4-Hydroxyandrostenedione is not an aromatase inhibitor in the neonatal guinea pig.
One-day-old newborn guinea pigs were treated with 4-hydroxyandrostenedione (50 mg/kg body weight/day) for 5 or 12 consecutive days. This compound did not decrease unconjugated or sulfoconjugated estradiol and estrone levels in the plasma or in the uterine tissue itself. It also did not have any effect on uterine wet weight or the estrogen and progesterone receptor concentrations in the uterus. Moreover, progesterone receptor synthesis which is maintained when neonatal uteri are placed in organ culture conditions for 2 days was not affected by the 4-hydroxyandrostenedione treatment.


Association of circulating calprotectin with lipid profile in axial spondyloarthritis.
Calprotectin (CPT) is released during inflammation, also in the context of atherosclerosis. The link between CPT and the atherosclerotic process was evaluated in several diseases. However, studies in axial spondyloarthritis (axSpA), associated with a high incidence of subclinical atherosclerosis, are scarce. Therefore, we assessed the association of CPT with subclinical atherosclerosis and metabolic risk factors in axSpA. CPT serum levels were measured by enzyme-linked immunosorbent assay in 163 axSpA patients and 63 controls. Subclinical atherosclerosis was determined in patients by carotid ultrasonography (assessing the presence/absence of carotid plaques and carotid intima-media thickness [cIMT]). Data on inflammation, disease activity, lipid profile and treatment were collected to evaluate its relationship with CPT. axSpA patients evidenced lower CPT levels than controls. CPT showed no association with plaques or cIMT in axSpA. CPT and HDL-cholesterol negatively correlated, while a positive association of CPT with the atherogenic index was disclosed. Additionally, axSpA patients with C-reactive protein values at diagnosis higher than 3 mg/L displayed higher CPT levels. Our study shows no relationship between CPT and markers of subclinical atherosclerosis in axSpA. Nevertheless, it demonstrates an association of CPT with adverse lipid profiles and inflammatory biomarkers, which could further influence on the development of atherosclerosis.


"It doesn't really apply to what I'm going through": a mixed-methods study of barriers to palliative care among patients with advanced ovarian cancer.
Palliative care aims to provide symptom relief and general support for patients with serious illness. Despite experiencing significant treatment side effects, specialty palliative care is under-utilized by patients with advanced ovarian cancer. We explored barriers to palliative care in this population. We conducted a sequential mixed-methods study. Qualitative: we interviewed patients with advanced ovarian cancer (N = 7). Guided by the Social Ecological Model (SEM), interviews assessed intrapersonal, interpersonal, organizational, and policy-level barriers to receipt of specialty palliative care. Interviews were audio-recorded, transcribed, and analyzed with directed content analysis. Quantitative: patients with advanced ovarian cancer (N = 38) completed self-report surveys assessing knowledge about, attitudes towards, and prior experiences with specialty palliative care. Descriptive statistics were used to characterize survey responses. Qualitative analysis identified barriers to specialty palliative care at each SEM level. Intrapersonal factors (e.g., knowledge, attitudes) were most frequently discussed. Other common barriers included insurance coverage and distance/travel time. Survey responses indicated most participants were aware of palliative care (74%) but had mixed attitudes towards palliative care and did not feel they needed for palliative care. No survey respondents had received a physician recommendation for palliative care, and a sizable minority (29%) thought palliative care referral should only take place when patients have no remaining treatment options. Among patients with advanced ovarian cancer, barriers to specialty palliative care exist at multiple levels. Our results underscore the potential value of a multilevel intervention to support receipt of palliative care in this population.


Contribution of plasma, placental, inflammatory and pro-resolving mediators in labor induction.
The onset of labor is regulated by endocrine, nervous and immunological factors. This study was designed to determine the inflammatory and pro-resolving mediator levels in plasma and placenta of women undergoing labor induction in late-term pregnancy. Healthy pregnant women admitted for delivery or labor induction were included. TNF, IL-1β, IL-6, IL-8, and IL-10 were quantified by ELISA in plasmatic and placental samples and Annexin A1 (ANXA1) in the placenta by Western Blotting, and immunofluorescence to CD15+ antibody. The data were analyzed using the Wilcoxon test and Spearman correlation. The p-value was significant when <0.05. There was a higher concentration of IL-8 was found in the amniotic plaque (p = 0.042) and IL-10 (p < 0.001) in the trophoblast of patients with spontaneous labor. Greater ANXA1 density in the trophoblast was also observed in those with induction failure. There was a positive correlation of ANXA1 density in trophoblast induction duration with (r = 0.580) and with the IL-6 level in amniotic plaque (r = 0.517), and a positive correlation between labor duration and density of ANXA1 was identified in the trophoblast (r = 0.419). An increase was identified in CD15+ cell immunocapturing among the groups with spontaneous labor compared to the group with induction failure (p < 0.001). The inflammatory process in labor involves both maternal and fetal participation. Induction failure is associated with higher levels of ANXA1 in the trophoblast.


Smoking and Its Association With Morbidity in Systemic Lupus Erythematosus Evaluated by the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index: Preliminary Data and Systematic Review.
Due to the increased availability of effective treatments, patients with systemic lupus erythematosus (SLE) now have longer survival times, and factors involved in cumulative chronic damage in SLE need to be better understood. This study was undertaken to evaluate the relationship between smoking and cumulative chronic damage in SLE patients. A cross-sectional study of SLE patients was performed to investigate the possible association between smoking exposure (ever [previous or current, active or secondhand smokers] or never) and cumulative chronic damage as measured by the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI). A systematic review of the literature was conducted by cross-searching Medline for the terms lupus and smoking. We enrolled 105 patients with SLE (96% female), with a mean ± SD age of 40.7 ± 11.4 years and a mean followup time of 8.98 years. Of the 105 patients, 74 had an SDI score of 1-10, and 31 had an SDI score of 0. The difference between smoking exposure and no smoking exposure was significant (P = 0.02 by chi-square test in contingency table analysis), and SLE patients who were never exposed to smoking had 0.78 times the risk of progressing toward a cumulative damage status (SDI score of > 0) (95% confidence interval 0.16-0.98) throughout the followup period compared to those who were ever exposed. In the systematic review of the literature, we found only a small number of articles that addressed some aspects of the relationship between smoking exposure and cumulative damage in SLE patients. Our findings indicate that smoking exposure is associated with cumulative chronic damage, as determined by the SDI score, in patients with SLE. Smoking exposure may have deleterious effects on lupus morbidity, and more detailed studies of this association are needed.


Longer-Term Anti-VEGF Therapy Outcomes in Neovascular Age-Related Macular Degeneration, Diabetic Macular Edema, and Vein Occlusion-Related Macular Edema: Clinical Outcomes in 130 247 Eyes.
The clinical practice visual acuity (VA) outcomes of anti-VEGF therapy for up to 5 years were assessed in patients with neovascular age-related macular degeneration (nAMD), diabetic macular edema (DME), branch retinal vein occlusion-related macular edema (BRVO-ME), and central retinal vein occlusion-related macular edema (CRVO-ME). A retrospective analysis was performed using the Vestrum Health Retina Database. Treatment-naive patients with nAMD, DME, BRVO-ME, or CRVO-ME who received anti-VEGF injections between 2014 and 2019 and had follow-up data for ≥12 months. Data on age, sex, the number of anti-VEGF treatments, and VA were analyzed. Mean VA change up to 3 years (BRVO-ME and CRVO-ME) and 5 years (nAMD and DME). At 1, 3, and 5 years, in 67 666, 21 305, and 5208 eyes with nAMD, after a mean of 7.6, 19.5, and 32 injections, there was a mean change of +3.1, -0.2, and -2.2 letters, respectively. At 1, 3, and 5 years, in 40 832, 7728, and 1192 eyes with DME, after a mean of 6.2, 15.4, and 26.0 injections, there was a mean change of +4.7, +3.3, and +3.1 letters, respectively. At 1 and 3 years, in 12 451 and 3027 eyes with BRVO-ME, after a mean of 7.1 and 18.2 injections, there was a mean change of +9.5 and +7.7 letters, respectively. At 1 and 3 years, in 9298 and 2264 eyes with CRVO-ME, after a mean of 7.3 and 18.8 injections, there was a mean change of +8.3 and +6.0 letters, respectively (P < 0.01 for all VA changes of > 1 letter). In all 4 conditions, the mean VA increased with the mean number of anti-VEGF injections, eyes with a baseline VA of 20/40 or better tended to lose VA, and eyes with progressively worse baseline VA experienced a progressively greater VA gain at 3 years. In practice, patients with nAMD, DME, BRVO-ME, and CRVO-ME showed limited visual outcomes, with patients with nAMD tending to lose VA at 3 and 5 years. Across all 4 disorders, the mean change in VA correlated with treatment intensity at 1, 3, and 5 years. Patients with better baseline VA are more vulnerable to vision loss.


ARID1A mutations and expression loss in non-small cell lung carcinomas: clinicopathologic and molecular analysis.
A subset of non-small cell lung carcinomas harbors mutations in ARID1A, a component of the SWI/SNF complex implicated in modulating response to immunotherapy in diverse tumors. This study characterized the spectrum of ARID1A mutations and expression by targeted sequencing and immunohistochemistry, respectively. In a consecutive series of 2440 non-small cell lung carcinomas, ARID1A mutations were present in 184 (7.5%), within which 69% harbored loss-of-function mutations. Of 139 ARID1A-mutated tumors available for immunohistochemistry, ARID1A expression was aberrant in 64 (46%), including diffuse complete loss in 13 (9%), diffuse diminished expression in 17 (12%), and heterogeneous loss with a geographic or interspersed pattern in 34 (25%). Complete loss of ARID1A expression correlated with ARID1A premature-truncating mutations with evidence of biallelic inactivation. Both ARID1A mutations and aberrant expression correlated with a lack of EGFR mutations, frequent TP53 mutations, and increased mutational burden. ARID1A-mutant tumors showed similar overall survival compared with ARID1A-wild-type tumors; however, among patients with ARID1A-mutant tumors, aberrant ARID1A expression correlated with worse overall survival. Lung tumors with diffuse loss of ARID1A expression were predominantly adenocarcinomas, poorly differentiated, almost exclusively from smokers, and enriched for mismatch repair deficiency. Geographic heterogeneous ARID1A loss was notable in three tumors, including an adenocarcinoma showing fetal-like differentiation in areas with ARID1A loss. Overall, loss of ARID1A expression at the protein level is seen in fewer than 2% of non-small cell lung carcinomas but is associated with distinct clinicopathologic features. Our findings suggest a need for caution in interpretation of the functional significance of ARID1A mutations from sequencing data.


Di-2-ethylhexyl phthalate (DEHP) induces apoptosis and autophagy of mouse GC-1 spg cells.
As a widely used plasticizer in industry, di-2-ethylhexylphthalate (DEHP) can cause testicular toxicity, yet little is known about the potential mechanism. In this study, DEHP exposure dramatically inhibited cellviability and induced apoptosis of mouse GC-1 spg cells. Furthermore, DEHP significantly increased the levels of autophagy proteins LC3-II, Beclin1 and Atg5, as well as the ratio ofLC3-II/LC3-I. Transmission electron microscopy (TEM) further confirmed that DEHP induced autophagy of mouse GC-1 spg cells. DEHP was also shown to induceoxidative stress; while inhibition of oxidative stress with NAC could increase cell viability and inhibit DEHP-induced apoptosis and autophagy. These results suggested that DEHP induced apoptosis and autophagy of mouse GC-1 spg cells via oxidative stress. 3-MA, an inhibitor of autophagy, could rescue DEHP-induced apoptosis. In summary, DEHP induced apoptosis and autophagy of mouse GC-1 spg cells via oxidative stress, and autophagy might exert a cytotoxic effect on DEHP-induced apoptosis.


The role of the human ventral striatum and the medial orbitofrontal cortex in the representation of reward magnitude - an activation likelihood estimation meta-analysis of neuroimaging studies of passive reward expectancy and outcome processing.
Reward maximization is a core motivation of every organism. In humans, several brain regions have been implicated in the representation of reward magnitude. Still, it is unclear whether identical brain regions consistently play a role in reward prediction and its consumption. In this study we used coordinate-based ALE meta-analysis to determine the individual roles of the ventral striatum (vSTR) and the medial orbitofrontal cortex (mOFC/VMPFC) in the representation of reward in general and of reward magnitude in particular. Specifically, we wanted to assess commonalities and differences in regional brain activation during the passive anticipation and consumption of rewards. Two independent meta-analyses of neuroimaging data from the past decade revealed a general role for the vSTR in reward anticipation and consumption. This was the case particularly when the consumed rewards occurred unexpectedly or were uncertain. In contrast, for the mOFC/VMPFC the present meta-analytic data suggested a rather specific function in reward consumption as opposed to passive anticipation. Importantly, when considering only coordinates that compared different reward magnitudes, the same parts of the vSTR and the mOFC/VMPFC showed concordant responses across studies, although areas of coherence were regionally more confined. These meta-analytic data suggest that the vSTR may be involved in both prediction and consumption of salient rewards, and may also be sensitive to different reward magnitudes, while the mOFC/VMPFC may rather process the magnitude during reward receipt. Collectively, our meta-analytic data conform with the notion that these two brain regions may subserve different roles in processing of reward magnitude.


Molecular-level effects on cell membrane models to explain the phototoxicity of gold shell-isolated nanoparticles to cancer cells.
Metallic nanoparticles are promising agents for photothermal cancer therapy (PTT) owing to their photostability and efficient light-to-heat conversion, but their possible aggregation remains an issue. In this paper, we report on the photoinduced heating of gold shell-isolated nanoparticles (AuSHINs) in in vitro experiments to kill human oropharyngeal (HEp-2) and breast (BT-474 and MCF-7) carcinoma cells, with cell viability reducing below 50 % with 2.2 × 1012 AuSHINs/mL and 6 h of incubation. This toxicity to cancer cells is significantly higher than in previous works with gold nanoparticles. Considering the AuSHINs dimensions we hypothesize that cell uptake is not straightforward, and the mechanism of action involves accumulation on phospholipid membranes as the PTT target for photoinduced heating and subsequent generation of reactive oxygen species (ROS). Using Langmuir monolayers as simplified membrane models, we confirmed that AuSHINs have a larger effect on 1,2-dioleoyl-sn-glycero-3-phospho-l-serine (DOPS), believed to represent cancer cell membranes, than on 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) taken as representative of healthy eukaryotic cells. In particular, data from polarization-modulated infrared reflection absorption spectroscopy (PM-IRRAS) revealed an increased conformational order of DOPS tails due to the stronger adsorption of AuSHINs. Furthermore, light irradiation reduced the stability of AuSHINs containing DOPC and DOPS monolayers owing to oxidative reactions triggered by ROS upon photoinduced heating. Compared to DOPC, DOPS lost nearly twice as much material to the subphase, which is consistent with a higher rate of ROS formation in the vicinity of the DOPS monolayer.


MRI-based texture analysis for differentiate between pediatric posterior fossa ependymoma type A and B.
The aim of the study was to evaluate the feasibility of texture analysis in differentiating between posterior fossa ependymoma type A (PF-EPN-A) and type B (PF-EPN-B) among children. Our retrospective study included 43 patients (37 PF-EPN-A and 6 PF-EPN-B) who were pathologically diagnosed with ependymomas in the posterior fossa. The texture features were extracted automatically from the volume of interests (VOIs), which were manually delineated on fluid-attenuated inversion recovery (FLAIR), contrast-enhanced T1-weighted (T1C), and diffusion-weighted imaging (DWI) MRI sequences. A receiver operating characteristic curve (ROC) was built to assess the diagnostic value of the texture parameters, and the prognostic value was evaluated by survival analysis. Texture parameter [Wavelet-LHH (H: High pass filter, L: Low pass. filter)_glcm (gray-level co-occurrence matrix)_Idn (Inverse difference normalized)] provides valuable information in distinguishing subgroups of ependymomas with higher specificity and positive predictive value (PPV). A total of 27 patients were divided into a high-risk group (IDN value>0.916) and a low-risk group (IDN value<0.916) with the most optimistic cut-off value (0.916). The Kaplan-Meier analysis of the survival curves showed significantly longer disease-free survival for low-risk groups compared to high-risk groups [hazard ratio (HR): 0.28, 95% confidence interval (CI): 0.11-0.69; p = 0.017]. Our results suggested that the texture parameters based on DWI images can be used to differentiate PF-EPN-A from PF-EPN-B. Texture analysis could be used as a noninvasive tool in distinguishing subgroup pediatric posterior fossa ependymomas and provide reliable prognostic information upon the verification of its reproducibility and feasibility by further studies.


New insight into the therapeutic role of the serotonergic system in Parkinson's disease.
Parkinson's disease (PD) is a common, late-onset neurodegenerative disorder that shows progressive extrapyramidal motor disorders (e.g., bradykinesia, resting tremors, muscle rigidity and postural instability) and various non-motor symptoms (e.g., cognitive impairment, mood disorders, autonomic dysfunction and sleep disorders). While dopaminergic agents such as L-3,4-dihydroxyphenylalanine (L-DOPA) and dopamine D2 agonists are widely used for the treatment of PD, there is still high clinical unmet need for novel medications that overcome the limitations of current therapies. Evidence is now accumulating that the serotonergic nervous system is involved in the pathophysiological basis of PD and can provide benefits in the treatment of PD through its diverse functions. Among 5-HT receptor subtypes, 5-HT1A, 5-HT2, 5-HT3 and 5-HT6 receptors play an important role in modulating extrapyramidal motor disorders. In addition, 5-HT1A, 5-HT2, 5-HT3, 5-HT4 and 5-HT6 receptors are implicated in modulation of cognitive impairment, mood disorders (e.g., depression and anxiety) and/or psychosis, which are frequently observed in patients with PD. Specifically, stimulation of 5-HT1A receptors seems to be effective for multiple PD symptoms including parkinsonism, L-DOPA-induced dyskinesia, cognitive impairment, mood disorders and neurodegeneration of dopamine neurons. Blockade of 5-HT2 receptors is also likely to improve parkinsonism, depressive mood and cognitive impairment. In addition, it was recently demonstrated that 5-HT2A inverse agonists can alleviate PD psychosis. All these findings emphasize the therapeutic roles of the serotonergic system in PD and stimulate new insight into novel treatments by modulating 5-HT1A and 5-HT2 receptors.


A survey of gastrointestinal pig parasites on free-range, organic and conventional pig farms in The Netherlands.
The prevalence of gastrointestinal parasites in suckling piglets, weaners, fattening pigs and sows was studied from November 2001 to October 2002 on 16 free-range farms (FRF), 11 organic farms (OF) and 9 conventional farms (CF) by means of faecal examinations of composite samples. Each farm was visited four times with a 3-month interval. Infections with coccidia were found on 43.8% of the FRF, 90.9% of the OF and 66.7% of the CF. Sows had the highest prevalence, particularly on FRF (87.5%) and OF (80%). Ascaris suum was present on 50% of the FRF, 72.7% of the OF and 11.1% of the CF, whereas fattening pigs on FRF (42.9%) and OF (54.5%) had the highest prevalence. Oesophagostomum spp. were observed on 25% of the FRF, 27.2% of the OF and 22.2% of the CF. The infection was most prevalent in the sows on all farm types: 37.5% on FRF, 30% on OF and 22.2% on CF.Trichuris suis was found on 37.5% of the FRF, 36.4% of the OF and 11.1% of the CF. Again, this infection was most prevalent in the sows, particularly on the FRF (50%) and OF (30%). No other gastrointestinal parasite species were found and no clinical signs were observed. No seasonal trends could be distinguished. In many cases, when an age group on a farm was positive for a certain parasite, it remained so during the whole study. This indicates that this parasite was really 'endemic' on that farm. The results of this study demonstrate that the prevalence of helminth infections of pigs on farms with outdoor facilities is higher than in pigs on conventional farms.


[Construction of the recombinant adenovirus vector bearing dual-survivin shRNA].
To construct a recombinant adenovirus vector bearing dual-survivin short hairpin RNA (shRNA). Dual-survivin shRNA was designed and synthesized respectively, both inserted into adenovirus DNA. The recombinant adenovirus vector was confirmed via both sequencing and restriction digestion analysis, and then linearized and transfected into the HEK 293 cell line to generate recombinant adenoviruses. The recombinant adenovirus vector was constructed and the target sequence was obtained. The construction of the recombinant adenovirus vector provides a basis for the research of potential gene therapy for prostate cancer.


Preoperative detection of pleural adhesions by chest ultrasonography.
The presence of pleural adhesions may render video-assisted thoracoscopic surgery difficult or impossible. The aim of this study was to assess the value of chest ultrasonography in the detection of pleural adhesions prior to thoracotomy. Between October 2001 and September 2002, 42 consecutive patients undergoing thoracotomies (including video-assisted thoracic surgery) were evaluated with chest ultrasonography. These patients underwent a preoperative ultrasonic examination of the chest wall using a 7-MHz linear ultrasound probe at 7 points along the chest wall. We measured the movement of the visceral pleural slide. When restricted viscera sliding was defined as less than 1 cm of excursion at the upper thoracic wall during exaggerated respirations, ultrasonography demonstrated a sensitivity of 63.6%, a specificity of 79.4%, a negative predictive value of 87.7%, a positive predictive value of 50.0%, and an overall accuracy of 75.6%. When restricted viscera sliding was defined as less than 2 cm of excursion at the lower thoracic wall during exaggerated respirations, ultrasonography demonstrated a sensitivity of 81.5%, a specificity of 81.0%, a negative predictive value of 96.0%, a positive predictive value of 44.0%, and an overall accuracy of 81.0%. Chest ultrasonography is moderately accurate in detecting the presence and location of pleural adhesions. Use of preoperative chest sonographic findings to plan trocar placement and to determine the need for an open approach is valuable in helping prevent visceral injury and facilitating video-assisted thoracoscopic surgery.


Characterization of the nuclear import signal of herpes simplex virus 1 UL31.
The herpes simplex virus 1 (HSV-1) UL31 protein is a multifunctional nucleoprotein that is important for viral infection; however, little is known concerning its subcellular localization signal. Here, by transfection with a series of HSV-1 UL31 deletion mutants fused to enhanced yellow fluorescent protein (EYFP), a bipartite nuclear localization signal (NLS) was identified and mapped to amino acids (aa) 1 to 27 (MYDTDPHRRGSRPGPYHGKERRRSRSS). Additionally, fluorescence results showed that the predicted nuclear export signal (NES) might be nonfunctional, and the functional NES of UL31 might require a specific conformation. Taken together, these results would provide significant information for the study of the biological function of UL31 during HSV-1 infection.


Prevalence of and factors associated with glucosamine use in Canada.
Glucosamine is commonly used for the treatment of osteoarthritis, and its use is increasing in the general population. The Canadian Multicentre Osteoporosis Study (CaMos) provided an opportunity to examine the prevalence of glucosamine use across age and gender groups, and to assess the factors associated with its use. CaMos is a random, population-based sample of 9423 Canadians. Baseline assessments took place in 1996-1997 and the 5-year follow-up assessments in 2001-2002. The primary outcome of this analysis was glucosamine use at year 5. Prevalence estimates were age- and sex-standardized to the Canadian population. A number of factors potentially associated with glucosamine use were identified from the literature. Multivariable logistic regression was used to identify variables associated with glucosamine use. At 5 years, complete data were available for 7652 of the original 9423 participants (81.2%). For men, glucosamine use increased from 0.9% to 4.7% (weighted values), and for women, it increased from 1.3% to 8.2%. Glucosamine use was higher among older participants, those living in western Canada, and those with arthritis, back pain, higher calcium intake from supplements, physical activity and prior glucosamine use. Glucosamine use increased substantially over 5 years, and its use is associated with a number of factors. Some may use glucosamine to manage pain and symptoms of arthritis and back pain, while others use it as a preventive measure to maintain health.


Development and validation of a new analytical method for the determination of 1,4-dichlorobenzene in honey by gas chromatography-isotope dilution mass spectrometry after steam-distillation.
A simple, fast, sensitive and robust analytical method using gas chromatography (GC)-isotope dilution mass spectrometry (MS) was developed and validated for the identification and quantification of 1,4-dichlorobenzene (p-DCB) residues in honey samples. The proposed methodology is based on steam-distillation using a Clevenger-type apparatus followed by gas chromatography-mass spectrometry (GC-MS) in the selected ion monitoring (SIM) mode employing the isotopically labeled analogue d4-1,4-dichlorobenzene (d4-p-DCB) as internal standard (IS). Validation of the method was performed in two different GC-MS systems, using quadrupole MS (QMS) and ion-trap MS (ITMS) detectors, with no statistically significant differences between two. Recoveries were better than 91% with percent relative standard deviations lower than 12%. The instrumental limits of detection were 1 microg kg(-1) in the GC-ITMS system and 0.6 microg kg(-1) in the GC-QMS system. The expanded uncertainty was estimated as 17% at the currently accepted "action level" of 10 microg kg(-1). The method was applied to the analysis of 310 honey samples in an extensive national monitoring study. A quality control (QC) system applied during the assays has demonstrated a good performance and long-term stability over a period of more than 8 months of continuous operation.


Effects of naloxone and its quaternary form on fluid consumption in rats.
Three studies were performed on albino rats to determine the effects of naloxone and its quaternary derivative, naloxone methylbromide, on fluid consumption. The doses of the quaternary naloxone were equated with naloxone by molarity and effectiveness in order to facilitate direct comparisons. All rats were deprived of food and water for 12 hr and exposed to a 20% sucrose solution for a 2 hr period. In Experiment 1, a low (0.01 mg/kg) dose of naloxone or an equated dose of quaternary naloxone was given ICV and immediate access allowed to the fluid on four consecutive days. Animals receiving naloxone were not significantly different from controls, and rats receiving quaternary naloxone exhibited seizures, resulting in decreased consumption. In Experiment 2, the low dose of naloxone or the equated dose of quaternary naloxone was given IP for four consecutive days and neither was significantly different from controls. In Experiment 3, animals were given an IP dose of either 1 mg/kg naloxone, a 1 mg/kg or 50 mg/kg dose of quaternary naloxone, or saline and tested for a single 2 hr period. The doses of 1 mg/kg naloxone and 50 mg/kg quaternary naloxone produced significantly less drinking than controls. In all studies, the initial 30 min period produced the most drinking. Suppression of drinking by a dose of 50 mg/kg quaternary naloxone suggested, in contrast to other studies, that it may cross the blood-brain barrier at high doses.


Nonylphenol effects on human prostate non tumorigenic cells.
Nonylphenol (NP) is an industrial chemical with estrogenic activity both in vivo and in vitro; estrogens play a critical role in the development of prostate and may be the cause of some pathological states, including cancer. In this study we examined the effects of NP on human prostate non tumorigenic epithelial cells (PNT1A) investigating on cell proliferation, interaction with estrogen receptors (ERs) and gene expression of genes involved in prostate diseases. We found that NP affects cell proliferation at 10(-6)M, promoting a cytoplasm-nucleus translocation of ERα and not ERβ, like the natural estrogen 17β-estradiol (E2). Moreover, we showed that NP enhances gene expression of key regulators of cell cycle. Estrogen selective antagonist ICI182780 in part reverted the observed effects of NP. These results confirm the estrogenic activity of NP and suggest that other transduction pathways may be involved in NP action on prostate.


Delayed Amplatzer device closure of atrial septal defect for persistent cyanosis after surgical correction of severe pulmonary stenosis in early infancy.
We present two patients who had delayed transcatheter closure of secundum atrial septal defects for persistent cyanosis after surgical repair of severe pulmonary stenosis. The defects (two in one patient) were closed uneventfully and successfully with Amplatzer ASO devices, with significant improvement in oxygen saturation. The staged approach and the complementary role of surgery and intervention are discussed.


Rhythmic changes in dry heat resistance of Bacillus subtilis spores after rapid changes in pH.
Heat resistance of freeze-dried Bacillus subtilis spores varied in a rhythmic manner as a function of time between acidification to about pH 1.5 and freezing. A comparable rapid shift to pH 11 produced little change in resistance to heat.


Inhibitory effects of novel nucleoside and nucleotide analogues on Epstein-Barr virus replication.
The anti-Epstein-Barr virus (EBV) activity of different classes of compounds was assessed by means of an EBV DNA hybridization assay using a digoxigenin-labelled probe specific for the BamHI W fragment of the EBV genome, as well as by measuring viral capsid antigen (VCA) expression after a 7 day incubation period of P3HR-1 producer cells with the test substances. Acyclovir, ganciclovir, cidofovir and zidovudine were included as reference compounds. Several compounds proved to be potent and selective inhibitors of EBV DNA synthesis and VCA expression. Of the new compounds that were evaluated for their anti-EBV activity, the highest efficacy (lowest EC50) and highest selectivity index (SI) were shown by the purine nucleoside analogue 2-amino-7-[(1,3-dihydroxy-2-propoxy)methyl]purine (S2242) (EC50 0.6 ng/ml; SI 600), the acyclic nucleoside phosphonate analogues 9-(2-phosphono -methoxyethyl)-6-dimethylaminopurine (EC50 1.1 micrograms/ml; SI 91), 9-(2-phosphonomethoxyethyl)-2- amino-6-benzhydrylaminopurine (EC50 1.3 micrograms/ml; SI 29), 7-(2-phosphonomethoxyethyl)-6-dimethyl-aminopurine (EC50 0.8 microgram/ml; SI 56), 9-(R)-(2-phosphonomethoxypropyl)-6-(2-dimethylaminoethyl)-aminopur ine (EC50 0.5 microgram/ml; SI 42), the 2',3'-dideoxythymidine derivative 3'-oximino-2',3'-dideoxythymidine (EC50 1.5 micrograms/ml; SI 65), and 1-(2,3- dideoxy-3-N-hydroxyamino-beta-D-threo-pentafuranyl)pentafuranos yl)thymine (EC50 4.1 micrograms/ml; SI > 24).


Functional topography of anger and aggression in the human cerebellum.
New insights into the functional neuroanatomic correlates of emotions point toward the involvement of the cerebellum in anger and aggression. To identify cerebellar regions commonly activated in tasks examining the experience of anger and threat as well as exerting an aggressive response, two coordinate-based activation likelihood estimation meta-analyses reporting a total of 57 cerebellar activation foci from 819 participants were performed. For anger processing (18 studies), results showed significant clusters in the bilateral posterior cerebellum, overlapping with results from previous meta-analyses on emotion processing, and implying functional connectivity to cognitive, limbic, and social canonic networks in the cerebral cortex. By contrast, active aggression expression (10 studies) was associated with significant clusters in more anterior regions of the cerebellum, overlapping with cerebellar somatosensory and motor regions and displaying functional connectivity with the somatomotor and default mode network. This study not only strengthens the notion that the cerebellum is involved in emotion processing, but also provides the first quantitative evidence for distinct cerebellar functional activation patterns related to anger and aggression.


Characteristic EEG findings in ring 20 syndrome as a diagnostic clue.
To review the EEG features of ring 20 syndrome in two patients and determine the characteristic pattern of this syndrome. The features of our cases and 24 patients reported in the literature will be discussed. Report of two patients and review of literature. The two patients had intractable epilepsy since childhood. Their clinical seizures were mostly complex partial seizures. Often the patients seizures were of prolonged duration. Ictal EEG revealed characteristic slow waves, and sharp waves. The slow waves were (1) usually synchronous high-voltage slow waves with or without a spike component predominantly in the frontal and frontopolar areas, (2) sometimes showed a change in frequency every several seconds, (3) continued for a long period, and (4) easily spread diffusely. The sharp waves were 5-6 Hz irregular and diffuse discontinuous sharp waves, and sometimes appeared predominantly in the centroparietal area. The clinical seizure pattern and EEG findings were similar in the 24 published cases. These EEG findings may be a characteristic feature of ring 20 syndrome and thus may be useful as a diagnostic clue.


Phosphatidylinositol and not phosphatidylglycerol is the important minor phospholipid in rhesus-monkey surfactant.
Pulmonary surfactant was isolated from lung tissue and alveolar washes of lungs of adult rhesus monkeys (Macaca mulatta). The phospholipid composition was determined and compared to the composition of human surfactant fractions. Contrary to human surfactant, phosphatidylinositol is the major acidic phospholipid, whereas phosphatidylglycerol is only a minor component in rhesus-monkey surfactant. These differences are not caused by a difference in plasma myo-inositol concentrations between the two species.


A classification scoring schema to validate protein interactors.
Hypothetical protein [HP] annotation poses a great challenge especially when the protein is putatively linked or mapped to another protein. With protein interaction networks (PIN) prevailing, many visualizers still remain unsupported to the HP annotation. Through this work, we propose a six-point classification system to validate protein interactions based on diverse features. The HP data-set was used as a training data-set to find putative functional interaction partners to the remaining proteins that are waiting to be interacting. A Total Reliability Score (TRS) was calculated based on the six-point classification which was evaluated using machine learning algorithm on a single node. We found that multilayer perceptron of neural network yielded 81.08% of accuracy in modelling TRS whereas feature selection algorithms confirmed that all classification features are implementable. Furthermore statistical results using variance and co-variance analyses confirmed the usefulness of these classification metrics. It has been evaluated that of all the classification features, subcellular location (sorting signals) makes higher impact in predicting the function of HPs.


Ischemic Preconditioning Upregulates Decoy Receptors to Protect SH-SY5Y Cells from OGD Induced Cellular Damage by Inhibiting TRAIL Pathway and Agitating PI3K/Akt Pathway.
As ischemic preconditioning (IPC) represents a potential therapy against cerebral ischemia, the purpose of the present study is to explore the molecular mechanisms of ischemic preconditioning induced cerebral protective effect. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a member of the tumor necrosis factor superfamily, which induces apoptosis through binding to its death receptors (DR4 and DR5). When TRAIL binds to decoy receptors (DcR1 and DcR2), as DcRs lack intact cytoplasmic death domain, TRAIL fails to induce neuronal apoptosis. In the present study, we demonstrated that ischemic preconditioning upregulated DcR1 and DcR2, which subsequently inhibited oxygen glucose deprivation-induced cellular apoptosis. Then, we investigated the protective molecular mechanism of DcRs after ischemic preconditioning treatment. Results showed that DcR1 could competitively bind to TRAIL and partially inhibit TRAIL-induced cellular apoptosis. On the other hand, DcR2 could disturb DRs-associated death-inducing signaling complex formation (DISC), which further inhibited capase-8 activation. Besides, we also found that ischemic preconditioning activated IPC-induced Akt phosphorylation via regulating DcR2 level. Thus, ischemic preconditioning upregulated decoy receptors, which protected cells from oxygen glucose deprivation-induced cellular damage by inhibiting TRAIL-induced apoptosis and agitating PI3K/Akt pathway. Our data complemented the knowledge of neuroprotective mechanism of ischemic preconditioning and provided new evidence for supporting its clinical application.


Trunk-to-peripheral fat ratio predicts a subsequent blood pressure in normal-weight pubertal boys: a 3-year follow-up of the Kitakata Kids Health Study.
Limited evidence exists regarding the relationship between central-to-peripheral fat ratio measured by dual-energy X-ray absorptiometry (DXA) and subsequent cardiometabolic risk in both pediatric and adult populations. The present cohort study investigated the relationship between DXA-measured body fat distribution and cardiometabolic parameters. The source population was 275 4th-6th graders (aged 9.6-12.6 years) in the northeast region of Japan (Shiokawa area in Kitakata). A 3-year follow-up was conducted to obtain complete information from 155 normal-weight children (87 boys and 68 girls). Normal-weight children were identified using sex- and age-specific international cut-offs for body mass index (BMI) based on adult BMI values of 25 kg/m2 and 18.5 kg/m2, respectively. Body fat distribution was assessed using the trunk-to-appendicular fat ratio (TAR) and trunk-to-leg fat ratio (TLR) measured by DXA. In boys, systolic blood pressure (SBP) at follow-up showed a significant relationship with TAR at baseline after adjusting for age, height, pubic hair appearance, SBP, and whole body fat at baseline (β = 0.24, P < 0.05), and SBP also showed a significant relationship with TLR after adjusting for confounding factors including whole body fat (β = 0.25, P < 0.05). In girls, there were no significant relationships between blood pressure and TAR/TLR. Body fat distribution in normal-weight boys predicted subsequent blood pressure levels in adolescence. The relationship between fat distribution and blood pressure was independent of fat volume.


Effect of left ventricular volume on right ventricular end-systolic pressure-volume relation. Resetting of regional preload in right ventricular free wall.
Effect of left ventricular (LV) volume on right ventricular (RV) end-systolic pressure-volume relation (ESPVR) was investigated, and the mechanism was examined from a standpoint of the alteration of RV free wall mean fiber length. Twelve cross-circulated isovolumically contracting canine hearts in which both ventricular volumes were controlled independently were used, and RV-ESPVR was determined at three different LV volume levels. At small (10.2 +/- 0.6 ml), middle (15.3 +/- 1.0 ml), and large (20.5 +/- 1.4 ml) LV volume, the slope of the RV-ESPVR was 2.63 +/- 0.13, 2.74 +/- 0.13, and 2.89 +/- 0.12 mm Hg/ml, respectively, and each value was significantly different from the others (p less than 0.01). The volume intercept (V0) of the relation (RV-V0) was significantly decreased with the increment of LV volume (RV-V0 in small, middle, and large LV volume; 3.92 +/- 0.68, 3.39 +/- 0.67, and 2.87 +/- 0.71 ml, respectively; p less than 0.01). In nine hearts, RV free wall lengths in latitudinal and meridional direction were measured at three LV volume levels when RV volume was held constant (16.1 +/- 1.1 ml). RV latitudinal end-diastolic length was significantly augmented with increasing LV volume (latitudinal length in small, middle, and large LV volume; 9.68 +/- 0.55, 9.81 +/- 0.56, and 9.92 +/- 0.55 mm, respectively). RV meridional end-diastolic length also increased significantly with increasing LV volume.(ABSTRACT TRUNCATED AT 250 WORDS)


Current status of Parkinson's disease treatment in Korea.
The health insurance system in Korea has been under governmental control, and has covered whole population since 1989. About 97% of Korean people have benefits from this system, while 3% are covered by a Medical Aid system for poor people. According to the statistical yearbook of Health Insurance Review in Korea, the number of claims under Parkinson's Disease, in whole country increased steeply from 44619 in 1995 to 96229 in 2000. If each patient were to take medication for the full duration of their insurance coverage, the average number of visits per year would be 11 in 2000. Thus the number of PD patients calculated using these statistics is about 8600. The prevalence is 19/100000, which is much lower than that in Japan. Considering the significant increase in the number of claims in last few years, however, there are still many PD patients who do not receive an accurate diagnosis and appropriate treatment. The other factor influencing these statistics is the fact that patients were able to buy their medications in drug stores without prescription, i.e. without visiting a hospital (since 2001 this has no longer been allowed). Almost all PD medications are available in Korea. There are several forms of levodopa drugs. Dopamine agonists include bromocriptine, pergolide, dihydroergocriptine, ropinirol, and pramipexole. Other parkinsonian medications are amantadine, benztropin, trihexyphenydil, deprenyl, and entacapone. Recently multicentre clinical trials were performed using ropinirol and entacapone, which showed reliable results. Currently deep brain stimulation is available in a number of medical institutes.


Medical decision support systems and therapeutics: The role of autopilots.
For decades, medical practice has increasingly relied on prescription medicines to treat, cure, or prevent illness but their net benefit is reduced by prescribing errors that result in adverse drug reactions (ADRs) and tens of thousands of deaths each year. Optimal prescribing requires effective management of massive amounts of data. Clinical decision support systems (CDSS) can help manage information and support optimal therapeutic decisions before errors are made by operating as the prescribers' "autopilot."


Synthesis of C-19 deuterium labelled steroids.
Preparation of the synthetically useful steroid intermediate 19-d3-androst-4-ene-3,17-dione (Ia) together with its 19-d2-(Ib) and 19-d1-(Ic) analogues is described. The conditions and work-up of the synthesis have been designed to eliminate tedious chromatographic separation and purification steps thus enabling decigrams of material to be conveniently prepared using standard laboratory apparatus. The deuterium label in the C-19 angular methyl group is inert to normal chemical exchange processes, thus offering the opportunity for synthesis of more complex, biologically active, stable labelled steroids, whose metabolism can be studied mass spectrometrically.


Splenic complications in chronic pancreatitis: prevalence and risk factors in a medical-surgical series of 500 patients.
The prevalence, course, treatment, outcome and risk factors of splenic complications in chronic pancreatitis are poorly documented. Patients with splenic complications in a medical-surgical series of 500 consecutive patients with proven chronic pancreatitis prospectively followed up for a mean of 7.0 years were compared with patients without splenic complications. Eleven men (2.2 per cent) with alcoholic chronic pancreatitis (median duration 2 (range 0-5) years) had a splenic complication: intrasplenic pseudocyst (n=5), subcapsular haematoma (n=2) or splenic rupture (n=4). All patients except one underwent splenectomy, five of whom also underwent distal pancreatectomy. There were no deaths. Patients with splenic complications had pancreatic tail necrosis (six of 11 versus 17.4 per cent; P=0.007), distal pseudocyst (six of 11 versus 11.7 per cent; P=0.0009) or splenic vein occlusion (seven of 11 versus 10.8 per cent; P< 0.0001) more frequently than those without. In the 22 patients with distal pseudocyst and splenic vein occlusion, the prevalence of splenic complications was 18 per cent (odds ratio 15.0 (95 per cent confidence interval 4.0-55.7). Splenic complications occur early in the course of chronic pancreatitis, are rare and are favoured by splenic vein occlusion and pseudocyst or necrosis of the pancreatic tail. Surgical treatment is usually required.


Tissue factor-induced fibrinogenesis mediates cancer cell clustering and multiclonal peritoneal metastasis.
Peritoneal metastasis is one of the most frequent causes of death in several types of advanced cancers; however, the underlying molecular mechanisms remain largely unknown. In this study, we exploited multicolor fluorescent lineage tracking to investigate the clonality of peritoneal metastasis in mouse xenograft models. When peritoneal metastasis was induced by intraperitoneal or orthotopic injection of multicolored cancer cells, each peritoneally metastasized tumor displayed multicolor fluorescence regardless of metastasis sites, indicating that it consists of multiclonal cancer cell populations. Multicolored cancer cell clusters form within the peritoneal cavity and collectively attach to the peritoneum. In vitro, peritoneal lavage fluid or cleared ascitic fluid derived from cancer patients induces cancer cell clustering, which is inhibited by anticoagulants. Cancer cell clusters formed in vitro and in vivo are associated with fibrin formation. Furthermore, tissue factor knockout in cancer cells abrogates cell clustering, peritoneal attachment, and peritoneal metastasis. Thus, we propose that cancer cells activate the coagulation cascade via tissue factor to form fibrin-mediated cell clusters and promote peritoneal attachment; these factors lead to the development of multiclonal peritoneal metastasis and may be therapeutic targets.


[Abdominoscrotal hydrocele complicated by hydroureteronephrosis].
Abdominoscrotal hydrocele is a very rare clinical entity especially in childhood with less than 100 paediatric cases reported in the literature. It is associated with various complications and its pathogenesis is still a matter for debate. The authors report a case of abdominoscrotal hydrocele in the child. The methods of the diagnosis as well as the specific treatment are pointed out.


Isolation of a spotted fever group rickettsia from a patient and related ecologic investigations in Xinjiang Uygur Autonomous Region of China.
Investigation of patients, healthy persons, and ticks in Jinghe County, Xinjiang Uygur Autonomous Region, People's Republic of China, for evidence of spotted fever group (SFG) rickettsiosis demonstrated strong evidence for a high prevalence of pathogenic SFG rickettsiae. Antibodies to SFG rickettsiae were detected in 62.5% of healthy subjects tested by enzyme-linked immunosorbent assay and 20% tested by complement fixation test. Two febrile patients were documented as having acute spotted fever rickettsiosis by complement fixation seroconversion. One, and 11-year-old Kazakh boy with eschar and regional lymphadenopathy, had an SFG rickettsia (An strain) isolated from his blood. A hemolymph test revealed that 20% of ticks contained rickettsiae. Two strains of SFG rickettsiae were isolated from male and female Dermacentor nuttalli ticks. The human SFG rickettsial isolate is the first to be obtained in the People's Republic of China.


Altered expression of laminin alpha1 in aganglionic colon of endothelin receptor-B null mouse model of Hirschsprung's disease.
Laminin, an extracellular matrix molecule, is essential for normal development of the nervous system. The alpha1 subunit of laminin-1 (LAMA1) has been reported to promote neurites and outgrowth and is expressed only during embryogenesis. Previously, we developed a Sox10 transgenic version of the Endothelin receptor-B (Ednrb) mouse to visualize Enteric neural crest-derived cell (ENCC)s with a green fluorescent protein, Venus. We designed this study to investigate the expression of LAMA1 using Sox10-VENUS mice gut. We harvested the gut on days 13.5 (E13.5) and 15.5 (E15.5) of gestation. Sox10-VENUS+/Ednrb -/- mice (n = 8) were compared with Sox10-VENUS+/Ednrb +/+ mice (n = 8) as controls. Gene expression of LAMA1 was analysed by real-time RT-PCR. Fluorescent immunohistochemistry was performed to assess protein distribution. The relative mRNA expression levels of LAMA1 were significantly increased in HD in the proximal and distal colon on E15.5 compared to controls (p < 0.05), whereas there were no significant differences on E13.5. LAMA1 was expressed in the serosa, submucosa and basal lamina in the gut, and was markedly increased in the proximal and distal colon of HD on E15.5. Altered LAMA1 expression in the aganglionic region may contribute to impaired ENCC migration, resulting in HD. These data could help in understanding the pathophysiologic interactions between LAMA1 and ENCC migration.


Plant leaf extracts as photocatalytic activity tailoring agents for BiOCl towards environmental remediation.
The inducement of plant leaf extracts for the synthesis of various nanostructures has intrigued researchers across the earth to explore the mechanisms of biologically active compounds present in the plants. Herein, a green modified hydrolysis route has been employed for the synthesis of bismuth oxychloride i.e. BiOCl-N, BiOCl-T and BiOCl-A using plant extracts of Azadirachta indica (Neem), Ocimum sanctum (Tulsi), and Saraca indica (Ashoka), and; simultaneously, without plant extract (BiOCl-C), respectively. The as-prepared samples were examined by several microscopic and spectroscopic techniques which revealed that the biosynthesized BiOCl attained certain favorable features such as hierarchical nano-flower morphology, higher porosity, higher specific surface area and narrower band gap compared to BiOCl-C. The degradation of methyl orange (MO) and bisphenol A (BPA) using biosynthesized BiOCl were improved by 21.5% within 90 min and 18.2% within 600 min under visible light irradiation, respectively. The photocurrent response, electrochemical impedance spectroscopy (EIS) and photoluminescence (PL) studies indicated the effective inhibition of the electron-hole pair recombination and enhanced photocatalytic activity of the biosynthesized BiOCl.


Improving Fertility Treatment Documentation - A Survey.
Many couples do not have adequate documentation following fertility treatments. To conduct a survey to understand the information needs of assisted reproductive technology physicians when assessing the reasons affecting treatment outcomes after intrauterine insemination (IUI) and in vitro fertilisation (IVF). Online survey. Anonymous online survey of 14 parameters related to IUI treatment and 21 parameters related to IVF treatment, followed by recommendation of selected parameters for routine documentation. Frequency distribution calculation of responses. For IUI, total motile sperm count and post-wash sperm count and motility and for IVF, the quality and number of gametes, embryo number and morphology were the most important parameters. The study creates recommendations for the minimum information desirable in the fertility treatment documentation given to the couple undergoing treatment.


Effects of inhaled gases on the ultrasound contrast produced by microspheres containing air or perfluoropropane in anesthetized dogs.
Inhaled gas mixtures with increased amounts of oxygen cause air containing ultrasound contrast agents to lose efficacy faster than during the inhalation of air. The authors hypothesized that contrast materials containing relatively insoluble gases would decrease the effects of inhaled gases on the ultrasound contrast. Anesthetized dogs were ventilated with compressed air and different oxygen/nitrogen gas mixtures. Video densitometric analysis was performed on end diastolic ultrasound images of the heart after administration of Albunex (air-filled microspheres) or Optison (perfluoropropane-filled microspheres). Increased concentrations of oxygen caused no change in the contrast intensity produced by Optison in the left ventricular chamber. In the myocardium, however, increases in oxygen caused Optison to produce significantly less enhancement of the myocardial tissue. The use of perfluoropropane within albumin microspheres prevented the effects of inhaled gas mixtures on contrast produced within the left ventricular chamber. In the myocardium, increased concentrations of oxygen in the inhaled gas mixtures reduce contrast intensity.


Intraventricular perineurioma: case report.
Perineurioma, a rare benign nerve sheath neoplasm occurring in either an intraneural or soft tissue form, has never been reported to arise in the central nervous system. We describe the clinical, radiological, and pathological features of a perineurioma arising in the choroid plexus of the third ventricle in a 65-year-old woman and causing obstructive hydrocephalus. The lesion, apparently unassociated with a nerve, was gross totally resected by frontal craniotomy using a left-sided transcallosal approach. Short-term follow-up showed no evidence of recurrence. Perineurioma of the variety found in soft tissue may occur in the central nervous system, wherein it shows the typical light microscopic, immunohistochemical (epithelial membrane antigen- and Collagen IV-positive, S-100 protein-negative), and ultrastructural (pinocytotic vesicles, discontinuous basement membrane) features.


Cyp4a12-mediated retinol metabolism in stellate cells is the antihepatic fibrosis mechanism of the Chinese medicine Fuzheng Huayu recipe.
Hepatic stellate cells (HSCs), which contain multiple retinol-containing lipid droplets, are important profibrotic cells in liver fibrosis. Under Cyp4a12a/b oxidation, HSC activation was accompanied by the downregulation of genes involved in retinol metabolism, inducing RAE-1 production. By eliminating activated HSCs, NK cells expressing the activating receptor NKG2D are recruited to alleviate fibrosis. FZHY was found to significantly reduce the severity of liver fibrosis by inhibiting the activation and proliferation of HSCs. The molecular processes that govern retinol metabolism, on the other hand, are largely unexplored. This study focused on the regulation of Cyp4a12a/b by FZHY to elucidate the antifibrotic molecular mechanisms underlying the effect of FZHY on retinol metabolism. To investigate mechanisms and altered pathways of FZHY against carbon tetrachloride (CCl4)-induced liver fibrosis based on transcriptomics data. Bioinformatics analysis was used to screen its pharmacological targets. The predicted targets were confirmed by a series of in vitro and in vivo experiments, including mass spectrometry, in situ hybridization, immunofluorescence assays and real-time PCR. Then, the results were further characterized by recombinant adenovirus vectors that were constructed and transfected into the cultured primary HSCs. Transcriptomics revealed that Cyp4a12a/b is nearly completely lost in liver fibrosis, and these effects might be partially reversed by FZHY therapy recovery. In vitro and in vivo studies indicated that Cyp4a12a/b deletion disrupted retinol metabolism and lowered Rae-1 expression. Activated HSCs successfully escape recognition and elimination by natural killer (NK) cells as a result of reduced Rae-1. Notablely, we discovered that FZHY may restore the Cyp4a12a/b capability, allowing the recovery of the cytotoxic function of NK cells against HSCs, and thereby reducing hepatic fibrosis by suppressing HSC activation. Our findings revealed a new role for Cyp4a in retinol metabolism in the development of hepatic fibrosis, and they highlight Cyp4a12/Rae-1 signals as possible therapeutic targets for antifibrotic medicines.


The unique lipid composition of gecko (Gekko Gekko) photoreceptor outer segment membranes.
This study investigated the lipid and fatty acid composition of gecko photoreceptor outer segment membranes which contain the P521 cone-type pigment. The lipids of gecko photoreceptor outer segment membranes were first extracted and separated by thin layer chromatography (TLC) and then analyzed by gas chromatography (GC). Our results show that gecko photoreceptor outer segment membranes contain less phosphatidylethanolamine (PE) and more phosphatidylcholine (PC) and phosphatidylserine (PS) compared with those of bovine and frog. The content of the polyunsaturated fatty acid, docosahexaenoic acid (DHA), in PC and PS is also the highest yet reported (55 and 63%, respectively). These lipid differences may provide some insight into the specific lipid requirements of cone-type pigments.


Self-medication practice in pregnant women from central Mexico.
Self-medication during pregnancy represents a serious threat for mother and child health. The objective of this study was to evaluate the prevalence and the factors associated with self-medication among Mexican women living in the central region of Mexico. This is a descriptive interview-study of 1798 pregnant women or women who were pregnant no more than 3 years ago, when the interview was carried out. Data analysis was carried out with chi-square analysis and odds ratio. The prevalence of self-medication (allopathic drugs, medicinal plants, and other products, including vitamins, food supplements, among others) was 21.9%. The factors associated (p < 0.05) with self-medication were: higher education (college and postgraduate), smoking, and consumption of alcohol. Smoking was the strongest factor (OR: 2.536; 1.46-4.42) associated to self-medication during pregnancy, followed by consumption of alcohol (OR: 2.06; 1.38-3.08), and higher education (OR: 1.607; 1.18-2.19). Medicinal plant consumption was associated with nausea, constipation, migraine, and cold (p < 0.05), whereas he self-medication of allopathy was associated with gastritis and migraine (p < 0.05). Self-medication was influenced mainly by a relative or friend, who recommended the use of herbal medicine/allopathic medication. Two of the most common medicinal plants (arnica and ruda) here informed are reported to induce abortion or toxicity during pregnancy. The findings showed that self-medication (medicinal plants and allopathic medication) is a common practice among pregnant women from central Mexico. Adequate counselling of pregnant women by healthcare professionals about the potential risks of self-medication with herbal medicine and allopathic drugs during pregnancy is strongly warranted.


Effectiveness of training programs based on mindfulness in reducing psychological distress and promoting well-being in medical students: a systematic review and meta-analysis.
Medical schools have used mindfulness meditation as a strategy to assist students in stress management. This study aimed to seek evidence regarding the effectiveness of mindfulness-based training programs in reducing psychological distress and promoting the well-being of medical students. We conducted a systematic review and meta-analysis. Cochrane Library, Embase, PubMed/MEDLINE, PsycINFO/PsycNet, LILACS/BVS, ERIC (ProQuest), Web of Science, OpenGrey, and Google Scholar were searched for randomized clinical trials published until March 2022, without time or language restrictions. Two authors independently screened the articles, extracted data using a standardized extraction form, and assessed the methodological quality of the included studies using the Cochrane's Risk of Bias 2 (ROB 2) tool and the quality of evidence using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) tool. Of the 848 articles retrieved, 8 met the inclusion criteria. Mindfulness-based training improved the outcomes: mindfulness (small post-intervention effect: SMD = 0.29; 95% CI: 0.03 to 0.54; p = 0.03; I2 = 46%; high evidence quality, and small effect at follow-up: SMD = 0.37; 95% CI: 0.04 to 0.70; p = 0.03; I2 = 53%; low evidence quality), psychological well-being/health (there was no statistically significant difference between the groups in the post-intervention effect: SMD = - 0.27; 95% CI: - 0.67 to 0.13; p = 0.18; I2 = 76%; moderate evidence quality, and a significant difference at follow-up: SMD = - 0.73; 95% CI: - 1.23 to - 0.23; p = 0.004; I2 = 61%; low evidence quality), and stress (small post-intervention effect: SMD = - 0.29; CI of 95%: - 0.56 to - 0.02; p = 0.04; I2 = 57%; moderate evidence quality, and moderate effect at follow-up: SMD = - 0.45, 95% CI: - 0.67 to - 0.22, p = 0.0001, I2 = 0%, moderate evidence quality). The quality of evidence for the anxiety, depression, and resilience outcomes is low and for the empathy outcome, very low. The results indicate that the students who participated in the mindfulness training perceived improvements in the stress and psychological distress symptoms and improved health perception and psychological well-being. However, the significant heterogeneity among studies should be considered when interpreting these findings. PROSPERO CRD42020153169.


MPF2-like MADS-box genes affecting expression of SOC1 and MAF1 are recruited to control flowering time.
A complex and intricate network of genes responding to various developmental and environmental signals control floral transition in plants. MADS-box genes are the key regulators and major contributors with regard to flowering time determination. Previously, MPF2-like genes belonging to the STMADS11 superclade were duplicated into MPF2-like-A and MPF2-like-B in Withania (WSA206 and WSB206) and Tubocapsicum (TAB 201). The present study was conducted to determine the effect of MPF2-like genes on flowering time by analyzing 35S:MPF2-like transgenic Arabidopsis plants as well as to probe their effects on the expression of SUPPRESSOR OF OVEREXPRESSION OF CONSTANS 1 (SOC1, a floral promoter) and MADS AFFECTING FLOWERING 1 (MAF1, a floral repressor) genes. The overexpression of WSA206 (35S:MPF2-like-A) moderately promoted flowering, while that of WSB206 and TAB 201 (35S:MPF2-like-B) exhibited no effects on floral transition. Concomitantly, an elevation in SOC1 transcript abundance and a reduction for MAF1 transcript levels were observed in 35S:WSA206 transgenic plants. Nucleotide diversity analysis indicated an extraordinary 8 aa extension at the C-terminus of the WSA206 protein. Ectopic expression of a truncated WSA206-version without these 8 aa (WSA206ΔC246) and of MPF2-like-B-versions elongated by these 8 aa (WSB206∇C257 and TAB 201∇C257) in Arabidopsis revealed an ambiguous role of the 8 aa signature in floral transition. It may influence a protein's ability to modulate flowering time but is neither sufficient nor strictly necessary for early flowering. Nevertheless, the 8 aa extension influences the expression of SOC1 and MAF1 in MPF2-like derivative constructs. Our studies provide insight into the role of MPF2-like genes in phase transition by interacting with SOC1 and MAF1 genes, thereby also pointing to their significance as potential candidates for modifying flowering in crop plants in the future.


Sustainable disposal of excess sludge: Incineration without anaerobic digestion.
Handling excess sludge produced by wastewater treatment is a common problem worldwide. Due to limited space available in landfills, as well as difficulties involved in using excess sludge in agriculture, there is a need for alternative disposal methods. Although anaerobic digestion (AD) is widely used in processing sludge, only partial energy recovery from methane and sludge volume reduction can be achieved, resulting in a substantial amount of sludge remaining, which needs to be disposed of. Direct incineration after sludge drying is one possible option, a practice that is already in place in some cities in China. A comparison between direct incineration and conventional AD (with or without pretreatment by thermal hydrolysis) has to be made with respect to the energy balance and investment & operational (I & O) costs. This comparison reveals direct incineration to have the lowest energy deficit and I & O costs. Therefore, it is expected that direct incineration without AD will become the preferred sustainable approach to handling sludge.


Differential expression analysis of Golgi apparatus proteomes in hepatocellular carcinomas and the surrounding liver tissues.
Hepatocellular carcinoma (HCC) is the sixth most common malignancy worldwide. Liver is the largest human digestive gland with abundant Golgi apparatus involved in cell division, migration and apoptosis and others. In the present study, Golgi apparatus of HCC and the surrounding liver tissues were isolated by sucrose density gradient centrifugation and identified by electron microscopy and enzymology methods. Using 2-D gel electrophoresis and mass spectrometry, 17 differentially expressed protein of Golgi apparatus in HCC and the surrounding liver tissue were screened and identified in the Mascot database. Of those differentially expressed proteins, six were upregulated and 11 were downregulated, some of them were related to the biological processes such as protein sorting, glycosylation, cell cycle regulation, transcription regulation and Golgi integrity. One protein, annexin A5, was verified to be upregulated in HCC by western blot. The differentially expressed proteins may provide new insight into HCC biology and potential diagnostic and therapeutic biomarkers.


Tumor sinuses- vascular channels.
The existence of tumor cell-lined sinuses (vascular channels) in various experimental and human cancer is known for almost a half a century described by a Hungarian pathologist, Béla Kellner. Meanwhile, even the existence as well as the pathomechanism and the possible functional significance of these sinuses are heavily challenged in the recent literature. Ultrastructural studies however provide evidence for the presence of tumor cell-lined sinuses in human melanoma and breast cancer. The generation of such sinuses can be suggested in two ways: by de novoformation, when tumor cells recapitulate an embryonic geno- and phenotype by reexpressing endothelial genes or by a secondary mechanism, where the incorporated microvessels degenerate due to the predominant expression of anti-angiogenic factors. Literature data are available for the potential diagnostic and clinical significance of the tumor sinuses (vascular channels) stimulating further studies on this issue.


Effects of 2450 MHz microwave radiation during the gestational period on the postnatal hematology of rats.
Pregnant Sprague-Dawley rats were exposed to 2.45 GHz CW radiation for 3 h daily from day 4 through day 20 of pregnancy at an average power density of 10.3 mW/cm2. At 2, 10, 20, and 30 d postpartum, several aspects of peripheral blood hematology of male and female pups were examined. No effects were noted on pregnancy rate or litter size; however, pup weight was reduced. Also, the white blood cell numbers were lower in male and female pups exposed to microwave radiation and the differential cell counts were altered in the female pups at 10 d postpartum. At 30 d of age, no differences were noted between the sham and exposed pups for any of the hematologic variables examined.


[Exposure level and characteristics of dioxins in children living near the waste incineration power plant].
To study the internal and external dioxins exposure level of children living near the waste incineration power plant. Peripheral blood of children (90 in S, 60 in L), soils, crucians, chicken eggs were sampled in town S (1 km away from a big waste incineration power plant), as well as in town L (200 km away from S), which is the control. The contents, distribution characteristics and toxic equivalent (TEQ) of dioxins in samples were evaluated by ultra-trace detection methods. The concentrations and TEQs of dioxins in blood, soils, crucians and chicken eggs from town S were significantly higher than those in town L (P < 0.05). The dominant dioxin detected from the samples is OCDD, while the dominant TEQ contribution dioxin is 2, 3, 4, 7, 8-PeCDF. The emission of dioxins from the waste incineration power plant may increase the internal and external dioxins exposure level of children living nearby.


Membrane topology of Kch, a putative K+ channel from Escherichia coli.
We have mapped the topology of the C-terminal half of the putative potassium channel protein Kch in the inner membrane of Escherichia coli using PhoA fusions. Our results are consistent with the widely assumed six-transmembrane helix model for eukaryotic voltage-gated ion channels and place both ends of the proposed channel-lining P-segment on the periplasmic side of the inner membrane. The rather hydrophobic P-segment is found to translocate only slowly across the inner membrane and seems to be near a threshold for stop-transfer function.


Foreign body-induced abscess resembling pancreatic neoplasia.
We report the case of a 44-year-old man presenting with abdominal pain and leukocytosis. His initial computed tomography demonstrated a pancreatic head mass concerning for pancreatic adenocarcinoma. However, on further review of the patient's imaging, the mass was determined to be an abscess caused by foreign body ingestion and gastric perforation rather than cancer. This report describes the clinical and radiographic distinctions between pancreatic neoplasia and abscess. It also reviews the pertinent medical literature on how such viscus perforations affect subsequent prognostication and clinical management.


Long-term follow-up and liver outcomes in children with cystic fibrosis and nodular liver on ultrasound in a multi-center study.
Nodular liver (NOD) in cystic fibrosis (CF) suggests advanced CF liver disease (aCFLD); little is known about progression of liver disease (LD) after detection of sonographic NOD. Clinical, laboratory, and ultrasound (US) data from Prediction by Ultrasound of the Risk of Hepatic Cirrhosis in CFLD Study participants with NOD at screening or follow-up were compared with normal (NL). Linear mixed effects models were used for risk factors for LD progression and Kaplan-Meier estimator for time-to-event. 54 children with NOD (22 screening, 32 follow-up) and 112 NL were evaluated. Baseline (BL) and trajectory of forced expiratory volume, forced vital capacity, height/BMI z-scores were similar in NOD vs NL. Platelets were lower in NOD at BL (250 vs 331×103/microL; p < 0.001) and decreased by 8600/year vs 2500 in NL. Mean AST to Platelet Ratio Index (1.1 vs 0.4; p < 0.001), Fibrosis-4 Index (0.4 vs 0.2, p < 0.001), and spleen size z-score (SSZ) [1.5 vs 0.02; p < 0.001] were higher in NOD at BL; SSZ increased by 0.5 unit/year in NOD vs 0.1 unit/year in NL. Median liver stiffness (LSM) by transient elastography was higher in NOD (8.2 kPa, IQR 6-11.8) vs NL (5.3, 4.2-7, p < 0.0001). Over 6.3 years follow-up (1.3-10.3), 6 NOD had esophageal varices (cumulative incidence in 10 years: 20%; 95% CI: 0.0%, 40.0%), 2 had variceal bleeding, and 2 underwent liver transplantation; none had ascites or hepatic encephalopathy. No NL experienced liver-related events. NOD developed clinically evident portal hypertension faster than NL without worse growth or lung disease.


Pedicle origin and intervertebral compartment in the lumbar and upper sacral spine. A biometric study.
The osseous boundaries of the intervertebral compartment are described. Measurements of the pedicles demonstrate that their configuration determines the shape of the intervertebral compartment. The pedicles originate in the upper lumbar spine (L 1 and L 2) in a vertical direction from the posterior aspects of the vertebral bodies. In the caudal lumbar spine (L 4 and L 5) the origin of the pedicles is more oblique and thereby moves much more laterally and ventrally. As a consequence the horizontal extension of the pedicles is increasing in the lower lumbar spine. In the upper lumbar region the intervertebral compartment corresponds more to a foramen, in the lower lumbar spine more to a canal. The resulting clinical relevance for the length of the intervertebral compartment and the nerve root course is discussed.


The Burden of Caregivers of Patients After Hip Replacement and Its Impact on the Cost of Living of the Family.
The aim of this study was the evaluation of the degree of burden of caregivers of patients with hip fracture surgery and the assessment of its impact on their cost of living. This is a cross-sectional study and the study sample, which was a sample of convenience, included 100 caregivers of patients after hip replacement from February to May 2019 at the General Hospital of Thessaloniki "G. Gennimatas" in Greece. The main tools of the survey were the Bakas Caregiving Outcomes Scale (BCOS) Care Outcome Scale and a Questionnaire used for measuring rehabilitation costs in trauma patients adjusted for the needs of the present study. Of the 100 caregivers in the sample, 35% were male, 65% women and children of patients. Most caregivers worked full-time (47%), or had retired (39%). The costs incurred by the carers, which were not covered by the insurer, were, with the highest concerns, the rehabilitation center, the services of another caregiver, the services of an exclusive nurse, and physiotherapy. Informal caregivers often fill the gaps and shortcomings of the health systems of many countries, saving large sums of money. The state should take care of consolation leave to caregivers so that they can provide the necessary assistance to their people, thereby reducing their burden. The development of ambulatory care would offer such important and necessary respite for caregivers, having a positive impact on the care and course of the patient.


Epistatic interactions involving DRD2, DRD4, and COMT polymorphisms and risk of substance abuse in women with binge-purge eating disturbances.
Substance abuse is common in individuals with bulimia-spectrum (binge-purge) eating disturbances, a co-occurrence that has been attributed to shared neurobiological substrates--notably alterations in dopaminergic activity. We examined the implications of variations of selected, dopamine-relevant polymorphisms (DRD2 Taq1A, DRD4 7R, and COMT) for risk of substance abuse in women with binge-purge eating syndromes. We genotyped 183 women (66.1% showing full-threshold BN and 33.9% showing sub-syndromic variants), and assessed lifetime presence of alcohol, cannabis, cocaine, and stimulant abuse or dependence using structured interviews. Tests for main and interaction effects of various allele combinations revealed that individuals who carried high function COMT and low-function DRD4 7R alleles (a combination expected to be associated with higher risk) did indeed show more lifetime substance abuse and, specifically, more cannabis abuse. Our findings suggest that a gene combination that, in theory, codes for low levels of dopaminergic neurotransmission coincides with sensitivity to substance abuse in a sample displaying binge-purge eating-disorder variants.


Immunogenicity of HSP-70, KMP-11 and PFR-2 leishmanial antigens in the experimental model of canine visceral leishmaniasis.
Zoonotic visceral leishmaniasis (ZVL) is a parasitic disease caused by Leishmania infantum/L. chagasi that is emerging as an important medical and veterinary problem. Dogs are the domestic reservoir for this parasite and, therefore, the main target for controlling the transmission to humans. In the present work, we have evaluated the immunogenicity of the Leishmania infantum heat shock protein (HSP)-70, paraflagellar rod protein (PFR)-2 and kinetoplastida membrane protein (KMP)-11 recombinant proteins in dogs experimentally infected with the parasite. We have shown that peripheral blood mononuclear cells (PBMC) from experimentally infected dogs proliferated in response to these recombinant antigens and against the soluble leishmanial antigen (SLA). We have also quantified the mRNA expression level of the cytokines induced in PBMC upon stimulation with the HSP-70, PFR-2 and KMP-11 proteins. These recombinant proteins induced an up-regulation of IFN-gamma. HSP-70 and PFR-2 also produced an increase of the TNF-alpha transcripts abundance. No measurable induction of IL-10 was observed and low levels of IL-4 mRNA were produced in response to the three mentioned recombinant antigens. Serum levels of specific antibodies against HSP-70, PFR-2 and KMP-11 recombinant proteins were also determined in these animals. Our study showed that HSP-70, KMP-11 and PFR-2 proteins are recognized by infected canines. Furthermore, these antigens produce a Th1-type immune response, suggesting that they may be involved in protection. The identification as vaccine candidates of Leishmania antigens that elicit appropriate immune responses in the canine model is a key step in the rational approach to generate a vaccine for canine visceral leishmaniasis.


Efficacy and safety of first-line avelumab in patients with advanced non-small cell lung cancer: results from a phase Ib cohort of the JAVELIN Solid Tumor study.
Avelumab, an antiprogrammed death ligand-1 antibody, is approved as a monotherapy for treatment of metastatic Merkel cell carcinoma and advanced urothelial carcinoma, and in combination with axitinib for advanced renal cell carcinoma. We report the efficacy and safety of first-line avelumab in advanced non-small cell lung cancer (NSCLC). In a phase I expansion cohort of the JAVELIN Solid Tumor trial, patients with treatment-naive, metastatic, or recurrent NSCLC received 10 mg/kg avelumab intravenously every 2 weeks. Endpoints included best overall response, duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Overall, 156 patients were enrolled and treated. Median duration of follow-up was 18.6 months (range, 15 to 23 months). The objective response rate was 19.9% (95% CI, 13.9 to 27.0), including complete response in 3 (1.9%) and partial response in 28 (17.9%). Median DOR was 12.0 months (95% CI, 6.9 to not estimable). Median PFS was 4.0 months (95% CI, 2.7 to 5.4) and the 6-month PFS rate was 38.5% (95% CI, 30.7 to 46.3). Median OS was 14.1 months (95% CI, 11.3 to 16.9) and the 12-month OS rate was 56.6% (95% CI, 48.2 to 64.1). Treatment-related adverse events (TRAEs) occurred in 107 patients (68.6%), including grade ≥3 TRAEs in 19 (12.2%). Immune-related adverse events and infusion-related reactions occurred in 31 (19.9%) and 40 patients (25.6%), respectively. No treatment-related deaths occurred. Avelumab showed antitumor activity with a tolerable safety profile as a first-line treatment in patients with advanced NSCLC. These data support further investigation of avelumab in the phase III JAVELIN Lung 100 study. ClinicalTrials.gov NCT01772004; registered January 21, 2013.


Familial white sponge nevus of the oral mucosa: report of occurrence in three generations.
White sponge nevus is a rare, inherited disorder that usually presents as nonpainful white plaque primarily involving the buccal mucosa, gingiva, and palate. Extraoral lesions most often occur in the esophagus or anogenital area, but almost invariably follow the development of typical buccal lesions. This article presents a familial case of white sponge nevus in which oral lesions were found in patients in three generations of the same family. Histologic findings include hyperkeratosis, acanthosis, and perinuclear eosinophilic condensation of epithelial cell cytoplasm, which serve to confirm white sponge nevus as the diagnosis. Clinical presentation and histopathology of white sponge nevus are discussed in relation to the differential diagnosis of other oral leukokeratoses.


Polycystic Ovary Syndrome: Personality and Temperamental Characteristics.
Polycystic ovary syndrome (PCOS) is a common gynaecological/endocrine disorder that affects 5%-10% of women of reproductive age. Its association with psychiatric conditions is well known. This study aimed to evaluate personality, temperamental, and stress-related characteristics among PCOS patients by comparing them with a control group. We found that PCOS patients presented more pronounced features of type D personality and had higher NEO Five-Factor Inventory (NEO FFI) scores on neuroticism and lower NEO FFI scores on openness to experience and conscientiousness. On the Polish version of the Emotionality Activity Sociability Temperament Survey (EAS-D), PCOS patients reported higher emotionality-fear and lower activity than controls. The PCOS group also had higher scores on state anxiety and trait anxiety, using the State-Trait Anxiety Inventory (STAI) and Distressed Personality Scale (DS-14) questionnaires. These findings underline the importance of a multidisciplinary approach to the care of PCOS patients.


Cardiovascular safety outcomes of once-weekly GLP-1 receptor agonists in people with type 2 diabetes.
People with type 2 diabetes (T2D) are at increased risk of cardiovascular disease (CVD), which in turn is associated with increased morbidity and mortality. The impact of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) on cardiovascular (CV) outcomes has been investigated in CV outcomes trials (CVOTs). This review aims to help pharmacists and other healthcare professionals (HCPs) gain a better understanding of such CVOTs in T2D with a primary focus on the once-weekly (QW) GLP-1 RAs. This narrative review mainly focuses on the evaluation of the similarities and differences in the design and results of CVOTs involving currently approved and marketed QW GLP-1 RAs-semaglutide subcutaneous, exenatide extended-release (ER) and dulaglutide. Results from CVOTs of dipeptidyl peptidase-4 inhibitors (DPP4is) and sodium-glucose cotransporter-2 inhibitors (SGLT2is) are also included. Three CVOTs of QW GLP-1 RAs were identified for inclusion in this review: SUSTAIN 6 (semaglutide), EXSCEL (exenatide ER) and REWIND (dulaglutide), all of which varied in terms of trial design, patient demographics and other baseline characteristics. Results from these CVOTs demonstrated the CV safety of QW GLP-1 RAs compared with standard of care. Additionally, CV and renal benefits were demonstrated for semaglutide and dulaglutide, but not for exenatide ER. The CV safety of four DPP4is and three SGLT2is was demonstrated. None of the DPP4is had a CV or renal benefit, whereas all three SGLT2is were associated with CV and renal benefits. This article provides an overview of the results from QW GLP-1 RA CVOTs, including the recently published results for dulaglutide, and places them within the broader T2D treatment landscape to help HCPs make informed decisions in daily practice. The QW GLP-1 RAs with benefits reaching beyond glycaemic control can provide a comprehensive treatment option for people with T2D at high risk of CVD, with CVD or chronic kidney disease.


Estrogen Receptor β Controls Muscle Growth and Regeneration in Young Female Mice.
Estrogens are female sex hormones that are important for comprehensively maintaining muscle function, and an insufficiency affects muscle strength and regeneration in females. However, it is still unclear whether estrogen signaling is mediated through receptors. To investigate the specific role of estrogen receptor β (ERβ) in skeletal muscle and satellite cells (muscle stem cells), we generated muscle-specific ERβ-knockout (mKO) and satellite cell-specific ERβ-knockout (scKO) mice, respectively. Young female mKO mice displayed a decrease in fast-type dominant muscle mass. Female, but not male, scKO mice exhibited impaired muscle regeneration following acute muscle injury, probably due to reduced proliferation and increased apoptosis of satellite cells. RNA-sequencing analysis revealed that loss of ERβ in satellite cells altered gene expression of extracellular matrix components, including laminin and collagen. The results indicate that the estrogen-ERβ pathway is a sex-specific regulatory mechanism that controls muscle growth and regeneration in female mice.


Evidence for C1q-mediated crosslinking of CD33/LAIR-1 inhibitory immunoreceptors and biological control of CD33/LAIR-1 expression.
C1q collagen-like region (CLR) engaging and activating the LAIR-1 inhibitory immunoreceptor represents a non-complement mechanism for maintaining immune quiescence. Given the binding promiscuity of C1q's globular region (gC1q), we hypothesized that C1q concurrently associates with distinct inhibitory immunoreceptors to produce C1q-mediated modulatory networking. Like LAIR-1, CD33 inhibitory immunoreceptors are highly expressed on monocytes. Binding CD33 restricts cell activation/differentiation; however, natural ligands for CD33 remain elusive. CD33 has IgC2-like domains potentially recognized by gC1q. Thus, we asked whether C1q binds to CD33 and if C1q mediates CD33/LAIR-1 crosslinking. Our findings demonstrate that C1q and gC1q interact with CD33 to activate its inhibitory motifs, while CLR does not. Whole C1q is required to crosslink CD33 and LAIR-1 and concurrently activate CD33/LAIR-1 inhibitory motifs. While C1q binds CD33C2 domains, decreased C1q-CD33 interactions resulting from sialic acid masking of CD33C2 domains suggests a process for regulating C1q-CD33 activity. Consistent with defective self-tolerance, CD33/LAIR-1 expression is reduced in systemic lupus erythematosus (SLE) myelomonocytes. The anti-inflammatory cytokine M-CSF, but not DC growth factors, sustains CD33/LAIR-1 expression on both healthy and SLE cells suggesting further biological control of C1q-CD33/LAIR-1 processes.


Possible mechanisms of salt-induced hypertension in Dahl salt-sensitive rats.
Genetic factors, diet, and salt sensitivity have all been implicated in hypertension. To further understand the mechanisms involved in salt-induced hypertension, cardiovascular, hemodynamics, and biochemical parameters in Dahl salt-sensitive rats were evaluated in animals on high- and low-sodium diets. During a 4-week treatment period, blood pressure was significantly elevated in the high (8.0%) salt group compared to the low (0.3%) salt group (p< or =0.05 for weeks 2 and 4, respectively). No significant changes were observed in heart rate. The increase in blood pressure was associated with significant increases in lower abdominal aortic and renal vascular resistance, along with a reduction in blood flow. A fourfold increase in arginine vasopressin was observed in animals on the high-salt diet. In contrast, there was no effect on plasma sodium, potassium, or aldosterone levels during the treatment period. As measured in isolated aortic rings, the high-salt diet also caused a significant elevation in stimulated norepinephrine release and a reduction in cyclic GMP levels. These data suggest that salt-induced elevation in blood pressure is due to activation of both the sympathetic and arginine vasopressin systems via mechanisms involving decreased cyclic GMP generation in vascular smooth muscle.


Cost of care for the initial management of cervical cancer in women with commercial insurance.
Women with newly diagnosed cervical cancer are often treated with extensive, multimodal therapies that may include a combination of surgery, radiation, and chemotherapy. Little is known about the cost of treatment or how these costs are passed on to the patients. The objectives of this study were to examine the cost of care during the first year after a diagnosis of cervical cancer, to estimate the sources of the costs, and to explore the out-of-pocket costs. We performed a study of women with commercial insurance who received a new diagnosis of cervical cancer, and whose cases were recorded in the MarketScan database from 2008 to 2016. Patients were categorized based on the primary treatment received being either surgery (hysterectomy with or without adjuvant radiation or chemotherapy) or radiation. The inflation-adjusted medical expenditures for a 12-month period beginning on the date of the first treatment were estimated. The payments were divided into the expenditures of inpatient care, outpatient care (including chemotherapy), and outpatient pharmacy costs. The out-of-pocket costs incurred by the patients in the form of copayments, coinsurance, and deductibles were estimated. A total of 4495 patients, including 3014 (67%) who underwent surgery and 1481 (33%) who primarily underwent radiotherapy, were identified. The median total expenditure per patient during the first year after the diagnosis was $56,250 (interquartile range, $25,767-$107,532). The median total expenditure for patients with surgery as the primary treatment was $37,222 (interquartile range, $20,957-$75,555). The median total expenditure for patients treated primarily with radiotherapy was $101,266 (interquartile range, $63,155-$160,760). For patients treated primarily with surgery, inpatient services accounted for $15,145 (interquartile range, $0-$26,898), outpatient services accounted for $18,430 (interquartile range, $5354-$48,047), and outpatient pharmacy costs accounted for $628 (interquartile range, $141-$1847). The median cost for those women who did not require adjuvant therapy was $26,164 compared with $89,760 for women treated with adjuvant radiation. The median out-of-pocket costs for the cohort was $2253 (interquartile range, $1137-$3990) or 3.9% of the total costs. The cost of care for women with newly diagnosed cervical cancer is substantial. Overall, patients are responsible for approximately 3.9% of the costs in the form of out-of-pocket expenditures.


Impact of concurrent naturalistic pharmacotherapy on psychotherapy of complicated grief.
Complicated grief (CG) is a debilitating syndrome that can be reliably identified, but there is a paucity of research examining treatment of CG. A targeted psychotherapy for complicated grief (CGT) was recently shown to be efficacious [Shear, K., Frank, E., Houck, P.R., Reynolds, C.F., 3rd, 2005. Treatment of complicated grief: a randomized controlled trial. Journal of the American Medical Association 293, 2601-2608]. We provide a detailed examination of the association of naturalistic pharmacotherapy use with treatment response and study completion in the psychotherapy study. Patients on an antidepressant medication were more likely to complete a full course of CGT (91% vs. 58% completed), while antidepressant use had no effect on completion rates for the comparator, interpersonal psychotherapy (70% vs. 77%). Our naturalistic data underscore the need for prospective, randomized controlled studies of CG pharmacotherapy and psychotherapy alone and in combination.


Environmentally stable and stretchable polymer electronics enabled by surface-tethered nanostructured molecular-level protection.
Stretchable polymer semiconductors (PSCs) are essential for soft stretchable electronics. However, their environmental stability remains a longstanding concern. Here we report a surface-tethered stretchable molecular protecting layer to realize stretchable polymer electronics that are stable in direct contact with physiological fluids, containing water, ions and biofluids. This is achieved through the covalent functionalization of fluoroalkyl chains onto a stretchable PSC film surface to form densely packed nanostructures. The nanostructured fluorinated molecular protection layer (FMPL) improves the PSC operational stability over an extended period of 82 days and maintains its protection under mechanical deformation. We attribute the ability of FMPL to block water absorption and diffusion to its hydrophobicity and high fluorination surface density. The protection effect of the FMPL (~6 nm thickness) outperforms various micrometre-thick stretchable polymer encapsulants, leading to a stable PSC charge carrier mobility of ~1 cm2 V-1 s-1 in harsh environments such as in 85-90%-humidity air for 56 days or in water or artificial sweat for 42 days (as a benchmark, the unprotected PSC mobility degraded to 10-6 cm2 V-1 s-1 in the same period). The FMPL also improved the PSC stability against photo-oxidative degradation in air. Overall, we believe that our surface tethering of the nanostructured FMPL is a promising approach to achieve highly environmentally stable and stretchable polymer electronics.


Exploring the UVB-protective efficacy of melanin precursor extracted from marine imperfect fungus: Featuring characterization and application studies under in vitro conditions.
The present study explores the production, characterization, and application of a potentially stable melanin precursor from marine imperfect non-spore-forming Aspergillus nidulans sp. strain SG 28. Growth of the culture in artificial seawater with galactose and monosodium glutamate, pH at 7.2-7.5, and temperature at 35 ± 0.5 °C exhibits pigment production with the yield of 0.700-0.800 g/L. The characterization studies revealed that the pigment is orange reddish pink in color, soluble in water, insoluble in both polar and non-polar organic solvents, and decolorized when exposed to H2O2, KMnO4, and K2Cr2O7. UV-visible spectrum exhibits maximum absorption peak at 330 nm and mild shoulders at 400 and 500 nm. The pigment displayed both antioxidant and reducing power properties when exposed with ABTS and ferricyanide, respectively. The sun protection factor of the pigment was determined as 9.9. The cytocompatibility of the obtained pigment studied using HaCaT cells revealed that the cells are viable up to 500 μM. Experiments on UVB protection of the pigment using HaCat cells demonstrated the appreciable protective effect by reducing the ROS generation upon UVB exposure. In conclusion, the pigment obtained from the marine imperfect fungus showed structural similarity with DHICA which is confirmed by LC-MS. The presence of metal ions in the growth medium mediates the reaction to proceed towards DHICA formation. The SPF analysis, antioxidant property, and the UVB protection studies authenticate the potential use of pigment for skin care.


Severe neurocysticercosis in a quaternary hospital from Mozambique: Case series analysis.
Neurocysticercosis (NCC) is severe and leading global cause of morbidity and mortality. The disease presents with a variety of clinical presentations from focal to diffuse neurological symptoms. Despite being an endemic country, there are no studies describing the clinico-epidemiological characteristics of NCC in Mozambique. Herein, we describe a consecutive cases series of NCC from the national reference Hospital in Maputo, capital of Mozambique. Consecutive cases of NCC diagnosed during a 3-year period (January/2020-December/2022) were retrieved from the institutional clinical files and imaging database. Six cases of NCC were identified, with mean age of 43.1 years (range 26-66). Four were males (66.6 %). The median time from the beginning of clinical manifestations to the diagnosis was 6 months (range 3-18 months). All patients presented with severe parenchymal NCC, with seizures (n = 5, 83 %) being the most common manifestation. Other clinical manifestations were dementia (n = 1) and hydrocephalus (n = 1). The imaging showed multiple lesions at different stages, with half (n = 3) of them showing the coexistence of nodular calcified lesions at earlier stages (vesicular, colloidal and granular stages). Patients were treated with anthelminthic drugs, corticosteroids and anticonvulsants and no deaths to report. The 3rd month modified Rankin scale was ≤ 2 in 83 % of patients. In our case series, patients with NCC presented very late, with severe advanced stage disease, with multiple coexistent short and long-term brain lesions. These findings can be explained eventually because of the Maputo Central Hospital being national referral center receiving commonly more severe cases. Studies aiming to clarify the diagnosis pathways/barriers and NCC awareness among medical doctors working at primary and secondary health care level is mandatory to assess the real burden of NCC and implement timely diagnosis and care of patients affected by this neglected disease.