can modify the apical localization activity of RNA molecules that contain other wingless localization signals. This suggests that, similar to other localized mRNAs like bicoid, wingless localization may require specific RNA-RNA interactions as well as recognition by cytoplasmic RNA localization complexes.


Biomarkers activity in Oreochromis niloticus under sub-chronic exposure to a UV filters ternary mixture.
The behavior of organic UV filters in aquatic ecosystems and living organisms raises concern. For the first time, biochemical biomarkers were evaluated in the liver and brain of juvenile Oreochromis niloticus exposed to 0.001 and 0.5 mg L-1 of a benzophenone-3 (BP-3), octyl methoxycinnamate (EHMC), and octocrylene (OC) mixture for 29 days. Before the exposure, the stability of these UV filters was investigated using liquid chromatography. The experiment with aeration in the aquarium showed a high percentage of concentration reduction (%) after 24 h: 62 ± 2 for BP-3, 96 ± 6 for EHMC, and 88 ± 2 for OC versus 5 ± 4 for BP-3, 8 ± 7 for EHMC, and 2 ± 3 for OC when without aeration. These results defined the bioassay protocol. The stability of the filters concentrations after being stored in PET flasks and subjected to freezing and thawing cycles was also verified. In PET bottles, the BP-3, EHMC, and OC presented concentration reductions of 8 ± 1, 28 ± 7 and 25 ± 5 respectively, after 96 h storage and four freezing cycles. In falcon tubes the concentration reductions observed were 47 ± 2 for BP-3, >95 ± 1 for EHMC and 86 ± 2 for OC after 48 h and two cycles. The 29 days of sub-chronic exposure indicated the occurrence of oxidative stress through the enhanced lipid peroxidation (LPO) levels for the groups exposed to both bioassay concentrations. The catalase (CAT), glutathione-S-transferase (GST), and acetylcholinesterase (AChE) activities did not show significant alterations. The genetic adverse effects were analyzed in erythrocytes of fish exposed to 0.001 mg L-1 of the mixture by comet and micronucleus biomarkers and no significant damage was observed.


Reduction in hepatic drug metabolizing CYP3A4 activities caused by P450 oxidoreductase mutations identified in patients with disordered steroid metabolism.
Cytochrome P450 3A4 (CYP3A4), the major P450 present in human liver metabolizes approximately half the drugs in clinical use and requires electrons supplied from NADPH through NADPH-P450 reductase (POR, CPR). Mutations in human POR cause a rare form of congenital adrenal hyperplasia from diminished activities of steroid metabolizing P450s. In this study we examined the effect of mutations in POR on CYP3A4 activity. We used purified preparations of wild type and mutant human POR and in vitro reconstitution with purified CYP3A4 to perform kinetic studies. We are reporting that mutations in POR identified in patients with disordered steroidogenesis/Antley-Bixler syndrome (ABS) may reduce CYP3A4 activity, potentially affecting drug metabolism in individuals carrying mutant POR alleles. POR mutants Y181D, A457H, Y459H, V492E and R616X had more than 99% loss of CYP3A4 activity, while POR mutations A287P, C569Y and V608F lost 60-85% activity. Loss of CYP3A4 activity may result in increased risk of drug toxicities and adverse drug reactions in patients with POR mutations.


Does postural instability affect the initiation of human gait?
During gait initiation (GI), decoupling of the center of mass and center of pressure allows the center of mass to fall forwards. Subjects initiated gait rapidly before and after tibial nerve block of the tibial nerve. Static single limb stability, stance limb ground reaction forces, electromyogram and temporal data were measured. It was hypothesized that postural stability would decrease post-block and that this would affect the kinetic and temporal properties of GI. Subjects had significantly decreased postural stability post-block and changes in normal gait kinetics, however, no changes were noted in ground reaction forces or relative temporal data of the GI task. The finding that GI was unaffected by diminished single leg postural instability suggests that GI is a pre-programmed task.


The induction of ferroptosis in posthemorrhagic hydrocephalus.
Posthemorrhagic hydrocephalus (PHH) is a common neurological disease characterized by the disordered secretion of cerebrospinal fluid from the choroid plexus, ventricular dilation, and increased intracranial pressure after hemorrhage. Although these pathological processes are well established, the effective biomarkers for the diagnosis of PHH are still limited, largely because the underlying mechanisms-including cell death in the choroid plexus-are not well defined. Ferroptosis, a newly recognized type of programmed cell death, has been found to play a key role in a variety of pathologic conditions and diseases, including Parkinson's and Alzheimer's diseases. However, whether ferroptosis is induced in PHH is still unknown. In the current study, a rat model of PHH was established to investigate the induction of ferroptosis in PHH. Along with defects in memory and cognition, we observed that rats with experimentally induced PHH also demonstrated lipid peroxidation (a key marker of ferroptosis), as well as a significant increase and a significant decrease in two ferroptosis-specific genes, ACSL4 and SLC7A11, respectively. Thus, ferroptosis may serve as an auxiliary indicator for the diagnosis of PHH.


Astrocytes control food intake by inhibiting AGRP neuron activity via adenosine A1 receptors.
It is well recognized that feeding behavior in mammals is orchestrated by neurons within the medial basal hypothalamus. However, it remains unclear whether food intake is also under the control of glial cells. Here, we combine chemical genetics, cell-type-specific electrophysiology, pharmacology, and feeding assays to show that stimulation of astrocytes within the medial basal hypothalamus reduces both basal- and ghrelin-evoked food intake. This occurs by a mechanism of adenosine-mediated inactivation of the orexigenic agouti-related peptide (AGRP) neurons in the hypothalamic arcuate nucleus (ARC) via adenosine A1 receptors. Our data suggest that glial cells participate in regulating food intake by modulating extracellular levels of adenosine. These findings reveal the existence of a glial relay circuit that controls feeding behavior, one that might serve as a target for therapeutic intervention in the treatment of appetite disorders.


Water quality near Estonian harbours in the Baltic Sea as observed from entire MERIS full resolution archive.
Variations and trends in water quality parameters (total suspended matter and coloured dissolved organic matter) were examined in five harbours in the eastern Baltic Sea using satellite imagery collected from 2002 to 2011 by the Medium Resolution Imaging Spectrometer (MERIS) at full spatial resolution (300×300m). In the eastern Gulf of Finland harbours (Sillamäe, Kunda) the TSM monthly variations were related to monthly mean wind speed. In Tallinn harbour, which operates >6000 vessels annually, evidence of anthropogenic impacts was identified through inter-annual TSM variations. The vessel traffic footprint was ascertained from the significant correlation (R=0.66; p=0.035) between the number of annual vessel visits and mean annual TSM concentration. In the harbour of Pärnu, located close to the river mouth, inter-annual water quality variations in terms of the CDOM concentrations were affected by the mean annual river discharge levels of the Pärnu River.


A homologous tandem translocation [45,XX,-13,-13,+t(13;13) (q12;q34)].
Chromosomal investigation of a young girl with mental and motor retardation and congenital anomalies revealed a translocation between both members of pair No. 13. Banding analysis showed that the translocation was "tandem," leading to monosomy for segments in both the long and short arms of No. 13.


Autocatalysed oxidative modifications to 2-oxoglutarate dependent oxygenases.
Ferrous iron and 2-oxoglutarate-dependent oxygenases and related enzymes catalyse a range of oxidative reactions, possibly the widest of any enzyme family. Their catalytic flexibility is proposed to be related to their nonhaem iron-binding site, which utilizes two or three protein-based ligands. A possible penalty for this flexibility is that they may be more prone to oxidative damage than the P450 oxidases, where the iron is arguably located in a more controlled environment. We review the evidence for autocatalysed oxidative modifications to 2-oxoglutarate-dependent oxygenases, including the recently reported studies on human enzymes, as well as the oxidative fragmentations observed in the case of the plant ethylene-forming enzyme (1-aminocyclopropane-1-carboxylic acid oxidase).


Immunotherapy in older patients with hepatocellular carcinoma.
Hepatocellular carcinoma (HCC) is one of the most common types of cancer globally and is currently the third leading cause of cancer-related deaths. Recently, immunotherapy using immune checkpoint inhibitors (ICIs) has been shown with encouraging anticancer activity and safety in clinical trials. To reverse the phenomenon of tumours evading immune response, ICIs can be used to stimulate the natural antitumour potential of cancer cells by blocking the relevant checkpoints to activate T cells. However, the components and functions of the immune system may undergo a series of changes with ageing, known as 'immunosenescence,' potentially affecting the antitumour effect and safety of immunotherapy. In the current phase III clinical trials of ICIs including nivolumab, pembrolizumab and atezolizumab, the proportion of patients with HCC older than 65 years in CheckMate 459, KEYNOTE-240 and IMbrave150 is 51%, 58% and 50%, respectively, which is less than 70%-73% of epidemiological investigation. Therefore, the elderly population recruited in clinical trials may not accurately represent the real-world elderly patients with HCC, which affects the extrapolation of the efficacy and safety profile obtained in clinical trials to the elderly population in the real world. This review provides the latest advances in ICIs immuno-treatment available for HCC and relevant information about their therapeutic effects and safety on elderly patients. We discuss the benefits of ICIs for older HCC patients, and relevant recommendations about conducting further clinical trials are proposed for more complete answers to this clinical issue.


Inappropriate rate response in a leadless pacemaker due to automatic rate profile optimization.
A three-axis accelerometer sensor is incorporated in a leadless pacemaker (MicraTM , MedtronicInc ) for rate adaptation. Three sensor setpoints at lower rate (LR), activity of daily living rate (ADLR), and upper rate (UR) are used to convert detected acceleration to a desired rate response. We describe inappropriate rate acceleration at rest and during chest physiotherapy in a sedentary elderly patient with leadless pacemaker. The underlying mechanism and various programming options are discussed.


Renal artery fibromuscular dysplasia: results of current surgical therapy.
This retrospective review describes current surgical management of renal artery (RA) fibromuscular dysplasia (FMD) to define contemporary clinical characteristics and surgical results in patients over the age of 21 years. From January 1987 through March 1994, 40 consecutive adults with hypertension had operative RA repair of FMD at our center and form the basis of this report. From histologic and angiographic appearance, FMD was classified with regard to specific type, noting the presence of RA dissections, RA macroaneurysms and branch RA involvement. Associations between blood pressure response to operation and patient age, duration of hypertension, presence of extrarenal atherosclerosis, presence of branch renal artery disease, and primary or secondary procedure were examined. Clinical characteristics and blood pressure response in these contemporary patients were compared with the results reported from an earlier surgical series. Unilateral RA repair was performed in 34 patients, and bilateral procedures were required in six patients. Branch renal artery repair was performed in 28 instances, including ex vivo RA repair in 11 patients. There were no perioperative or follow-up deaths; however, three RA grafts (7%) failed within 30 days of operation. Initial blood pressure response was considered cured in 33%, improved in 57%, and failed in 10%. Analysis demonstrated that patients older than 45 years of age had a significantly decreased rate of hypertension cure compared with younger patients; among patients younger than 45 years of age, duration of hypertension was inversely related to cure. Compared with earlier surgical series, our current group of patients was significantly older, with more frequent branch renal artery involvement and extrarenal atherosclerosis, and demonstrated decreased rate of hypertension cure. A beneficial blood pressure response is currently observed in most selected patients after surgical correction of RA-FMD. Compared with earlier series, however, the present day patient differs in many respects, including a significantly decreased chance for hypertension cure after surgical repair.


Beta-blockers for hypertension: time to call a halt.
Beta-blockers are not very effective at lowering blood pressure in elderly hypertensive patients or in Afro-Caribbeans and these two groups represent a large proportion of people with raised blood pressure. Furthermore they do not prevent more heart attacks than the thiazide diuretics. Beta-blockers can also be dangerous in many hypertensive patients and even when these drugs are not contraindicated, they cause subtle and depressing side effects which should preclude their usefulness. The time has come therefore to reconsider the endorsement of beta-blockers by the British Hypertension Society and other guidelines committees, except possibly for severe resistant hypertension, high risk post-infarct patients and those with angina pectoris. The time has come to move across to newer, safer, more tolerable and more effective antihypertensive agents whilst continuing to use thiazide diuretics in low doses in the elderly as first choice, providing there are no contraindications.


Computer analyzed histology of ischemic injury to the gut.
Histopathologic alterations in the intestinal mucosa after ischemic injury have been extensively described in the literature, but these descriptions have primarily been qualitative in nature. The purpose of this study was twofold: (1) to establish parameters obtained by computerized digital image analysis that would be useful in identifying ischemic injury, and (2) to use these parameters to identify the critical period of intestinal ischemia producing measurable histopathologic change. Seventy male Sprague-Dawley rats weighing 80 to 150 g underwent various times of gut ischemic injury by vascular occlusion of the superior mesenteric artery and vein with a microaneurysm clamp. The clamp times were 0, 1, 20, 30, 40, 50, 60, 70, 80, and 90 minutes. Histological sections of the terminal ileum were quantitatively analyzed using Jandel Scientific's computerized morphometric image analysis system. Parameters studied were surface index (SI, surface length per linear unit of mucosa), average villous thickness (AVT), average villous height (AVH), and the number of villous cells/100 microns length (VC). Ischemic times of 1, 20, 30, and 40 minutes produced no measurable injury as compared with baseline (P[40 minutes versus baseline] = SI, .60; AVT, .84; AVH, .93; VC, .09). At 50 minutes, SI and AVH showed a measurable change from baseline (P[50 minutes versus baseline] = SI, .01; AVH, .02). Sixty minutes of ischemic time produced measurable change in all parameters (P[60 minutes versus baseline] = SI, .007; AVT, .001; AVH, .002; VC, .007).(ABSTRACT TRUNCATED AT 250 WORDS)


Thromboatherosclerotic complications in hypertensives: results of the Stockholm Metoprolol (secondary prevention) Trial.
The outcome of postinfarction patients with a history of hypertension who participated in a randomized, double-blind, secondary prevention study with metoprolol or placebo treatment for 3 years has been evaluated. There were 41 patients in the placebo group and 35 patients in the metoprolol group. Elevated blood pressure was treated primarily by the addition of thiazide diuretics. Blood pressures were nearly identical in the two treatment groups. During the 3 years, 11 patients died in the placebo group and seven died in the metoprolol group. Occurrence of nonfatal events was also higher in the placebo than in the treated group: 12 patients vs one patient for reinfarction (p less than 0.005), three patients vs no patients for coronary artery bypass grafting, four patients vs no patients for cerebrovascular events, and one patient vs no patients for lower limb amputation. The total number of patients with any event was 24 vs eight (p less than 0.01). The present results may imply that treatment after infarction with metoprolol reduces nonfatal thromboatherosclerotic complications, especially nonfatal reinfarctions, in patients with a history of hypertension. However, inasmuch as the results were obtained from a retrospective subgroup analysis, they must be interpreted with caution.


Recurrence of Helicobacter pylori infection after eradication: incidence and variables influencing it.
Our aim was to study the incidence of Helicobacter pylori recurrence in our country and to assess the different variables that might influence it. We studied prospectively 331 duodenal ulcer patients (mean age, 48 +/- 14 years, 71% male) in whom H. pylori had been eradicated. Several therapies were used, classified as low-efficacy (omeprazole + amoxycillin, 32% eradication rate; omeprazole + amoxycillin + metronidazole, 56%) and high-efficacy therapies (omeprazole + clarithromycin + amoxycillin or metronidazole, 88%; bismuth triple therapy, 77%). One month after completion of therapy an endoscopy with biopsies and/or 13C-urea breath test was performed. A breath test was carried out again at 6 months, 1 year, and 2 years, to study H. pylori recurrences. Endoscopy (with biopsies) was performed only to confirm recurrences. Multiple logistic regression analysis was used. Differences between Kaplan-Meier curves were evaluated with the log-rank test. Sixty-seven patients were followed up for 6 months, 136 for 1 year, and 128 for 2 years, giving 425 patient-years of follow-up. A total of 18 H. pylori recurrences was observed (12 at 6 months, 4 at 1 year, and 2 after 2 years), yielding a yearly recurrence of 4.2% patient-years(-1). The respective risk of H. pylori recurrence for each period was 3.6% (95% confidence interval (CI), 2.1%-6.2%), 1.5% (0.6%-3.8%), and 1.5% (0.4%-5.5%). The probability of being H. pylori-negative at 6 months, 1 year, and 2 years was, respectively, 96.4% (94.4%-98.4%), 94.9% (92.5%-97.4%), and 93.4% (90.3%-96.6%). Duodenal ulcer was found in half of the reinfected patients. The recurrence rate at 6 months was 10.3% (5.7%-18%) in patients <40 years old and only 0.85% (0.2%-3.1%) in those > or =40 years old (P = 0.0002). Of the patients who became reinfected at 6 months 27% (6%-61%) had delta breath test values between 3 per thousand and 5 per thousand 1 month after therapy, whereas only 4.6% (2.7%-7.7%) of non-reinfected patients had delta after eradication > or =3 per thousand (P = 0.0097). H. pylori recurrence at 6 months was 8.2% (4.5%-15%) in patients previously treated with low-efficacy therapies and only 1.7% (0.7%-4.3%) when high efficacy therapies were used (P = 0.0098). In the multivariate analysis age (odds ratio (OR), 0.9; 95% CI, 0.8-0.96; P = 0.0008), the delta breath test value after therapy (OR, 2.2; CI, 1.2-4.1; P = 0.0076), and therapy regimen (OR, 6.4; CI, 1.5-27; P = 0.0109) were the only variables that correlated with H. pylori recurrence at 6 months. Differences were observed when Kaplan-Meier curves were compared, depending on age (<40 or > or =40 years; P = 0.0054), breath test value (delta) 1 month after therapy (<3 or > or =3 per thousand; P = 0.0089), and therapy regimen (high or low efficacy; P = 0.0006). Risk of post-eradication H. pylori recurrence is higher during the first 6 months, which suggests that most recurrences during this period are recrudescences and not true reinfections. Patients who have H. pylori recurrence tend to be younger and have higher delta 13C-urea breath test values after therapy, which suggests that a 'negative' value between 3 per thousand and 5 per thousand needs to be confirmed. Recurrence of H. pylori is more frequent in patients treated with low-efficacy therapies but is exceptional when high-efficacy therapies are used, in which case post-therapy eradication can be safely confirmed at 4 weeks. Finally, recurrence of H. pylori is clinically relevant, as ulcer recurrence is observed in a considerable proportion of these patients.


Kynurenic acid: a new effector of valproate action?
We investigated the changes in hippocampal kynurenic acid (KYNA) concentrations and the amino acids involved in neuronal activity regulation following valproate (VPA) administration (400 mg/kg ip) in pentylenetetrazole-kindled rats (in vivo). We found a remarkably long-lasting increase in KYNA levels following VPA administration, and this effect correlated with a rise in GABA levels. No changes in the concentration of other analyzed amino acids were present. It is likely that the antiepileptic and neuroprotective properties of VPA may also be a consequence of an increase in the hippocampal KYNA concentration.


BCR-ABL oncoprotein is expressed by platelets from CML patients and associated with a special pattern of CrkL phosphorylation.
Constitutive tyrosine phosphorylation of CrkL was recently demonstrated in platelets from chronic myelogenous leukaemia (CML) patients but BCR-ABL tyrosine kinase could not be detected in the platelet lysates. We studied platelets from 14 CML patients with different types of BCR-ABL mRNA and with maximal platelet counts ranging from 149 to 3069 x 10(9)/l. P210BCR-ABL protein was detected by Western blotting in platelet lysates of 12/13 CML patients with active disease but not in the lysate of platelets from a Ph-positive acute lymphoblastic leukaemia (ALL) patient in remission or eight BCR-ABL-negative controls including one essential thrombocythaemia (ET) patient. Immunoblotting of p210BCR-ABL-positive platelets lysates with anti-CrkL antibody revealed a CrkL triplet consisting of one unphosphorylated and two phosphorylated forms of the protein. This CrkL phosphorylation pattern was not observed in normal platelets or CML platelets treated with ABL tyrosine kinase inhibitor CGP57148B. The presence of BCR-ABL provides an explanation for the constitutive tyrosine phosphorylation of CrkL in CML platelets. As no correlation was observed between platelet counts and platelet BCR-ABL protein expression, thrombocytosis or thrombocythaemia in CML cannot be explained by constitutive BCR-ABL-mediated CrkL tyrosine phosphorylation.


The first year after successful cardiac resuscitation: function, activity, participation and quality of life.
To assess cognitive function, activities of daily living (ADL) and living situation longitudinally up to 1 year after cardiac arrest. University hospital. The study continued for 3 years and consecutive patients (18-75 years of age) who survived resuscitation were included. A longitudinal study with examinations using the National Institute of Health Stroke Scale for assessing brain damage, along with the Mini Mental State Examination. To assess ADL, we used the Functional Independence Measure and the Instrumental Activity Measure. Life satisfaction was assessed, together with health-related quality of life. Social status and vocational status were recorded. Mortality was high during the first 90 days (31%). After discharge, not much improvement was seen in cognitive function. This was reflected in reduced dependency in ADL. Work capacity at 1 year was only 13%. The health related quality of life showed great improvement during the first year, being almost the same as for Swedish reference values. Most of the improvement resulting in the independence of ADL occurred during the first 45 days. It is important to give the next of kin information about the patient's progress and need for assistance in order to enable them to plan for the future before discharge.


Cognitive and brain imaging measures of Alzheimer's disease.
Diagnosis of Alzheimer's disease (AD) during life relies upon clinical and neurobehavioral symptoms but is presumptive without microscopic verification of neuropathology. Studies in this review observed considerable heterogeneity in AD symptoms and did not agree on how to detect the earliest symptoms. Problems exist in diagnosis. Differences in symptoms and diagnosis result from how AD is defined neurobehaviorally and on the model used for description. The studies reviewed have been considered under three basic models: A severity (staging) model; a heterogeneity (subtyping) model; and an information processing model. Differences in model intent have resulted in differences in disease description. Brain imaging measures have not invalidated models but add the neural substrate needed to examine correlation of measures within each model.


Rehabilitation in a war zone.
Supported by international partners, Ukraine is building on rehabilitation work initiated by the government prior to the current conflict. Fid Thompson reports.


Examination of inter-rater and intra-rater reliability during retentive force measurement of different clasps using the developed small-sized retentive force measurement device.
The design process of a removable partial denture (RPD) consists of rests, major connectors, minor connectors, denture base, and retainer. The abutment tooth contour determines the location of the retention portion of the clasp at the retention areas. The load capacity of the clasp depends on various factors such as type, the position of a clasp, tooth position, clasp length, and pullout location. As a general rule, the amount of retention required to dislodge the RPD from the supporting structure should always be the minimum necessary to resist reasonable dislodging forces. Excessive force from the clasps may cause many problems. Although there are many reports on the retentive force of cast clasps using large devices, it has not been possible to measure it using simple devices until now. The purpose of the present study is to develop a small-sized retentive force measurement device that can easily measure the retentive force of a clasp used for an RPD. It is to examine inter-rater and intra-rater reliability. A small-sized retentive force measurement device that can be easily measured in the laboratory has been developed. Using commercially available hard plaster cast, a skilled dental technician has made 10 types of cast clasps used in clinical practice using conventional techniques. Three assessors measured the retentive force of 10 types of cast clasps. To confirm the reliability, the intra-class correlation coefficients ICC (1,1) and ICC (1,3) of the 3 assessors were calculated, and the reliability within the assessor was examined. The inter-class correlation coefficients ICC (3,1) and ICC (3,3) were calculated, and the reliability of the assessors was examined. The intra-class correlation coefficients of 3 assessors are as follows: assessor 1 has ICC (1,1) = 0.971, ICC (1,3) = 0.990, assessor 2 has ICC (1,1) = 0.967, ICC (1,3) = 0.989, assessor 3 has ICC (1,1) = 0.962, ICC (1,3) = 0.987. The inter-class correlation coefficients of 3 assessors are as follows: ICC (3,1) = 0.993, ICC (3,3) = 0.998. From the evaluation standard of the intraclass correlation coefficients of reliability value by ICC, it was evaluated as almost perfect and high reproducibility was confirmed. The developed small-sized retentive force measurement device has reproducibility within and between the assessors.


Simulation of water and nitrogen movement mechanism in cold regions during freeze-thaw period based on a distributed nonpoint source pollution model closely coupled water, heat, and nitrogen processes at the watershed scale.
The nitrogen cycle in cold regions during the freeze-thaw period is complex. Although previous studies have investigated the phenomenon of nitrogen transport and transformation, the underlying mechanisms are vague. Existing models have limitations in terms of loose coupling or weak physical mechanisms. Therefore, a new distributed nonpoint source pollution model, the water and energy transfer processes and nitrogen cycle processes model in cold regions, was developed in this study, with closely coupled water, heat, and nitrogen processes at the watershed scale. The model considered the driving effects of pressure, gravity, solute, and temperature potentials on water and nitrogen movement in soil and the transformation relationship among nitrogen forms. Physical evaluation and simulations were conducted for the Heidingzi River Watershed during two freeze-thaw periods: 2017-2018 and 2018-2019. The soil temperature absolute error was < 0.82 ℃. The relative errors in stratified liquid water, soil nitrogen content, river flow rate, and river nitrogen concentration were mostly < 10%. Nitrogen transport with water had an obvious "upward agglomeration effect" during the freezing period and a "concentrated release effect" during the thawing period, which was attributed to changes in soil water potential as the freezing front moved down. Disregarding the effects of solute potential and temperature potential will result in an underestimate of the outflow of pollutants during the thawing period. The model can be applied to reveal water quality deterioration in cold regions during thawing.


Kinetic resolution of alcohols using a 1,2-dihydroimidazo[1,2-a]quinoline enantioselective acylation catalyst.
A new enantioselective acylation catalyst (Cl-PIQ), designed to provide enhanced pi-stacking with benzylic and cinnamyl alcohol substrates, was found to give considerably increased reaction rates and selectivities compared with the first-generation catalyst CF(3)-PIP. [reaction: see text]


Six rounds of annual praziquantel treatment during a national helminth control program significantly reduced schistosome infection and morbidity levels in a cohort of schoolchildren in Zimbabwe.
The World Health Organization recommends that schistosomiasis be treated through Mass Drug Administration (MDA). In line with this recommendation, Zimbabwe commenced a national helminth control program in 2012 targeting schoolchildren throughout the country for 6 years. This study, part of a larger investigation of the impact of helminth treatment on the overall health of the children, determined the effect of annual praziquantel treatment on schistosome infection and morbidity in a cohort of children during Zimbabwe's 6-year national helminth control program. A school-based longitudinal study was carried out in 35 sentinel sites across Zimbabwe from September 2012 to November 2017. The sentinel sites were selected following a countrywide survey conducted in 280 primary schools. Schistosoma haematobium was diagnosed using the urine filtration technique. Schistosoma mansoni was diagnosed using both the Kato-Katz and formol-ether concentration techniques. S. haematobium morbidity was determined through detection of macro and microhaematuria. A cohort of children aged 6-15 years old was surveyed annually before MDA and 6 weeks post treatment. Maximum treatment coverage reached 90% over the 6 rounds of MDA. At baseline S. haematobium infection prevalence and intensity were 31.7% (95% CI = 31.1-32.2) and 28.75 eggs/10ml urine (SEM = 0.81) respectively, while S. mansoni prevalence and intensity were 4.6% (95% CI = 4.4-4.8) and 0.28 eggs/25mg (SEM = 0.02). Prior to the 6th round of MDA, S. haematobium infection prevalence had reduced to 1.56% (p<0.001) and infection intensity to 0.07 (SEM 0.02). Six weeks later after the 6th MDA, both were 0. Similarly the prevalence of S. haematobium morbidity as indicated by haematuria also fell significantly from 32.3% (95% CI = 29.9-34.6) to 0% (p< 0.0001) prior to the final MDA. For S.mansoni, both prevalence and intensity had decreased to 0 prior to the 6th MDA. After 6 rounds of annual MDA, prevalence and intensity of both schistosome species decreased significantly to 0% (p< 0.0001). Zimbabwe's helminth control program significantly reduced schistosome infection intensity and prevalence and urogenital schistosomiasis morbidity prevalence in a cohort of school-aged children, moving the schistosome prevalence in the children from moderate to low by WHO classification. These findings will inform the design of the country's next stage interventions for helminth control and eventual elimination.


Improving behavioral test data collection and analysis in animal models with an image processing program.
Behavioral studies are commonly used as a standard procedure to evaluate anxiety and depression in animal models. Recently, different methods have been developed to improve data collection and analysis of the behavioral tests. Currently available methods, including manual analysis and commercially available products, are either time-consuming or costly. The objective of this study was to improve the collection and analysis of behavioral test data in animal models by developing an image processing program. Eleven behavioral parameters were evaluated by three different methods, including (i) manual detection, (ii) commercially available TopScan software (CleverSys Inc, USA), and (iii) In-housed-developed Advanced Move Tracker (AMT) software. Results obtained from different methods were compared to validate the accuracy and efficiency of AMT. Results showed that AMT software provides highly accurate and reliable data analysis compared to other methods. Less than 5% tolerance was reported between results obtained from AMT compared to TopScan. In addition, the analysis processing time was remarkably reduced (68.3%) by using AMT compared to manual detection. Overall, the findings confirmed that AMT is an efficient program for automated data analysis, significantly enhancing research outcomes through accurate analysis of behavioral test data in animal models.


Pharmacokinetics of cis-dichloro-trans-dihydroxy-bis-isopropylamine platinum IV (CHIP) in patients with advanced cancer.
The pharmacokinetics of a second-generation platinum (Pt) analog cis-dichloro-trans-dihydroxy-bis-isopropylamine platinum IV (CHIP) have been studied in 12 patients at doses from 20 to 350 mg/m2. Three Pt species have been measured: total Pt and non-protein-bound Pt by atomic absorption spectrophotometry, and unchanged CHIP by separation on high-performance liquid chromatography followed by atomic absorption spectrophotometry. Plasma decay of total Pt was biexponential at all doses with a beta-phase half-life of 32.1-124 h. Plasma decay of filterable Pt was monoexponential at low doses but biexponential at high doses, with a terminal-phase half-life of 17.8-54.6 h. Plasma decay of unchanged CHIP was monoexponential at all doses, with a half-life of 0.64-1.27 h. Excretion of Pt after CHIP was rapid up to 10 h after the end of infusion and then slow. The total recovery of Pt was 15%-61% of the dose at 24 h in 19 patients. The data indicated that essentially all plasma Pt after 12 h is in the form of metabolites, most of which are protein-bound. The most striking difference between CHIP and reported data for cisplatin is the biexponential decay of non-protein-bound Pt.


The neural mechanisms of affect infusion in social economic decision-making: a mediating role of the anterior insula.
Though emotions have been shown to have sometimes dramatic effects on decision-making, the neural mechanisms mediating these biases are relatively unexplored. Here, we investigated how incidental affect (i.e. emotional states unrelated to the decision at hand) may influence decisions, and how these biases are implemented in the brain. Nineteen adult participants made decisions which involved accepting or rejecting monetary offers from others in an Ultimatum Game while undergoing functional magnetic resonance imaging (fMRI). Prior to each set of decisions, participants watched a short video clip aimed at inducing either a sad or neutral emotional state. Results demonstrated that, as expected, sad participants rejected more unfair offers than those in the neutral condition. Neuroimaging analyses revealed that receiving unfair offers while in a sad mood elicited activity in brain areas related to aversive emotional states and somatosensory integration (anterior insula) and to cognitive conflict (anterior cingulate cortex). Sad participants also showed a diminished sensitivity in neural regions associated with reward processing (ventral striatum). Importantly, insular activation uniquely mediated the relationship between sadness and decision bias. This study is the first to reveal how subtle mood states can be integrated at the neural level to influence decision-making.


Sonographic predictors of ovarian malignancy.
To identify a combination of sonographic features that best predicts ovarian malignancy. Subjects included 249 women who had a transvaginal sonogram for a pelvic mass at Brigham and Women's Hospital between December 2005 and February 2010. Subjects underwent surgery for removal of the mass and pathologic diagnosis was available. Images were reviewed retrospectively by one sonologist blinded to diagnosis and clinical information. Twelve sonographic features were scored for each mass. The dataset was divided into training (n = 149) and testing (n = 100) sets. Within the training set, a stepwise logistic regression was used to weigh each variable and combination of features to identify those associated with malignancies. Using the results from the logistic regression analyses, we created a three-level risk stratification that was applied to the sonograms of subjects in the testing set to assess its ability to distinguish benign lesions from invasive and borderline cancers. High risk lesions included all masses with internal vascularity. In our testing set, this feature was present in 9 out of 12 (75%) invasive cancers, 1 out of 6 (16.7%) borderline lesions, and 9 out of 82 (11%) benign masses. The intermediate risk level included lesions with a thick wall or thick septa without internal blood flow. This combination of features identified one additional invasive cancer and 5 out of 6 (83.3%) borderline tumors. Masses with low risk features had a 2/49 (4.0%) incidence of malignancy. In the absence of high or intermediate risk sonographic features, the risk of malignancy is low.


The Effect of Whole-Body Cryostimulation in Healthy Adults : Whole-Body Cryostimulation According to Gender and Smoking Status.
Whole-body cryostimulation (WBC) refers to the therapeutic application of extremely cold dry air for a short period of time. The method has beneficial results in various diseases as well as the recovery of athletes. The effects of WBC in healthy individuals have not been extensively investigated. We aim to explore differences in the effects of WBC on blood pressure (BP), oxygen saturation (SpO2), and heart rate (HR) in healthy adults (not athletes) as well as differences according to gender and smoking status. Fifty adults (male/female: 32/18) smokers/nonsmokers: 26/24) were included in the study. WBC was performed in a cryochamber at -85 °C for 3 min. Systolic BP (SBP) and diastolic BP (DBP), HR, and SpO2 were measured before and immediately after WBC. Males and females differed significantly in SBP after WBC (138.1 ± 13.0 vs 128.5 ± 17.0 mmHg, respectively, p = 0.029), SpO2 after WBC (96.6 ± 1.8 vs 98.3 ± 1.5%, respectively, p = 0.001) and HR after WBC (60.1 ± 9.6 vs 70.2 ± 7.7 bpm, respectively, p < 0.001). In males, SpO2 remained unchanged before and after WBC, whereas in women SpO2 increased by 1.0 ± 1.4% (p = 0.038) (Table 2). HR after WBC displayed a downward trend by -9.8 ± 5.9% in males compared to an upward trend by 3.6 ± 15.1 in females (p < 0.001). Nonsmokers displayed higher increase in SBP after WBC (4.3 ± 9.0% in smokers compared to 13.3 ± 13.2% in nonsmokers, p = 0.007). Smokers presented an increase by 1.0 ± 1.6% in SpO2, while in nonsmokers, SpO2 decreased by 0.8 ± 2.1% following WBC (p = 0.001). Our results suggest that WBC affects the cardiovascular and the respiratory system differently in males versus females and smokers versus nonsmokers. More studies are needed in order to fully explore the effects of WBC in these population groups in order to design individualized treatment protocols.


Switch to biological agent in psoriasis significantly improved clinical and patient-reported outcomes in real-world practice.
Although clinical studies have shown efficacy of biological agents in moderate to severe psoriasis, observational studies of real-world effectiveness are rare. To analyse the psoriasis area and severity index (PASI) and quality of life by the EQ-5D questionnaire and dermatology quality of life index (DLQI) in psoriasis patients who switched from conventional systemic treatment to biological agents in clinical practice. Furthermore, to analyse patient groups with the highest benefit of biological agents. Longitudinal, observational study based on the Swedish National Registry for Systemic Treatment of Psoriasis, PsoReg. Outcomes of biological-naïve patients who switched to a biological agent (n = 267) were analysed before switch and at the first follow-up. Patients significantly improved in EQ-5D, DLQI and PASI (p < 0.001). Patients with DLQI ≥10 and/or PASI ≥10 had the greatest benefits from biological agents in terms of EQ-5D. Patients with moderate to severe psoriasis benefit from biological agents in clinical practice; the patients with the highest benefits were those with high pretreatment PASI and DLQI scores.


Patient exposure and radiation environment of an extracorporeal shock wave lithotriptor system.
Radiation exposures to the patient undergoing extracorporeal shock wave lithotripsy were assessed along with the scattered radiation levels around the lithotriptor systems. The data gathered from 2 Dornier lithotriptor systems suggest that the lead shieldings required for this particular make and model are minimal. Owing to the physical size of the lithotriptor system, the treatment room housing it may not require additional lead shielding when the walls are constructed with appropriate materials. Typical radiation exposures to the patient have been assessed from the experimental data. The total amount of radiation exposures a patient is likely to receive has been estimated to be approximately 26 roentgens, for example 21 roentgens from 3 to 4 minutes of fluoroscopic exposure and 5 roentgens from 8 frames of video spot filming. The scattered radiation has been found to be approximately 0.5 mR. per hour at 3 feet or 91 cm. from the center of the lithotriptor water tank.


The specificity of antibody in chickens immunised to reduce intestinal colonisation with Campylobacter jejuni.
Poultry consumption has been identified as a major risk factor for human infection with Campylobacter jejuni in developed countries. C. jejuni is present in the gastrointestinal tract of broiler chickens at the time of slaughter, and faecal contamination of carcases during processing results in significant campylobacter loads on carcases. One approach to reducing the level of carcase contamination with C. jejuni is to control campylobacter infection in broiler chickens. To this end, the study described here investigated the specificity of antibody in serum and intestinal secretions of chickens that had been immunised with campylobacter antigens and then challenged with viable bacteria. The immunodominant antigens in the serum of birds that showed a 2-log reduction in caecal colonisation with C. jejuni included flagellin protein (61-63 Kd) and three additional antigens of 67, 73.5 and 77.5 Kd. Only flagellin and the 67 Kd antigen were recognised by IgG antibody in gastrointestinal secretions of the same birds. Antibody from chickens immunised with purified native flagellin protein recognised flagellin protein and the 67 Kd antigen in Western blots probed with serum, but only the flagellin proteins (61-63 Kd) in Westerns probed with gastrointestinal secretions. Analysis of the specificity of the response to flagellin protein using recombinant clones that expressed regions of the flagellin gene suggests that epitopes in each region of the flagellin protein were immunogenic. Of the immunodominant antigens, only flagellin appeared to be surface-exposed on viable C. jejuni, although conformational epitopes of flagellin appeared to be sensitive to the method of antigen purification. The results of this study suggest that flagellin and possibly the 67 Kd antigen may be valuable for immunological control of intestinal infection with C. jejuni in chickens, but that further work is required to purify these as vaccine candidates by using methods that preserve conformational epitopes.


Soluble and cellular markers of immune activation in patients with systemic sclerosis.
The peripheral blood lymphocyte pattern, the lymphocyte responses in vitro, as well as the soluble markers of immune activation were studied in 24 patients with systemic sclerosis (SSc patients). The proportions of total T cells (CD3), their CD4 subset, as well as B lymphocytes were within the normal range. The relative proportion of CD8 lymphocytes, however, was significantly reduced. Patients with SSc had a slightly lower percentage of CD4/4B4+ cells, whereas their proportion of CD4/2H4+ cells was elevated as compared to healthy controls. The proportion of lymphocytes expressing the interleukin-2 receptor (IL-2R) was significantly higher in SSc patients. The proliferative responses of peripheral blood mononuclear cells to PHA stimulation were reduced in the patient group, while expression of IL-2R on lymphocytes after such in vitro stimulation was comparable to that of controls. Expression of IL-2R on patient but not control lymphocytes was increased after in vitro exposure to laminin. Such exposure failed to induce IL-2 production or cell proliferative responses. Soluble plasma IL-2R level (sIL-2R) and soluble CD8 (sCD8) molecule levels in SSc patients were significantly elevated. These results indicate the presence of an ongoing lymphocyte activation in this disease process.


Techniques for registration of myoelectric activity of women's pelvic floor muscles: a scoping review protocol.
The objective of this review is to identify the most frequently used protocols for analyzing the myoelectric activity of the pelvic floor muscles during surface electromyography in women aged 18 years or older. Surface electromyography is normally used in assessment and treatment for research purposes when it is intended to quantitatively measure the electrophysiological behavior of the neuromuscular system. However, although there are internationally standardized, non-invasive assessment protocols for most muscle groups, there is no consensus for pelvic floor muscles, which makes it difficult to standardize in scientific research and clinical applicability. Studies that explore registration protocols and filtering parameters of surface electromyographic signals in women aged over 18 years old with or without pelvic floor dysfunction will be considered. Studies encompassing either electromyographic biofeedback as a treatment resource only or electroneuromyography (needle electrode) will be excluded. Primary studies published in the previous 10 years in MEDLINE, Embase, Scopus, Web of Science, CINAHL, and Cochrane Central databases will be included. The search will encompass descriptors registered in MeSH. The identified articles will be assessed for eligibility by two independent reviewers in three stages: evaluation by title, abstract, and full text. If there is any disagreement, a third reviewer will be consulted. Data will be extracted and organized in standardized spreadsheets. The results will be assigned to categories in order to facilitate the organization of a protocol with the most commonly used parameters for non-invasive assessment of myoelectric activity of pelvic floor muscles.


Identification of factors associated with non-adherence to recommended COVID-19 preventive behaviours: a cross-sectional study based on a survey among 1004 French primary care professionals.
Since the beginning of the COVID-19 pandemic, adherence to preventive behaviours to limit virus spread has been a major issue. The study objective was to identify factors associated with non-adherence to preventive behaviours among general practitioners (GPs) during the COVID-19 pandemic using data from a questionnaire completed during the French National Congress of General Medicine in June 2021. This descriptive study relied on data collected with a questionnaire during the national congress on general medicine in Bordeaux, France, from 16-18 June 2021. The study was conducted in primary care in France. Out of a total of 1004 GPs and GP trainees, 755 completed the questionnaire during conferences and 249 were contacted by mail. The questionnaire included questions on sociodemographic characteristics and COVID-19 related preventive behaviours, beliefs and experiences. Answers to questions that explored the Health Belief Model components were selected and then compared among participants who reported appropriate preventive behaviours (wearing face masks and social distancing) and participants who reported non-adherence. Analysis was based on multivariate logistic regression.The responders' mean age was 35.8 years; 61.64% were women, 61.9% were practising GPs and 37.2% were GP trainees. Moreover, 96.6% of participants had completed the COVID-19 vaccination schedule. Non-adherence (reported by 72/1004 participants) was more frequent among smokers (OR=2.57, 95% CI 1.29 to 4.83, p=0.005) and younger participants (OR=0.95, 95% CI 0.92 to 0.98, p=0.005). Complete COVID-19 vaccination or a previous infection was not associated with non-adherence and has been poorly described. More studies are needed to confirm the factors involved in the adoption of COVID-19 preventive behaviours by healthcare professionals and to explore the beliefs and barriers to the adoption of these behaviours.


Habitat quality assessment of wintering migratory birds in Poyang Lake National Nature Reserve based on InVEST model.
Poyang Lake National Nature Reserve (PLNNR) is an important resting place for wintering migratory birds on the East Asian-Australasian Flyway (EAAF). In recent years, due to human activities and climate change, the area of wetlands has shown a downward trend, and the number and habitat of wintering migratory birds have been threatened. It is urgent to evaluate the habitat quality of wintering migratory birds in PLNNR. Therefore, the InVEST model and landscape index were used to evaluate the habitat quality of wintering migratory birds, and the grey correlation theory was used to reveal the response of typical wintering migratory bird population to habitat quality. The results showed that the habitat quality of the PLNNR was still at a high level, but showed a downward trend, with the average index of habitat quality decreasing from 0.872 to 0.817. The area of the highest quality habitat decreased by 3394.92 hm2, the area of the lowest, low, and medium quality habitats increased by 3112.11 hm2, and the area of the high quality habitat remained stable. The lowest, low, and medium quality habitat expanded from the middle to the south of the PLNNR mainly because of the expansion of construction land and cultivated land. The area with deterioration in habitat quality was 10,477.53 hm2, mainly concentrated in the center and south of the PLNNR. The area with restoration in habitat quality was 6148.26 hm2, mainly concentrated in the Bang Lake and Dacha Lake. The area with no change in habitat quality remained stable. The fragmentation degree and shape complexity of highest and high quality habitats increased, dominance degree and connectivity decreased, and the landscape pattern of habitat quality showed a downward trend. Typical wintering migratory birds have a strong correlation with highest, high, and low habitat quality, and there is a downward trend with the deterioration of habitat quality. Finally, this paper puts forward constructive suggestions on the degradation of habitat quality caused by land-use change.


Knowledge and practice in mental health nursing care.
To understand mental health nursing care based on the concept of the subject of the unconscious proposed by Lacan. A narrative study was carried out with 19 nurses, chosen based on their theoretical approach or referral by other participants, through the snowball sampling technique. The interviews were carried out in person or digitally, and were recorded and fully transcribed. The analysis was carried out based on Freudian and Lacanian psychoanalysis, approaching nursing care as it acts on the body, secretions, and excretions, to distinguish it from the spirit of fineness. Effects on care are discussed, considering the subject of the unconscious with its knowledge, creating unique exits (sinthome). In this situation, professionals are required to abstain from a position of knowing what is better for the Other. This nursing care perspective offers contributions when discussing the centrality of the subject and words in the care process. Compreender o cuidado de enfermagem em saúde mental a partir da concepção de sujeito do inconsciente proposta por Lacan. Pesquisa narrativa, realizada com 19 enfermeiros, determinados por meio de abordagem teórica ou indicação de outro participante, pela técnica de snowball. As entrevistas foram realizadas pessoalmente ou por meio digital, gravadas e transcritas na íntegra. Da análise, fundamentada na psicanálise freudiana e lacaniana, tomou-se o cuidado de enfermagem em seus atos sobre o corpo, suas secreções e excreções, para localizá-lo a partir do espírito de fineza. Discutem-se os efeitos para o cuidado quando se considera o sujeito do inconsciente com seu saber construindo saídas únicas - Sinthoma. Essa condição requer do profissional abster-se de uma posição de saber o que é melhor para o outro. Essa perspectiva de cuidado de enfermagem traz contribuições ao problematizar a centralidade do sujeito e da palavra nas práticas de cuidado.


Time-threshold curve determined by single photon emission CT in patients with acute middle cerebral artery occlusion.
In patients with ischemic stroke, not only the degree of ischemia but also its duration are key determinants of tissue survival. The purpose of this study was to show the synergistic effects of these two factors on tissue survival in humans. We retrospectively reviewed findings in 19 patients with middle cerebral artery occlusion who had clearly defined ischemic duration from onset to angiographic complete recanalization and who underwent pretreatment single photon emission CT. Pretreatment single photon emission CT and final CT scans were compared, and hypoperfusion cortices were divided into reversible and irreversible ischemia. Regions of interest were placed in both irreversible and reversible ischemic cortices, and the residual cerebral blood flow was analyzed by side-to-side comparison with a calculated asymmetry index. To show the relationship between the reversibility of ischemia and the ischemic duration/severity, discriminant analyses were conducted. The analyses were conducted separately using data obtained within 3 hours of ischemic duration and data obtained more than 3 hours after ischemic duration. Within 3 hours of ischemic duration, analysis revealed a discriminant line of asymmetry index (%) = 21.53 time (h) - 19.15. After more than 3 hours of ischemic duration, it revealed a discriminant line of asymmetry index = 0.50 time + 48.27. These discriminant lines rose rapidly within the first 3 hours after stroke onset and thereafter reached almost a plateau level. These pilot data suggest urgency for treatment, less need for triage based on cerebral blood flow measurement during the first few hours, and more time to triage based on cerebral blood flow measurement for patients with later presentations.


Segmentation of vestibular schwannoma from MRI, an open annotated dataset and baseline algorithm.
Automatic segmentation of vestibular schwannomas (VS) from magnetic resonance imaging (MRI) could significantly improve clinical workflow and assist patient management. We have previously developed a novel artificial intelligence framework based on a 2.5D convolutional neural network achieving excellent results equivalent to those achieved by an independent human annotator. Here, we provide the first publicly-available annotated imaging dataset of VS by releasing the data and annotations used in our prior work. This collection contains a labelled dataset of 484 MR images collected on 242 consecutive patients with a VS undergoing Gamma Knife Stereotactic Radiosurgery at a single institution. Data includes all segmentations and contours used in treatment planning and details of the administered dose. Implementation of our automated segmentation algorithm uses MONAI, a freely-available open-source framework for deep learning in healthcare imaging. These data will facilitate the development and validation of automated segmentation frameworks for VS and may also be used to develop other multi-modal algorithmic models.


Tradeoffs between phenotypic plasticity and local adaptation influence the ecophysiology of the moss, Sphagnum magellanicum.
Bryophytes are a diverse plant group and are functionally different from vascular plants. Yet, their peculiarities are rarely considered in the theoretical frameworks for plants. Currently, we lack information about the magnitude and the importance of intraspecific variability in the ecophysiology of bryophytes and how these might translate to local adaptation-a prerequisite for adaptive evolution. Capitalizing on two ecologically distinct (hummock and hollow) phenotypes of Sphagnum magellanicum, we explored the magnitude and pattern of intraspecific variability in this species and asked whether the environmental-mediated changes in shoot and physiological traits are due to phenotypic plasticity or local adaptation. Size, pigmentation, and habitat type that distinguished the phenotypes in the field did not influence the trait responses under a transplant and factorial experiment. In addition, the magnitude and pattern of trait variability (e.g., branch, stem and capitulum mass) changed with the treatments, which suggest that trait responses were due largely to phenotypic plasticity. The trait responses also suggest that the ecophysiological needs for mosses to grow in clumps, where they maintain a uniform growth may have an overriding effect over the potential for a fixed adaptive response to environmental heterogeneity, which would constrain local adaptation. We conclude that extending the trait-based framework to mosses or making comparisons between mosses and vascular plants under any theoretical framework would only be meaningful to the extent that growth form and dispersal strategies are considered.


Organizing emotions in health care.
To introduce the articles in this special issue, discussing emotion in the in health-care organisations. Discusses such topics as what makes health care different, editorial perspectives, how health care has explored emotion so far, and the impact of emotion on patients and the consequences for staff. Health care provides a setting that juxtaposes emotion and rationality, the individual and the body corporate, the formal and the deeply personal, the public and the private, all of which must be understood better if changes in expectations and delivery are to remain coherent. The papers indicate a shared international desire to understand meaning in emotion that is now spreading across organizational process and into all professional roles within health care.


Ontogeny of a new enteric peptide, neuropeptide W (NPW), in the developing rat stomach.
Neuropeptide W (NPW), a novel endogenous peptide for G protein-coupled receptors GPR7 and GPR8, is expressed in the gastric antral mucosa of rat, mouse, and human stomachs. Here, we studied the ontogeny of NPW in the developing rat stomach. Real-time RT-PCR showed that NPW gene expression was initially detectable in embryonic day 14 (E14) stomach and gradually increased during the progress of age until birth, postnatal day 1 (P1). NPW mRNA level in the stomach increased again from the weaning period (P21) until reaching adulthood. Immunohistochemistry using polyclonal antibodies raised against rat NPW revealed that NPW-positive cells were detected in the P1 antral stomach and gradually increased during the development of age. Furthermore, double immunohistochemistry demonstrated that NPW colocalized with gastrin in P1 rat stomach. These data will provide clues to physiological functions of NPW in the development of rat stomach.


Central administration of a caspase inhibitor impairs shuttle-box performance in rats.
Recent studies suggest that caspase-3-mediated mechanisms are essential for neuronal plasticity. N-benzyloxycarbonyl-Asp(OMe)-Glu(OMe)-Val- Asp(OMe)-fluoromethyl ketone (z-DEVD-fmk), a caspase inhibitor with predominant specificity toward caspase-3, has been shown to block long-term potentiation in hippocampal slices. Intrahippocampal infusion of a caspase-3 inhibitor to rats has been shown to significantly impair spatial memory in the water maze. The present work was designed to study whether i.c.v. administration of a caspase-3 inhibitor z-DEVD-fmk impairs learning in other tasks related to specific forms of memory in rats. The rats received bilateral injections of z-DEVD-fmk or N-benzyloxycarbonyl-Phe-Ala-fluoromethyl ketone (z-FA-fmk) ("control" peptide) at a dose of 3 nmol. Administration of z-DEVD-fmk significantly decreased the number of avoidance reactions in some blocks of trials in the active avoidance (shuttle box) learning, while z-FA-fmk had no effect as compared with intact rats. However, only a slight effect of the caspase inhibitor across the session was found. z-DEVD-fmk impaired development of some essential components of the two-way active avoidance performance, such as escape reaction, conditioned fear reaction, and inter-trial crossings. Measurement of caspase-3 activity in rat brain regions involved in active avoidance learning revealed most expressed z-DEVD-fmk-related inhibition of the enzyme activity (about 30%) in the fronto-parietal cortex. A similar effect was close to significant in the hippocampus, but not in the other cerebral structures studied. In primary cultures of cerebellar neurons z-DEVD-fmk (2-50 microM) inhibited caspase-3 activity by 60-87%. We suggest that moderate inhibition of caspase-3 resulting from the central administration of z-DEVD-fmk to rats may impair active avoidance learning. Taking into account previous data on the involvement of neuronal caspase-3 in neuroplasticity phenomena we assume that the enzyme may be important for selected forms of learning.


ACE inhibitor quinapril reduces the arterial expression of NF-kappaB-dependent proinflammatory factors but not of collagen I in a rabbit model of atherosclerosis.
Increasing evidence supports an association between inflammation and plaque rupture. Macrophages and vascular smooth muscle cells are a source of cytokines and growth factors, which contribute to ongoing inflammation during atherogenesis. In a rabbit model of atherosclerosis, we evaluated the effect of the ACE inhibitor quinapril on different parameters implicated in the pathogenesis of the plaque, such as the presence of chemokines (interleukin-8, monocyte chemoattractant protein-1), collagen I, and vascular smooth muscle cell proliferation (PDGF-B). Since nuclear factor kappaB (NF-kappaB) has been implicated in the control of chemokine transcription and cell proliferation, we also investigated its activation and localization in the lesion. Quinapril administration for 28 days caused a down-regulation in arterial expression of interleukin-8 and monocyte chemoattractant protein-1 (mRNA and protein). However, collagen I expression (mRNA and protein) was not modified. PDGF-B expression was reduced in both the intima and the media. Active NF-kappaB, found in both macrophages and vascular smooth muscle cells, was also reduced by quinapril. Nevertheless, no significant changes were noted in the mild neointima formation, although a certain trend toward normalization was found in the quinapril-treated group. In conclusion, our results show that quinapril treatment attenuates several parameters associated with inflammation within the atherosclerotic lesions that are controlled by NF-kappaB, although it has no effect on collagen I expression. Both effects could contribute to the stabilization of the atherosclerotic plaque.


Dysregulated circular RNAs as novel biomarkers in esophageal squamous cell carcinoma: a meta-analysis.
Circular RNAs (circRNAs) play critical roles in tumorigenesis, but their clinical efficacy in esophageal squamous cell carcinoma (ESCC) still retains controversial. This meta-analysis aims at evaluating the associations between circRNA expressions and clinicopathologic features as well as the diagnostic and prognostic values of circRNAs in ESCC. PubMed, EMBASE, and other online databases were systematically searched to collect studies on circRNAs and clinicopathological features, diagnostic, and/or prognostic assessments of ESCC. The quality of included studies was evaluated using the Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2) and Newcastle-Ottawa Scale (NOS) scales. The included studies were quantitatively weighted and merged, and diagnostic indicators, hazard ratios (HRs) and the corresponding 95% confidence intervals (CIs) were calculated. P values were merged by Fisher᾽s method. Sources of heterogeneity were traced using subgroup, sensitivity, and meta-regression analyses. As a result, 12 studies were included, representing 769 ESCC patients. The meta-analysis showed that abnormal expressions of circRNAs were associated to TNM stage as well as lymph node and distant metastases in ESCC cases. CircRNA was used to distinguish ESCC patients from healthy controls, and the merged sensitivity, specificity, and the area under the curve (AUC) of ESCC were 0.78 (95% CI: 0.74-0.81), 0.79 (95% CI: 0.75-0.83), and 0.86, respectively. The survival analysis showed that upregulated oncogenic circRNA levels in ESCC tissues was associated with the shorter overall survival (OS) of the patients (univariate analysis: HR = 2.25, 95% CI: 1.71-2.95, p = 0.000, I2 = 0.0%; multivariate analysis: HR = 2.50, 95% CI: 1.61-3.89, p = 0.000, I2 = 0.0%), while the OS of ESCC patients presenting overexpressions of tumor-suppressive circRNAs was significantly ameliorated (HR = 0.29, 95% CI: 0.20-0.42, p = 0.000, I2 = 0.0%). The subgroup analyses based on circRNA biofunctions, sample size, and reference gene also revealed robust results. CircRNAs can be used as promising molecular biomarkers for the early diagnosis and prognosis monitoring of ESCC.


Age-dependent change of the effect of a cytostatic drug on the proliferation kinetics of a solid tumor of the mouse.
The aim of the present investigations was to study the effectiveness of a cytostatic drug (VCR) during different phases of tumor growth (1st, 7th, 14th days a.t.) and at the periphery and at the centre of the tumor (on the 14th day a.t.). Furthermore the inducement of a partial synchronization in the proliferation of tumor cells was attempted. It was found that the intensity of the cytostatic effect significantly decreased both with the passage of time after transplantation and within the tumor from the periphery to the centre. The changing cytostatic sensitivity probably is due to the diminishing vascular supply and the decreased rate of cell proliferation; especially the decline of the growth fraction. A partial synchronization of the proliferation of tumor cells could not be demonstrated.


Comparative proteome analysis of Chlamydia trachomatis serovar A, D and L2.
Chlamydia trachomatis represents a group of human pathogenic obligate intracellular and gram-negative bacteria. The genome of C. trachomatis D comprises 894 open reading frames (ORFs). In this study the global expression of genes in C. trachomatis A, D and L2, which are responsible for different chlamydial diseases, was investigated using a proteomics approach. Based on silver stained two-dimensional polyacrylamide gel electrophoresis (2-D PAGE), gels with purified elementary bodies (EB) and auto-radiography of gels with 35S-labeled C. trachomatis proteins up to 700 protein spots were detectable within the range of the immobilized pH gradient (IPG) system used. Using mass spectrometry and N-terminal sequencing followed by database searching we identified 250 C. trachomatis proteins from purified EB of which 144 were derived from different genes representing 16% of the ORFs predicted from the C. trachomatis D genome and the 7.5 kb C. trachomatis plasmid. Important findings include identification of proteins from the type III secretion apparatus, enzymes from the central metabolism and confirmation of expression of 25 hypothetical ORFs and five polymorphic membrane proteins. Comparison of serovars generated novel data on genetic variability as indicated by electrophoretic variation and potentially important examples of serovar specific differences in protein abundance. The availability of the complete genome made it feasible to map and to identify proteins of C. trachomatis on a large scale and the integration of our data in a 2-D PAGE database will create a basis for post genomic research, important for the understanding of chlamydial development and pathogenesis.


Thienopyrimidine derivatives prevent cartilage destruction in articular disease.
The effects of a series of thienopyrimidine derivatives on the prevention of cartilage destruction in articular disease were investigated. Anti-degenerative activity was assayed on culture of nasal pig cartilage in the presence or in the absence of interleukin 1beta (IL-1beta). The amount of glycosaminoglycans (GAGs) and the production of nitric oxide (NO) in the culture medium were determined. Some thienopyrimidine derivatives, in the presence of IL-beta, blocked the cartilage breakdown by inhibiting both the NO production and GAGs release in a dose-dependent manner.


Comparative evaluation of five plant extracts and juices for nanoiron synthesis and application for hexavalent chromium reduction.
The effectiveness of five plant extracts and juices, i.e. extracts of Camellia sinensis (green tea, GT), Syzygium aromaticum (clove, CL), Mentha spicata (spearmint, SM), Punica granatum juice (pomegranate, PG) and Red Wine (RW), for the production of nanoiron suspensions and their application for Cr(VI) reduction was investigated. Polyphenols contained in extracts act as reducing agents for iron ions in aqueous solutions, forming thus iron nanoparticles, and stabilize the nanoparticles produced from further oxidation and agglomeration. The maximum amount of polyphenols extracted per g of herbs was obtained at herb mass to water volume ratio varying from 10 to 20g/L. Suspensions of nanoparticles with sizes below 60nm were produced by mixing iron chloride solution with the plant extracts and juices investigated. The maximum concentration of nanoiron in suspensions was estimated to 22mM, obtained using RW and PG at a mixing ratio of iron solution to extract equal to 2. Lower concentrations, up to 18mM, were achieved using GT and CL extracts. Therefore, PG juice and RW were considered as more effective for nanoiron production, and, together with GT extracts, they were selected for the production of nanoiron suspensions, which have been proven effective for Cr(VI) reduction, reaching removal capacity as high as 500mg Cr(VI) per g of iron in nanoparticles.


Validity of the visual analogue scale as an instrument to measure self-efficacy in resuscitation skills.
Self-efficacy is an important factor in many areas of medical education, including self-assessment and self-directed learning, but has been little studied in resuscitation training, possibly because of the lack of a simple measurement instrument. We aimed to assess the validity of a visual analogue scale (VAS) linked to a single question as an instrument to measure self-efficacy with respect to resuscitation skills by comparing the VAS with a questionnaire and using known-groups comparisons. We developed questionnaires to measure self-efficacy for a number of resuscitation tasks and for computer skills. These were compared with VASs linked to a single question per task, using a multi-trait, multi-method matrix. We also used known-groups comparisons of self-efficacy in specific professional groups. There was good correlation between the questionnaires and the VASs for self-efficacy for specific resuscitation tasks. There was a less clear correlation for self-efficacy for paediatric resuscitation overall. There was no correlation between self-efficacy for resuscitation and computer tasks. In specific professional groups, measured self-efficacy accorded with theoretical predictions. A VAS linked to a single question appears to be a valid method of measuring self-efficacy with respect to specific well defined resuscitation tasks, but should be used with caution for multi-faceted tasks.


The correlation of cyclic AMP and protein kinase activity in adipocytes with lipolysis stimulated by ACTH: the effect of adenosine deaminase and actinomycin D.
ACTH at levels as low as 0.05 mU/ml stimulated lipolysis, protein kinase and cyclic AMP accumulation in isolated fat cells from fed and fasted rats. Changes in cyclic AMP levels and in the protein kinase activity ratio were well correlated temporally. The protein kinase activity ratio was potentiated by adenosine deaminase. A sudden increase or decrease in either ACTH or dibutyryl cyclic AMP concentration was associated with a rapid and corresponding change in the rate of glycerol production. With ACTH, the changes in glycerol production were accompanied by appropriate changes in cyclic AMP levels. Actinomycin-D (10 UM) did not affect lipolysis or cyclic AMP accumulation activated by ACTH in fat cells.


Termination of paroxysmal supraventricular tachycardia by digital rectal massage.
A 71-year-old woman with an episode of paroxysmal supraventricular tachycardia (PSVT) complicated by angina pectoris and hypotension had her arrhythmia abruptly terminated by digital rectal massage (DRM) after other vagotonic maneuvers had failed. DRM termination of PSVT has not been heretofore reported. In treating PSVT by physical vagotonic maneuvers, DRM may be preferable to other techniques because of the decreased likelihood of complications noted with other such maneuvers.