DC ablation in mice: promises, pitfalls, and challenges.
Dendritic cells (DC) play pivotal roles in orchestrating immunity and tolerance, and, as such, they are key targets for immunotherapy. Exploiting their function depends on a precise understanding of the part that different DC subsets play in vivo, but attempts to identify definitive functions have been limited by problems depleting individual DC populations in mice. Inducible cell ablation via transgenic expression of a high-affinity diphtheria toxin receptor (DTR) is a new and powerful approach to DC research. Here, we discuss the impact of CD11c-DTR and Langerin-DTR mice on DC immunobiology, and we highlight the problems to be aware of when interpreting data from these models. The challenge now will be to refine transgenic strategies so that other DC subsets can be inducibly depleted in vivo.


Prognostic significance of the brachial-ankle pulse wave velocity in patients with essential hypertension: final results of the J-TOPP study.
Brachial-ankle pulse wave velocity (baPWV) is a new tool for measuring arterial stiffness. The prognostic significance of this measure, however, is not fully established. We initiated a multicenter cohort study to examine the prognostic significance of baPWV in patients with essential hypertension in 2002. After baseline measurements were obtained, 662 previously untreated patients (mean age 60±12 years, mean blood pressure 156±19/94±12 mm Hg, 45% men) underwent long-term follow-up according to the current hypertension treatment guidelines. During the follow-up period (mean: 3 years, range: 3 months-8 years), 24 cardiovascular events were observed. The subjects were divided into high and low baPWV groups according to the median value (1750, cm s(-1)). Patients in the high baPWV group were older and had a lower body mass index, higher blood pressure, faster heart rate and higher fasting glucose and plasma creatinine concentrations compared with those in the low baPWV group. Cardiovascular morbidities per 1000 person-years for the high and low baPWV groups were 17.48 and 6.38, respectively (P<0.05), and the 8-year cardiovascular event-free survival rates were 78.2% and 93.5%, respectively (log-rank test, P=0.01). A multivariate Cox proportional hazard analysis showed that high baPWV compared with low baPWV was associated with a significantly poorer outcome (hazard ratio (HR) 2.97; 95% CI: 1.006-9.380). In conclusion, baPWV is an independent risk factor for future cardiovascular events in patients with essential hypertension.


Erratum: A multiplex inhalation platform to model in situ like aerosol delivery in a breathing lung-on-chip.
[This corrects the article DOI: 10.3389/fphar.2023.1114739.].


Intramural myomas: to treat or not to treat.
A debate among gynecologic and reproductive surgeons is whether or not there is a clinical need to treat all intramural myomas. Considerations include myoma size and number, ability to access them, whether or not they compromise the endometrium, and treatment effect on gynecologic, reproductive, and obstetric outcomes. We conducted a detailed study regarding intramural myomas, their prevalence in subject populations, the imaging methods used to detect them, their growth rate, their suspected adverse effects on gynecologic, fertility, and obstetric outcomes, and the effectiveness of various treatment methods. The growing body of evidence reported in the literature supports the need to manage intramural myomas and to treat them appropriately.


SHORT-TERM MODIFICATIONS OF ELLIPSOID ZONE IN BEST VITELLIFORM MACULAR DYSTROPHY.
To assess ellipsoid zone (EZ) alterations in Best vitelliform macular dystrophy using spectral-domain optical coherence tomography. Prospective, observational case series. Forty-three patients (43 eyes) underwent complete ophthalmological examination at baseline and at 24 months: best-corrected visual acuity (BCVA), biomicroscopy, fundus photography, and spectral-domain optical coherence tomography were performed. Acquisition protocol included 19-line raster scan. Alterations in EZ were marked on spectral-domain optical coherence tomography, and the area was manually calculated on a near-infrared reflectance image. Three patterns were identified: A (decrease >0.25 mm2), B (±0.25 mm2), and C (increase >0.25 mm2). Primary outcome was to describe different patterns of EZ alteration. Secondary outcomes included their correlation with BCVA and the description of a central optically preserved islet. At baseline, altered EZ was identified in 40 eyes. Worse BCVA significantly correlated with larger EZ alterations but not with lesion extension on fundus photograph. Only "pattern-C" eyes unveiled BCVA worsening at follow-up. Optically preserved islet was detected in 16 eyes (37%), disclosing significantly better vision; its disappearance at follow-up (n = 7; 44% of 16 eyes) correlated with a decrease in BCVA. The assessment of EZ status might represent a valuable functional marker in Best vitelliform macular dystrophy because stable alterations and the maintenance of a central optically preserved islet are associated with better visual acuity.


Vitamins inhibit oxidant-induced apoptosis of corneal endothelial cells.
To determine the effects of vitamins A, C, and E supplementation on lipid peroxidation and apoptosis in corneal endothelial cells. Murine corneal endothelial cells were maintained in tissue culture medium supplemented with free iron ions, known to lead to increased lipid peroxidation. The concentration of antioxidative vitamins (ascorbic acid, tocopherol, and retinoic acid) in the cells and supernatant was determined using reversed-phase high-performance liquid chromatography. Apoptosis was assessed by quantification of caspase-3-like activity, using annexin-V/propidium iodide stains for flow cytometry. Lipid peroxidation was assessed using the malondialdehyde method. Supplementation of antioxidative vitamins was tested in the setting of apoptosis. Increasing levels of free iron led to a rapid loss of antioxidative vitamins in the supernatant and corneal endothelial cells. This was correlated with rising levels of malondialdehyde and increased apoptosis. Supplementation with ascorbic acid or alpha-tocopherol alone was not sufficient to prevent lipid peroxidation in the cells, whereas a combination of vitamins C and E was able to do so. In contrast, supplementation with vitamin A alone significantly reduced oxidative stress and apoptosis. We present an in vitro model to test the direct influence of vitamin supplementation on corneal endothelial cells with regard to lipid peroxidation and apoptosis. We show that supplementation with antioxidative vitamins of corneal endothelial cells significantly prevents the generation of free-radical injury, lipid peroxidation, and consequent apoptosis.


Pediatric urinary tract infection. Diagnosis, classification, and significance.
The initial task is to establish the diagnosis of a urinary tract infection. The clinical setting, method of specimen collection, bacterial colony count, and species are all important considerations. Next, the infection is classified as complicated or uncomplicated. Complicated infections require hospitalization and parenteral antibiotic therapy. Appropriate imaging studies are imperative to determine whether urologic intervention is necessary. All children with well-documented urinary tract infections deserve diagnostic evaluation, regardless of sex or presence of systemic symptoms.


Effect of neonatal sympathectomy on the postnatal differentiation of the submandibular gland of the rat.
Right superior cervical sympathectomy was performed in one-day old rats. This operation had a small but definite effect on the postnatal development of the submandibular gland. The gland on the sympathectomized side weighed less and contained smaller amounts of DNA, RNA and protein than the contralateral intact gland. The postnatal development of acinar cells and granular convoluted ductal cells was retarded in the sympathectomized gland. The acinar cells which differentiated after the ganglionectomy were smaller than those in the contralateral intact gland and were filled with secretory granules but devoid of basal basophilia. The rate of cellular proliferation in the sympathectomized gland was, however, similar to that intact gland at various ages studied.


Low-level mercury exposure and peripheral nerve function.
Mercury is known to be neurotoxic at high levels. There have been few studies of potential peripheral neurotoxicity among persons with exposure to elemental mercury at or near background levels. The present study sought to examine the association between urinary mercury concentration and peripheral nerve function as assessed by sensory nerve conduction studies in a large group of dental professionals. From 1997 through 2006 urine mercury measurements and sensory nerve conduction of the median and ulnar nerves in the dominant hand were performed, and questionnaires were completed, on the same day in a convenience sample of dental professionals who attended annual conventions of the American Dental Association. Linear regression models, including repeated measures models, were used to assess the association of urine mercury with measured nerve function. 3594 observations from 2656 subjects were available for analyses. Urine mercury levels in our study population were higher than, but substantially overlap with, the general population. The only stable significant positive association involved median (not ulnar) sensory peak latency, and only for the model that was based on initial observations and exclusion of subjects with imputed BMI. The present study found no significant association between median or ulnar amplitudes and urine mercury concentration. At levels of urine mercury that overlap with the general population we found no consistent effect of urine mercury concentration on objectively measured sensory nerve function.


Efficacy of Cimicifuga racemosa, Hypericum perforatum and Agnus castus in the treatment of climacteric complaints: a systematic review.
The systematic review examines whether Cimicifuga racemosa (CR), Hypericum perforatum (HP), Agnus castus, vitamins and minerals, either as monotherapy or in combination, have an evidence-based impact on vasomotor, genital and psychological climacteric complaints. DATA SOURCES AND METHODS OF STUDY SELECTION: We searched in the databases EMBASE, OVID and PubMed using the keywords "vasomotor symptoms, hot flashes, vaginal atrophy, psychological problems, endometrium, sleep, concentration, cognition in combination with vitamins, multivitamins, minerals, multiminerals, black cohosh, Cimicifuga, Agnus castus, chasteberry, chaste tree, monk's pepper and menopause" for randomized controlled trials (RCT). Relevant studies were reviewed by four independent reviewers qualitatively. Most of the studies with a comparison of CR vs. placebo do not show an evidence-based significant effect of CR on climacteric symptoms. The combination of CR and HP shows an improvement of climacteric complaints in comparison to placebo. In some RCTs, there was no significant difference between CR and hormone-replacement therapy. The combination of HP and Agnus castus showed no significant difference in the treatment of climacteric complaints. CR monotherapy as well as HP and Agnus castus showed no better effect than placebo. The combination of CR with HP demonstrated a positive effect on climacteric complaints.


Epidemiological Profile of ENT Emergencies: Our Experience.
Emergencies in otorhinolaryngology are common occurrence. Early diagnosis and management result in reduction in morbidity and mortality. To assess the epidemiology, pattern and distribution of ENT emergencies at a tertiary level hospital. Cross sectional, retrospective, descriptive study over a period of 5 years. Medical records of these patients were studied, noting the age, sex, diagnosis on admission and outcome of emergency care. A total of 38,793 patients, age ranging from 15 days to 85 years were included in the study. The number of male and female patients were 25,971 (66.95%) and 12,822 (33.05%) respectively and the male to female ratio 2:1. The most commonly encountered emergency was epistaxis, which accounted for 25.58% of the emergencies attended. This was followed by ear ache and ear discharge. The ENT emergency ward plays a key role in the management of life-threatening conditions requiring immediate evaluation and management by specialized physician. It is important to prioritize and reduce the number of non-urgency/emergency cases attending the emergencies in order to ensure proper care is given to the emergency cases.


Optimization of sample extraction and injection-related parameters in HILIC performance for polar metabolite analysis. Application to the study of a model of pulmonary hypertension.
HILIC is a separation technique increasingly used for the study of polar metabolites. However, HILIC suffers of a drawback related to the solvents used for these analyses: acetonitrile as sample solvent leads to the best chromatographic peaks, but it is not capable to extract/dissolve the most polar compounds. In this work we evaluated the use of several strategies for the extraction of polar compounds from plasma samples and, although methanol was the ideal solvent for analyte extraction, distorted peaks were obtained in the chromatography. Different strategies were tested included changing the solvent after extraction or modifying the injection volume and type. Finally, the best solution was using the lowest injection volume possible and to employ a simple sandwich injection including acetonitrile during the injection of the sample. This remarkably improves the peak shape when methanol is used in the sample. We evaluated and applied two HILIC-MS methods, in positive and negative ionization modes, on plasma samples from pigs with pulmonary hypertension produced by aorto-pulmonary shunting to identify metabolic signatures underlying damage to the right heart. Our analyses revealed altered relevant metabolic pathways, suggestive of oxidative stress and reduced energy demands.


Exploration of the direct metabolic effects of mercury II chloride on the kidney of Sprague-Dawley rats using high-resolution magic angle spinning 1H NMR spectroscopy of intact tissue and pattern recognition.
Mercury II chloride (HgCl2) toxicity was investigated in Sprague-Dawley rats using high-resolution magic angle spinning (HRMAS) 1H NMR spectroscopy in conjunction with principal component analysis (PCA). Intact renal cortex and papilla samples from Sprague-Dawley rats treated with HgCl2 at two dose levels (0.5 and 2 mg/kg) and from matched controls (n=5 per group) were assessed at 48 h p.d. HgCl2) caused depletion of renal osmolytes such as glycerophosphocholine (GPC), betaine, trimethylamine N-oxide (TMAO), myo-inositol and taurine in both the renal cortex and the papilla. In addition, relatively higher concentrations of valine, isobutyrate, threonine and glutamate were observed in HgCl2-treated rats, particularly in the renal cortex, which may reflect a counterbalance response to the observed loss of other classes of renal osmolytes. Increased levels of glutamate were present in the cortex of treated rats, which may be associated with HgCl2-induced renal acidosis and disruption of the tricarboxylic acid cycle. A dose response was observed in both cortical and papillary tissue with increasing severity of metabolic disruption in the high dose group. 1H HRMAS NMR profiles of individual animals correlated well with conventional clinical chemistry and histology confirming the reproducibility of the technology and generating complementary molecular pathway information.


Outcome of prenatally detected bilateral higher urinary tract obstruction or megacystis: sex-related study on a series of 709 cases.
To compare the sex specific outcome of fetuses with prenatally detected urinary tract dilatation, with the exclusion of pyelectasia. Included in the study were 709 cases of major dilatation of the fetal urinary tract, diagnosed at routine ultrasound scan. For each sex group, cases were divided into two subgroups depending on the level of dilatation. Final diagnosis was based on postnatal evaluation or on fetal autopsy. Postnatal renal function was evaluated using serum creatinine at two years of age. Bilateral higher urinary tract dilatation was prenatally observed in 148 (20.8%) and lower urinary tract obstruction or bladder dilatation in 561 (79.1%) of the 709 cases (121 female and 588 male fetuses) (P <0.001). Bladder dilatation was less frequent in female fetuses (62%) than in males (82.6%) (P <0.001). At final diagnosis, associated malformations were observed in 53.7% of female fetuses versus 11% in males (P <0.001). The survival rate was 42.7%. Postnatal renal function, evaluated in 289/303 live infants, was impaired in 29.7% of cases and depended on the level of obstruction, but not on the sex. Prenatally detected urinary tract dilatation has a poor prognosis both in male and female fetuses. Associated malformations are observed more frequently in female than in male fetuses.


Microneedling with Biologicals: Advantages and Limitations.
Microneedling is a popular and cost-effective treatment with little down time. The application of topical agents to enhance outcomes is common practice. Microchannels created with nonthermal needling close at 4 hours to 6 hours due to fibrin plugs. Channels created with thermal needling or fractional laser stay open longer and enhance drug or biological uptake more due to the dermal sponge injury pattern that is created. Nonthermal microneedling devices may need Food and Drug Administration clearance, which also notes that dermaceuticals should be considered drugs in many cases.


Computer simulations of lipid membrane domains.
There is great diversity in the composition and structure of biological lipid membranes. We are beginning to appreciate the crucial role of lipids in many cellular processes, and characterize some of the lateral structures within membranes that could play a role in the activity of lipids. Simulations probe molecular level interactions between single molecules, which provide complementary information to experiments. Lipid membrane simulations have reached an exciting point, where the time and length scales of our simulations are approaching experimental resolutions and can be used to interpret experiments on increasingly complex model membranes. The focus of this review is on recent molecular simulations of domain formation in lipid bilayers. We highlight a number of recent examples where simulations are used in collaboration with experiments. We review recent simulation studies on lipid-lipid interactions related to domain formation and on lipid-protein interactions relevant for lipid raft function.


Bladder storage and emptying disorder frequencies in hemorrhagic and ischemic stroke patients with bladder dysfunction.
Bladder dysfunction is common in stroke patients and it has a considerable impact on their lives. The objective of this study was to investigate the frequencies of urine storage and emptying disorders in hemorrhagic and ischemic stroke patients with persistent bladder dysfunction. A total of 48 stroke patients who underwent urodynamic tests because of persistent bladder dysfunction were evaluated retrospectively. Urine storage and emptying disorder frequencies were determined and compared in hemorrhagic and ischemic stroke subgroups. Storage disorder frequencies were 73.3 and 63.6% in hemorrhagic and ischemic stroke groups, respectively (p > 0.05), while emptying disorder frequencies were 13.3 and 51.5% (p < 0.02). Evaluation of the stroke type may be helpful in the determination of the type of urinary dysfunction and in choosing the appropriate bladder management strategy, but further studies with larger sample sizes are needed.


ATP and fructose-2,6-bisphosphate regulate skeletal muscle 6-phosphofructo-1-kinase by altering its quaternary structure.
Recently, it has been demonstrated that fructose-2,6-bisphosphate (F2,6BP) protects skeletal muscle 6-phosphofructo-1-kinase (PFK) from thermal inactivation (50 degrees C) and against the deleterious effects of guanidinium hydrochloride (GdmCl). On the other hand, ATP, when added at its inhibitory concentrations, that is, >1 mM, enhanced either the thermal- or GdmCl-induced inactivation of PFK. Moreover, we concluded that these phenomena were probably due to the stabilization of PFK tetrameric structure by F2,6BP, and the dissociation of this structure into dimers induced by ATP. Aimed at elucidating the effects of F2,6BP and ATP on PFK at the structural and functional levels, the present work correlates the effects of these metabolites on the equilibrium between PFK dimers and tetramers to the regulation promoted on the enzyme catalytic activity. We show that ATP present a dual effect on PFK structure, favoring the formation of tetramer at stimulatory concentrations (up to 1 mM), and dissociating tetramers into dimers at inhibitory concentrations (>1 mM). Furthermore, F2,6BP counteracted this later ATP effect at either the structural or catalytic levels. Additionally, the effects of both F2,6BP or ATP on the equilibrium between PFK tetramers and dimers and on the enzyme activity presented a striking parallelism. Therefore, we concluded that modulation of PFK activity by ATP and F2,6BP is due to the effects of these ligands on PFK quaternary structure, altering the oligomeric equilibrium between PFK tetramers and dimers.


Work, environment and the fetus.
The opportunities for women to work in traditionally male oriented industries will increase substantially within the next 10 years exposing them to substances and processes which might adversely affect their reproductive health. The effects which known and putative reproductive toxins may have on pregnancy outcome are reviewed against the knowledge of normal development. Any epidemiological study which looks for an association between exposure and outcome must take into account confounding factors and sources of bias which may influence the result and lead to unsound conclusions. Some of these sources of error are discussed in relation to adverse reproductive outcomes. Where there is positive evidence of an adverse effect on reproduction policies must be formulated to provide equal protection for male and female reproductive health whilst, at the same time, allowing for the unique role of women in providing a safe internal environment for the developing fetus.


Long-term bonding effectiveness of simplified etch-and-rinse adhesives to dentin after different surface pre-treatments.
To evaluate the effect of 2% chlorhexidine (CHX) and 30% proanthocyanidin (PA) application on the immediate and long-term bond strength of simplified etch-and-rinse adhesives to dentin. One hundred twenty extracted human molar teeth were ground to expose the flat dentin surface. The teeth were equally divided into six groups according to the adhesives used, either Tetric N Bond or Solobond M and pretreatments given either none, CHX, or PA. Composite cylinder was bonded to each specimen using the respective adhesive technique. Half the samples from each group (n = 10) were then tested immediately. The remaining samples were tested after 6 month storage in distilled water. The mean bond strength of samples was not significantly different upon immediate testing being in the range of 8.4(±0.7) MPa. The bond strength fell dramatically in the control specimens after 6 month storage to around 4.7(±0.33) MPa, while the bond strength was maintained in the samples treated with both CHX and PA. Thirty percent PA was comparable to 2% CHX with respect to preservation of the resin dentin bond over 6 months.


Rapid high-performance liquid chromatographic determination of vancomycin in human plasma.
A rapid simple and robust reversed-phase HPLC method was developed for rapid screening in bioavailability studies or comparative bioequivalence studies. The method is specific for vancomycin as no interference from acetylsalicylic acid, paracetamol and caffeine was observed. The mean intra-day precision was from 11.7% (low concentration) to 0.3% (high concentration) and the within-day precision from 15.0 to 0.3%, determined on spiked samples. The accuracy of the method was 106.4-99.8% (intra-day) and 103.5-100.2% (inter-day).


Sorption properties of Th(IV) on the raw diatomite--effects of contact time, pH, ionic strength and temperature.
Diatomite has a number of unique physicochemical properties and has diversified industrial uses. Natural diatomite has been tested as a potential sorbent for the removal of Th(IV) from aqueous solutions. The results indicate that sorption of Th(IV) is strongly dependent on ionic strength at pH<3, and is independent of ionic strength at pH>3. Outer-sphere complexation or ion exchange may be the main sorption mechanism of Th(IV) to diatomite at low pH values, whereas the sorption of Th(IV) at pH>3 is mainly dominated by inner-sphere complexation or precipitation. The competition for Th(IV) between aqueous or surface adsorbed anions (e.g., herein ClO(4)(-), NO(3)(-) and Cl(-)) and surface functional groups of diatomite is important for Th(IV) sorption. The thermodynamic data (DeltaH(0), DeltaS(0), DeltaG(0)) are calculated from the temperature-dependent sorption isotherms. The results suggest that sorption process of Th(IV) on diatomite is spontaneous and endothermic.


Flow-cytometry-based evaluation of peripheral blood lymphocytes in prognostication of newly diagnosed DLBCL patients.
We aimed to analyse whether quantitative assessment of peripheral blood lymphocyte CD19(+)CD20(+)CD22(+)CD79a(+) B cells, CD3(+)CD4(+)CD5(+)CD8(+) T cells and CD4(+)CD25(+++)Foxp3high Treg can improve prognostication in DLBCL patients. The absolute count of lymphocytes, B-cells, T-cells and Treg-cells as well as the percentage of apoptotic cells were assessed by means of flow cytometry in all studied subjects. Significantly lower level of ALC and the percentage of apoptotic cells have been observed exclusively in DLBCL patients with HR. We also showed, that in comparison with LR, in HR and MR groups, there is a significant decrease in the absolute number of T-cells and Tregs. The applied treatment does no normalize the number of B-cells, Tregs and apoptotic cells only in the case of HR patients. Lymphopenia, the decreased absolute number of T cells, Tregs, and a percentage of apoptotic cells, correlates with clinical staging in DLBCL patients. The increased number of B cells and the decreased level of Tregs and apoptotic cells after treatment might predict a poor clinical outcome in patients treated with RCHOP. Thereby, flow-cytometry-based evaluation of peripheral blood lymphocytes may be useful in prognostication of newly diagnosed DLBCL patients.


2-Chloro-N-(4-chloro-3-iodo-phen-yl)-4-(methyl-sulfon-yl)benzamide.
In the title compound, C(14)H(10)Cl(2)INO(3)S, the dihedral angle between the benzene rings is 52.13 (10)°. In the crystal, the components are linked by pairs of N-H⋯O(sulfon-yl) hydrogen bonds into centrosymmetric dimers.


Factors affecting the quality of voice in the early glottic cancer treated with radiotherapy.
To prospectively analyze the objective voice quality before and after radiotherapy (RT) for early glottic cancer and to evaluate the role of different factors that may affect it. Patients with T1-T2N0M0 glottic cancer underwent voice quality assessment before treatment and after radical RT. Post-RT voice quality was compared to the voice at diagnosis and the voice of healthy individuals used as controls. A comprehensive set of voice parameters were measured. The effects of age, smoking history, T stage, anterior commissure (AC) involvement, radiation dose, fractionation and volumes on pre-treatment and post-treatment voice quality were analyzed. The voice quality data of 50 patients were analyzed. Following treatment, there was a significant improvement in the majority of measured parameters. However, perturbation and HNR remained inferior compared to controls. A history of smoking, AC involvement and larger RT volumes resulted in poorer voice parameters following RT. There was no significant impact of age alone. T2 tumors had an inferior voice quality before treatment, but did not remain inferior following RT. Hypofractionated RT did not show any negative impact. There is a considerable improvement of voice quality following RT. Several factors may have specific effects on pre-treatment and post-treatment voice.


What Makes a Piece of Art or Science a Masterpiece?
Works of art and science that achieve masterpiece status share several characteristics: they convey a special type of originality that captures the imagination, they stand the test of time, and they change the way artists or scientists think about their field.


Association of Genetic Variants of HLA-DQA1 with Bullous Pemphigoid Induced by Dipeptidyl Peptidase-4 Inhibitors.
Bullous pemphigoid (BP) is the most common autoimmune blistering disorder. Several factors, including an antidiabetic (dipeptidyl peptidase-4 inhibitor [DPP-4i]), have been reported to trigger BP. To identify the genetic variants associated with BP, GWAS and HLA fine-mapping analyses were conducted. The 21 cases of noninflammatory BP induced by DPP-4i (i.e., DPP-4i-induced noninflammatory BP) and 737 controls (first cohort) and the 8 cases and 164 controls (second cohort) were included in the GWAS. Combining GWAS satisfied the genome-wide significant association of HLA-DQA1 (chromosome 6, rs3129763 [T/C]) with the risk of DPP-4i-induced noninflammatory BP (allele T carrier of 72.4% [21 of 29] in cases vs. 15.3% [138 of 901] in controls; dominant model, OR = 14, P = 1.8 × 10-9). HLA fine mapping revealed that HLA-DQA1∗05 with serine at position 75 of HLA-DQα1 (Ser75) had the most significant association with the combined cohort of DPP-4i-induced noninflammatory BP (79.3% [23 of 29] cases vs. 16.1% [145 of 901] controls; dominant model, OR = 21, P = 2.0 × 10-10). HLA-DQα1 Ser75 polymorphism was located inside the functional pocket of HLA-DQ molecules, suggesting the impact of HLA-DQα1 Ser75 on DPP-4i-induced noninflammatory BP.


Characterization of low density lipoprotein-like particle in the human aorta from grossly normal and atherosclerotic regions.
Physical and chemical criteria of lipoproteins containing apolipoprotein B, extracted from human aortic intima, were compared with those of plasma low density lipoproteins (LDL). Homogenates of grossly normal intima and advanced atherosclerotic lesions were subjected to differential ultracentrifugation to isolate a d = 1.006--1.063 g/ml density fraction which was extensively characterized. By electroimmunoassay, over 90% of the recovered apolipoprotein B immunological reactivity was found in isolates from both plaques and normal intima. In isolates of plaque and normal intima, particles of the same size as LDL were found, although a small population of very large structures was also present in plaque fractions. Apolipoprotein composition was similar to that of plasma LDL except for the presence of human serum albumin in aortic isolates. Fractions from aorta demonstrated greater electrophoretic mobilities than LDL. The lipid composition of isolates from normal intima was similar to that of LDL. The lipid composition of plaque fractions showed a significant decrease in the cholesteryl ester to free cholesterol ratio and in the triglyceride content in comparison to LDL and to fractions from normal intima. The fatty acid pattern of the cholesteryl ester fraction from isolates of both normal and plaque aortic homogenates demonstrated a significant decrease in the linoleate to oleate ratio as compared to LDL. Our initial studies suggest that althought aortic fractions are similar to LDL by certain criteria, some differences observed are more pronounced in fractions from lesions than from normal intima.


Social determinants of health and survivorship in parotid cancer: An analysis of the National Cancer Database.
Given the rarity of parotid cancer, there is relatively few data published regarding outcomes. Utilizing the large sample population of the National Cancer Database (NCDB), we aim to examine the relationship between two key social determinants of health, demographics and socioeconomic status (SES), and parotid malignancy survival rates. Our analytic sample consists of patients with a diagnosis of primary malignancy of the parotid gland between 2004 and 2012 in the NCDB. We used univariable and multivariable Cox proportional hazard models to evaluate the relationship between overall survival rate and two key social determinants of health: demographics and SES. 15,815 cases met inclusion criteria. Average age was 60.1 years and 8255 were male (52.2%). Median overall survival was 121 months with 5-year overall survival of 67.4%. Male sex and older age at diagnosis were associated with poorer overall survival (p < 0.0001). We found that Asian Americans compared to whites had better overall survival (HR 0.75; 95% CI [0.58-0.95]). Black patients had improved survival compared to whites on univariate (HR 0.71; 95% CI [0.64-0.79]); but not multivariate analysis. Hispanic ethnicity and higher education level were protective (HR 0.76 95% CI [0.63-0.91] and HR 0.84 95% CI [0.74-0.96], respectively). We found no significant survival association based on income level. In this national sample of patients with parotid malignancy, a rare form of cancer, we found a significant correlation between important social determinants of health and overall survival rate. Females, Asian-Americans, Hispanics, and patients with higher education level have better overall survival.


Robotic instrument insulation failure: initial report of a potential source of patient injury.
To report our experience with failures in the accessory tip covers that insulate the monopolar robotic cautery scissor instruments and the patient injuries that have resulted. Currently, there is no data in the literature regarding the failure rate of robotic instruments or their accessory components. All robotic surgeries performed at our institution were recorded from July 2008 to January 2009. Instrument tip cover failures were recorded at the time of failure regardless of whether a patient complication occurred. Failure was identified by the arching of the electrical current from the insulated portion of the monopolar scissors or by an intraoperative injury. Four-hundred fifty-four robotic procedures were recorded. A total of 12 accessory tip cover failures were discovered, demonstrating a failure rate of 2.6%, with a patient complication rate of 0.6% (25% of all failures). Failure in robotic accessory tip covers can lead to patient complications. The cause for failure can be attributed to a variety of electrical and mechanical causes. All centers and surgeons performing robotic surgery should be aware of the potential for this problem to occur, and the possible interventions that may reduce tip cover failure.


Schizophrenia succeeded by affective illness; catamnestic study and statistical enquiry.
On the basis of data derived from a long-term follow-up of 12 cases and a 2-year follow-up of the International Pilot Study of Schizophrenia it is suggested that some patients with remitting schizophrenic illnesses can subsequently present clear-cut affective disorders. The implications of these findings are discussed.


How dermatology units can improve psychological wellbeing.
Skin conditions can result in many complex emotional and social problems. Psychological factors have long been associated with the onset, maintenance and exacerbation of many cutaneous disorders. This article is based on experience gained from contact with patients while on clinical placement at a specialist dermatology unit. It aims to assist nurses to understand the diverse ways in which stressors, coping strategies, acceptance, adaptation and compliance affect skin conditions. It will stimulate the reader to think about the psychological effect of skin conditions on everyday life and explore the advantages of specialised dermatology care in addressing the emotional problems of patients with such conditions.


RNF173 suppresses RAF/MEK/ERK signaling to regulate invasion and metastasis via GRB2 ubiquitination in Hepatocellular Carcinoma.
The role of the membrane-associated RING-CH (MARCH) family in carcinogenesis has been widely studied, but the member of this family, RNF173, has not yet been thoroughly explored in the context of hepatocellular carcinoma (HCC). With the use of an HCC tissue microarray and IHC staining, we aim to determine the differential expression of RNF173 in HCC patients and its clinical significance. The biological role of RNF173 is investigated through in vitro and in vivo experiments. RNA sequencing, mass spectrometry, and immunoprecipitation are performed to uncover the underlying mechanism of RNF173's impact on the development of HCC. The mRNA and protein levels of RNF173 were significantly lower in HCC tissues than in normal tissues. HCC patients with low RNF173 expression had shorter overall survival and recurrence-free survival, and RNF173 was significantly correlated with tumor number, tumor capsule, tumor differentiation, and BCLC stage. In addition, in vitro and in vivo experiments showed that RNF173 downregulation exacerbated tumor progression, including migration, invasion, and proliferation. GRB2 is a key molecule in the RAF/MEK/ERK pathway. RNF173 inhibits the RAF/MEK/ERK signaling by ubiquitinating and degrading GRB2, thereby suppressing HCC cell proliferation, invasion and migration. Combining clinical samples, we found that HCC patients with high RNF173 and low GRB2 expression had the best prognosis. RNF173 inhibits the invasion and metastasis of HCC by ubiquitinating and degrading GRB2, thereby suppressing the RAF/MEK/ERK signaling pathway. RNF173 is an independent risk factor for the survival and recurrence of HCC patients. RNF173 may serve as a novel prognostic molecule and potential therapeutic target for HCC. Video Abstract Graphical abstract Model of RNF173 on RAF/MEK/ERK signaling. RNF173 knockdown resulted in impaired ubiquitination and degradation of GRB2, leading to the activation of the RAF/MEK/ERK signaling pathway and promotion of invasion and metastasis in HCC cells.


An epirubicin-conjugated nanocarrier with MRI function to overcome lethal multidrug-resistant bladder cancer.
Multidrug resistance (MDR) presents a major obstacle to curing cancer. Chemotherapy failure can occur through both cell membrane drug resistance (CMDR) and nuclear drug resistance (NDR), and anticancer effectiveness of chemotherapeutic agents is especially reduced by their nuclear export. Here we report an exciting magnetically-targeted nanomedicine formed by conjugation of epirubicin (EPI) to non-toxic and high-magnetization nanocarrier (HMNC). Strikingly, HMNC-EPI overcomes both CMDR and NDR in human bladder cancer cell models, without using P-glycoprotein (P-gp) and nuclear pore inhibitors. Besides, the half-life of drug is prolonged ~1.8-fold (from 45 h to 81 h) at 37 °C, with a ~10-fold increase in concentration at the tumor site through magnetic targeting (MT). Moreover, malignant NDR bladder cancer can be effectively inhibited after 14 days in mice by just two injections and MT. We are the first to demonstrate the nanomedical strategy that can overcome the CMDR and NDR bladder cancers simultaneously, and proceed to the excellent MT therapy, significantly reducing the dosage and cardiotoxicity and holding great promise for incurable human MDR bladder cancer.


Involvement of curli fimbriae in the biofilm formation of Enterobacter cloacae.
In this study, we examined the biofilm forming ability, the mRNA expression of curli genes and the morphologies of curli fimbriae and biofilms in clinical isolates of Enterobacter cloacae. The csgBA operon was found in 11 (78.6%) of the 14 isolates. The ability of E. cloacae isolates to form biofilms was significantly correlated with the mRNA expression level of the csgA and csgD genes. The curli protein fimbriae appeared as tangled fibers and the curli-proficient strain formed mature biofilms. Our data suggest that the expression of the curli fimbriae play an important role in biofilm formation in E. cloacae.


EMD 281014, a specific and potent 5HT2 antagonist in humans: a dose-finding PET study.
While serotonin 5HT2-receptors have been implicated in the etiology and pharmacological treatment of a number of neuropsychiatric conditions, there are few potent and specific agents available for use in human clinical studies. EMD 281014 is a highly specific 5HT2-receptor antagonist that is currently under development. To find optimal doses for early clinical studies, we conducted a PET study using [18F]setoperone in nine healthy subjects scanned at baseline and following the administration of 1, 3, and 7 mg EMD 281014. The study drug was well tolerated by all study participants, and all doses resulted in > or =70% occupancy at frontal 5HT2-receptors 3 h after drug administration. The data suggest that daily dosing of > or =3 mg EMD 281014 should be sufficient to provide sustained high levels of 5HT2-receptor occupancy in future clinical trials.


The role of real-time interactive video consultations in dental practice during the recovery and restoration phase of the COVID-19 outbreak.
The COVID-19 outbreak has caused many challenges for the dental profession and workforce. With the suspension of routine dental services at the end of March 2020, there is a significant number of the general population with acute dental problems. In addition to these, there are patients who had treatment suspended partway through their treatment plans and therefore there is now a backlog of patients awaiting dental care. One challenge that will face the profession moving forward will be facilitating access to these patients and determining which patients should be seen as a priority for necessary dental care. This article looks at the role of real-time interactive video consultations in dental practice during the recovery and restoration phase of the COVID-19 outbreak and how they could facilitate the management of patients waiting to access dental care.


Cardiomyopathy in children: Can we rely on echocardiographic tricuspid regurgitation gradient estimates of right ventricular and pulmonary arterial pressure?
Introduction Agreement between echocardiography and right heart catheterisation-derived right ventricular systolic pressure is modest in the adult heart failure population, but is unknown in the paediatric cardiomyopathy population. All patients at a single centre from 2001 to 2012 with a diagnosis of cardiomyopathy who underwent echocardiography and catheterisation within 30 days were included in this study. The correlation between tricuspid regurgitation gradient and catheterisation-derived right ventricular systolic pressure and mean pulmonary artery pressure was determined. Agreement between echocardiography and catheterisation-derived right ventricular systolic pressure was assessed using Bland-Altman plots. Analysis was repeated for patients who underwent both procedures within 7 days. Haemodynamic data from those with poor agreement and good agreement between echocardiography and catheterisation were compared. A total of 37 patients who underwent 48 catheterisation procedures were included in our study. The median age was 11.8 (0.1-20.6 years) with 22 males (58% total). There was a modest correlation (r=0.65) between echocardiography and catheterisation-derived right ventricular systolic pressure, but agreement was poor. Agreement between tricuspid regurgitation gradient and right ventricular systolic pressure showed wide 95% limits of agreement. There was a modest correlation between the tricuspid regurgitation gradient and mean pulmonary artery pressure (r=0.6). Shorter time interval between the two studies did not improve agreement. Those with poor agreement between echocardiography and catheterisation had higher right heart pressures, but this difference became insignificant after accounting for right atrial pressure. Transthoracic echocardiography estimation of right ventricular systolic pressure shows modest correlation with right heart pressures, but has limited agreement and may underestimate the degree of pulmonary hypertension in paediatric cardiomyopathy patients.


Innovative problem-solving in a threatened gull species, the Olrog's Gull (Larus atlanticus).
Innovation, a process that plays an important role in the ecology and evolution of species, is considered an expression of behavioral flexibility in animals. Here we analyzed innovative problem-solving ability and performance enhancement through learning in the Olrog's Gull (Larus atlanticus), under controlled processes and experimental conditions. Trials were undertaken with nine adult individuals captured at a highly urbanized coastal area of Argentina. Each individual was presented with a Plexiglas box that could be opened by pushing or pulling two lids, each lid leading to a separated food reward. We measured problem-solving ability through consumption latency and the number of solved lids. As explanatory variables, we measured contact rate, as a measure of persistence, and the number of effective contacts. The results showed that the contact rate and effective contacts did not affect variables related to problem-solving ability during the first confrontation of the individuals with the closed box. Consumption latency decreased significantly throughout the trials, and with increasing contact rate and effective contacts. The number of solved lids increased through the trials independently of the contact rate and the total effective contacts with the box. Although persistence did not influence individuals' performance during the problem-solving test; this variable affected individuals' ability to solve the task throughout trials. Learning was evidenced by the decrease in the resolution time across experiments, suggesting that successful individuals improved their performance probably through a trial-and-error process. Evaluation of behavioral responses of a threatened seabird to a novel problem-solving task adds knowledge to previous field studies and provides a better understanding of the ability of individuals to adjust their foraging behavior in highly urbanized areas used during the non-breeding season.


Safe medicine recommendation via star interactive enhanced-based transformer model.
With the rapid development of electronic medical records (EMRs), most existing medicine recommendation systems based on EMRs explore knowledge from the diagnosis history to help doctors prescribe medication correctly. However, due to the limitations of the EMRs' content, recommendation systems cannot explicitly reflect relevant medical data, such as drug interactions. In recent years, medicine recommendation approaches based on medical knowledge graphs and graph neural networks have been proposed, and the methods based on the Transformer model have been widely used in medicine recommendation systems. Transformer-based medicine recommendation approaches are readily applicable to inductive problems. Unfortunately, traditional Transformer-based medicine recommendation approaches require complex computing power and suffer information loss among the multi-heads in Transformer model, which causes poor performance. At the same time, these approaches have rarely considered the side effects of drug interaction in traditional medical recommendation approaches. To overcome the drawbacks of the current medicine recommendation approaches, we propose a Star Interactive Enhanced-based Transformer (SIET) model. It first constructs a high-quality heterogeneous graph by bridging EMR (MIMIC-III) and a medical knowledge graph (ICD-9 ontology and DrugBank). Then, based on the constructed heterogeneous graph, it extracts a disease homogeneous graph, a medicine homogeneous graph, and a negative factors homogeneous graph to get auxiliary information of disease or drug (named enhanced neighbors). These are fed into the SIET model in conjunction with the relevant information in the EMRs to obtain representations of diseases and drugs. It finally generates the recommended drug list by calculating the cosine similarity between disease combination representations and drug combination representations. Extensive experiments on the MIMIC-III, DrugBank, and ICD-9 ontology datasets demonstrate the outstanding performance of our proposed model. Meanwhile, we show that our SIET model outperforms strong baselines on an inductive medicine recommendation task.


Microbial community structure and settlement induction capacity of marine biofilms developed under varied reef conditions.
Coral larval settlement relies on biogenic cues such as those elicited by microbial biofilm communities, a crucial element of coral recruitment. Eutrophication can modify these biofilm-associated communities, but studies on how this affects coral larval settlement are limited. In this study, we developed biofilm communities on glass slides at four sites with increasing distance from a mariculture zone. Biofilms farthest from the mariculture area were more effective at inducing the settlement of Acropora tenuis larvae. These biofilms were characterized by a greater proportion of crustose coralline algae (CCA) and gammaproteobacterial taxa compared to biofilms from sites closer to the mariculture zone, which had a greater proportion of cyanobacteria and no CCA. These findings suggest that nutrient enrichment due to mariculture activities alters the composition of biofilm-associated microbiome at nearby reef sites and indirectly causes poor coral larval settlement.


Habitat selection of three chrysomelid species associated with Rumex spp.
Habitat selection of three chrysomelid beetles feeding on the Rumex plants was studied in relation to the ecological requirements of the three species and the habitat characteristics arising in their unstable and often unpredictable environment. The different ecological requirements and bionomic characteristics of the three chrysomelids were associated not only with their differing degrees of feeding specialization; they also influenced habitat selection. For example, the small body size and lower food demands of Mantura clavareaui, which is a feeding specialist, allowed it to exploit any habitat, irrespective of habitat size and duration. The other specialist, Gastrophysa atrocyanea, selected larger habitats because of the relatively brief lifespan of its adults after overwintering, its reduced mortality, and greater food demand. On the other hand, Galerucella vittaticollis, which is a multivoltine, general feeder, selected the habitat that lasted longer, rather than one that was larger. This species' life cycle is not synchronized with Rumex phenology, but its adults are long-lived and it has a flexible life cycle. The different patterns in habitat selection among these three chrysomelids prevented serious overlapping of their habitats; thus, the habitat overlapping of 2 or 3 species was 34.62%, that of all 3 species 3.85%. Most of the habitats utilized by Gastrophysa, however, overlapped those of the other two species, because Gastrophysa's habitat utilization range was the narrowest of the three. In Mantura, the degree of overlap with the other two species was lowest because this beetle had the broadest range of habitat utilization. On the other hand, Galerucella adjusted the temporal, rather than the spatial coordinates of its habitat usage when it occupied habitats where the other two specialists were also present. Galerucella, unlike the other two species, is multivoltine. Consequently, it was able to coexist in habitats occupied by the others by exploiting the host plants at times when the other species were numerically few, or even absent. No direct interspecific competition among adults of the three species was observed. Their different patterns of habitat selection created by their different responses to available food allowed them to coexist on Rumex without direct competition.


siRNA knock down of glutamate dehydrogenase in astrocytes affects glutamate metabolism leading to extensive accumulation of the neuroactive amino acids glutamate and aspartate.
Glutamate is the most abundant excitatory neurotransmitter in the brain and astrocytes are key players in sustaining glutamate homeostasis. Astrocytes take up the predominant part of glutamate after neurotransmission and metabolism of glutamate is necessary for a continuous efficient removal of glutamate from the synaptic area. Glutamate may either be amidated by glutamine synthetase or oxidatively metabolized in the mitochondria, the latter being at least to some extent initiated by oxidative deamination by glutamate dehydrogenase (GDH). To explore the particular importance of GDH for astrocyte metabolism we have knocked down GDH in cultured cortical astrocytes employing small interfering RNA (siRNA) achieving a reduction of the enzyme activity by approximately 44%. The astrocytes were incubated for 2h in medium containing either 1.0mM [(15)NH(4)(+)] or 100 μM [(15)N]glutamate. For those exposed to [(15)N]glutamate an additional 100 μM was added after 1h. Metabolic mapping was performed from isotope incorporation measured by mass spectrometry into relevant amino acids of cell extracts and media. The contents of the amino acids were measured by HPLC. The (15)N incorporation from [(15)NH(4)(+)] into glutamate, aspartate and alanine was decreased in astrocytes exhibiting reduced GDH activity. However, the reduced GDH activity had no effect on the cellular contents of these amino acids. This supports existing in vivo and in vitro studies that GDH is predominantly working in the direction of oxidative deamination and not reductive amination. In contrast, when exposing the astrocytes to [(15)N]glutamate, the reduced GDH activity led to an increased (15)N incorporation into glutamate, aspartate and alanine and a large increase in the content of glutamate and aspartate. Surprisingly, this accumulation of glutamate and net-synthesis of aspartate were not reflected in any alterations in either the glutamine content or labeling, but a slight increase in mono labeling of glutamine in the medium. We suggest that this extensive net-synthesis of aspartate due to lack of GDH activity is occurring via the concerted action of AAT and the part of TCA cycle operating from α-ketoglutarate to oxaloacetate, i.e. the truncated TCA cycle.


Carnitine status in early-treated children, adolescents and young adults with phenylketonuria on low phenylalanine diets.
In patients with phenylketonuria (PKU), the carnitine status may be impaired for metabolic or dietary reasons, including low carnitine intake, a deficient synthesis and acylcarnitine production from phenylalanine (Phe) metabolites. Free carnitine and acylcarnitine status was assessed in 30 PKU patients, aged 0.5-36 years, mean age 13.8 years. Our cohort was divided into 2 groups according to the preparations of Phe-free amino acids (AA) prescribed, with or without carnitine supplementation. Daily Phe intake, dosage of AA mixtures and body weight were recorded along with measurements of acylcarnitines in blood spots (by tandem mass spectrometry) and serum AA. Control data were obtained from 50 healthy volunteers (aged 0.2-39 years, mean age 14.2. years). Statistical analysis comprised the t test, ANOVA and Pearson's correlation. PKU patients had lower free carnitine (C0) concentrations than controls (25.82 +/- 7.38 vs. 31.28 +/- 6.17 micromol/l; p < 0.001) and lower octanoyl- and decanoylcarnitine. Mean C0 and acylcarnitine concentrations did not differ between PKU patients taking the various protein substitutes with or without carnitine; mean C0 levels in PKU patients receiving AA enriched with carnitine were still lower compared with controls (p < 0.05). Actual dietary regimens can not completely normalize the carnitine status; therefore, carnitine levels should be given careful consideration in subjects with PKU.


Morphological changes in early melanoma development: influence of nutrients, growth inhibitors and cell-adhesion mechanisms.
Current diagnostic methods for skin cancers are based on some morphological characteristics of the pigmented skin lesions, including the geometry of their contour. The aim of this article is to model the early growth of melanoma accounting for the biomechanical characteristics of the tumor micro-environment, and evaluating their influence on the tumor morphology and its evolution. The spatial distribution of tumor cells and diffusing molecules are explicitly described in a three-dimensional multiphase model, which incorporates general cell-to-cell mechanical interactions, a dependence of cell proliferation on contact inhibition, as well as a local diffusion of nutrients and inhibiting molecules. A two-dimensional model is derived in a lubrication limit accounting for the thin geometry of the epidermis. First, the dynamical and spatial properties of planar and circular tumor fronts are studied, with both numerical and analytical techniques. A WKB method is then developed in order to analyze the solution of the governing partial differential equations and to derive the threshold conditions for a contour instability of the growing tumor. A control parameter and a critical wavelength are identified, showing that high cell proliferation, high cell adhesion, large tumor radius and slow tumor growth correlate with the occurrence of a contour instability. Finally, comparing the theoretical results with a large amount of clinical data we show that our predictions describe accurately both the morphology of melanoma observed in vivo and its variations with the tumor growth rate. This study represents a fundamental step to understand more complex microstructural patterns observed during skin tumor growth. Its results have important implications for the improvement of the diagnostic methods for melanoma, possibly driving progress towards a personalized screening.


Stability and cellular studies of [rac-1,2-bis(4-fluorophenyl)-ethylenediamine][cyclobutane-1,1- dicarboxylato]platinum(II), a novel, highly active carboplatin derivative.
The synthesis of the diastereomeric [1,2-bis(4-fluorophenyl)ethylenediamine][cyclobutane-1, 1-dicarboxylato]platinum(II) complexes, rac- and meso-4F-Pt(CBDC), the evaluation of their structures, their tumor-inhibiting properties and their stability in physiological environment are described (reference complexes: the dichloro- and sulfatoplatinum(II) analogues, carboplatin and cisplatin). The most interesting diastereomer, rac-4F-Pt(CBDC), equals cisplatin and surpasses carboplatin in its effect on human breast cancer cell lines (MCF-7 and MDA-MB-231). Rac-4F-Pt(CBDC) is largely insensitive against attack of nucleophiles e.g. Cl-, a prerequisite for sufficient stability in vivo and for fewer side effects. In accordance with this, in vitro studies on the binding of rac-4F-Pt(CBDC) to albumin, the main plasma protein, show that the free, non-protein-bound fraction is relatively high, coming close to that of carboplatin. These properties are of importance for the transferability of the promising effects found in the cell culture experiments to in vivo conditions. The distinctly better anti-breast cancer activity of rac-4F-Pt(CBDC) than of carboplatin has been attributed to its ability to accumulate in the tumor cells. The human ovarian cancer cell line NIH-OVCAR-3 is also strongly inhibited by rac-4F-Pt(CBDC).


Molecular characterisation and infection dynamics of Dentitruncus truttae from trout (Salmo trutta and Oncorhynchus mykiss) in Krka River, Croatia.
Dentitruncus truttae (Acanthocephala, Palaeacanthocephala) is an intestinal parasite of fish that can cause extensive damage to the host digestive tract, yet little is known about its epidemiology and genetic variability. It is a member of the Illiosentidae family with a worldwide distribution restricted to parts of southeast Europe. Its usual host is brown trout (Salmo trutta), but we report here the first detection in the intestine of rainbow trout (Oncorhynchus mykiss). We examined the physiology of D. truttae-infected S. trutta and O. mykiss, seasonal and spatial variability of D. truttae infections, and genetic variability of the parasite population in Krka River, Croatia. D. truttae was more abundant in both trout populations in the autumn, with no seasonal variation in prevalence. The parasite was more abundant in male than female trout (n=75, p<0.01). Analysis of the spatial distribution of the parasite across various sampling sites along the river showed the lowest prevalence and abundance of parasitic infections at the most downstream sampling site, which may reflect the predominance of female fish there and/or the smaller population of intermediate hosts. To provide the first molecular insights into D. truttae, we analysed sequences at three marker loci: the 18S rRNA gene, the cytochrome c oxidase subunit 1 (COI) gene and the internal transcribed spacer region. Phylogenetic analysis based on 18S rRNA confirmed the taxonomic grouping of D. truttae in the Illiosentidae family, first made more than 50 years ago based on morphology. The COI haplotype network did not show discrete genetic clusters corresponding to the different sampling sites, suggesting a stable population. These insights into D. truttae haplotype frequency distribution and intrapopulation genetic variation revealed minimal genetic variability, compared to the other acanthocephalan species.


Biological markers in osteoarthritis.
Osteoarthritis (OA) is considered as a chronic disease with a long "silent" period. The diagnosis is generally based on clinical symptoms and radiographic changes. However X-ray has a poor sensitivity and a relatively large precision error that does not allow an early detection of OA or the monitoring of joint damage progression. The limitations of the tools that are currently available for OA assessment have been the impetus to identify specific biological markers that reflect quantitative and dynamic variations in joint remodeling. Research has focused on the structural components of cartilage matrix, especially type II collagen degradation markers. In spite of a significant increase of some markers in individuals with early stage of OA, the large overlap with control subjects indicates that the current biomarkers used alone have limited diagnostic potential. However, the combination of specific markers seems to improve the prediction of disease progression at the individual level. Several types of treatment have been investigated but the lack of medications with definitively demonstrated chondroprotective activity has limited the assessment of the potential role of biomarkers for monitoring patients' responses to the treatment of OA. In this review, we will use the BIPED classification that appeared in 2006 for OA markers to describe the potential usage of a given marker [5]. This article is part of a Special Issue entitled "Osteoarthritis".


Characterization of the gene encoding both growth hormone-releasing hormone (GRF) and pituitary adenylate cyclase-activating polypeptide (PACAP) in the zebrafish.
The purpose of this research was to isolate and characterize the gene encoding growth hormone-releasing hormone (GRF) and pituitary adenylate cyclase-activating polypeptide (PACAP) from the zebrafish. The gene is comprised of five exons with two distinct peptides encoded on separate exons, GRF on exon 4 and PACAP on exon 5. Our evidence indicates that the zebrafish genome contains a single copy of the GRF-PACAP gene. The tissue distribution pattern of the mRNA transcript shows expression in the brain, eye, gastrointestinal tract, ovary and testis; each transcript was sequenced and found to be identical to the gene. This is the first report of GRF-PACAP mRNA expression in the eye of a non-mammalian species. Evidence that a duplication of the PACAP gene gave rise to the vasoactive intestinal peptide (VIP) gene is supported by the high amino acid sequence identity between PACAP in zebrafish and VIP in other fish species.


The effect of filament shortening on the mechanical properties of gel-filtered actin.
To address the claim that filaments polymerized from highly purified (gel-filtered) F-actin acquire the elastic properties of a solid attributable to chemical cross-linking, we measured the rheologic spectrum of the dynamic storage modulus, G', and loss modulus, G'' from 5 x 10(-4) to 0.5 Hz for gel-filtered actin alone and in the presence of the actin shortening protein, gelsolin. We confirmed that gel-filtered filamentous actin is a highly elastic material as evidenced by a relatively frequency-independent G', which is consistent with either topologically constrained filaments or a chemically cross-linked gel. Introduction of gel-filtered actin oligomers, however, caused the behavior of gel-filtered actin to become more frequency-dependent and almost identical to that of non-gel-filtered actin, suggesting that the effect of gel filtration on the mechanical behavior of actin is topologic. This conclusion is further supported by the finding that shortening of the actin filaments by the addition of gelsolin at molar ratios to actin of from 1:8000 to 1:500 causes a gradual decrease in elasticity and increase in the amount of flow.


The metabolism and kinetics of 125I-labeled human intravenous IgG preparation (C-425) in rats and rabbits. I. Blood clearance, excretion into urine and feces, and brain uptake.
The metabolism of intravenous human IgG preparation (C-425) was studied by the use of 125I-C-425 in rats and rabbits after intravenous injection of the compound particularly with regard to changes in the levels of radioactive compound or metabolites in the blood as a function of time as well as levels excreted in urine and feces. Brain uptake index of 125I-C-425 was estimated by a slightly modified Oldendorf's method. 125I-Polyglobin was used as the control compound. The half-life of blood clearance of 125I-C-425 radioactivity after the 2nd day was about 8 days in rats and about 5 days in rabbits, respectively. Within a relatively short period of 1 hour, a rapid decrease of blood concentration of radioactivity was recorded. This was due to the transfer of labelled compound from blood into the extravascular compartment. A high concentration of radioactivity in the blood was maintained for one week after intravenous injection of the labelled compound in both rats and in rabbits. Most of the radioactive compound or metabolites were excreted in the urine and relatively little in feces. Excretion in urine of rats reached about 22% for 125I-C-425 and about 17% for 125I-Polyglobin. The excretion rate slowed down over 24 hours. The total recovery rates in rats were about 40% for 125I-C-425 and 125I-Polyglobin and about 55% in rabbits for both drugs. The permeability through the blood-brain barrier was found to be negligible for both drugs.


Hamstrings fascicle length and physical performance changes after a single bout of dynamic stretching or neurodynamic gliding in healthy young and older adults.
The physiological and structural alterations have been less reported in response to dynamic stretching (DS) or neurodynamic nerve gliding (NG). Accordingly, this study investigated the changes in fascicle lengths (FL), popliteal artery velocity, and physical fitness in response to a single bout of DS or NG. The study included 15 healthy young adults (20.9 ± 0.7 yrs) and 15 older adults (66.6 ± 4.2 yrs) who randomly performed three different interventions (DS, NG, and rest control) for 10 min and 3 days apart. The biceps femoris and semitendinosus FL, popliteal artery velocity, sit and reach (S&R), straight leg raise (SLR), and fast walking speed were measured before and immediately after the intervention. After NG intervention, S&R was largely greater by 2 cm (1.2, 2.8 cm) and 3.4 cm (2.1, 4.7 cm) with largely increased SLR angles of 4.9° (3.7°, 6.1°) and 4.6° (3.0°, 6.2°) with all p < 0.001 for the older adults and young groups, respectively. A similar magnitude improvement in the S&R and SLR testing was also seen for both groups after DS (p < 0.05). Moreover, no changes were seen in FL, popliteal artery velocity, fast gait speed, and age effect following all three intervention occasions. Stretching with DS or NG immediately increased flexibility, which appeared to be largely due to changes in stretch tolerance rather than an increase in fascicle length. Furthermore, age dependency in response to stretching exercise was not seen in the present study.


The Impact of the Animal Housing System on Immune Cell Composition and Function in the Blood of Dromedary Camels.
The dromedary camel (Camelus dromedarius) is an important livestock animal of desert and semi-desert ecosystems. In recent years, several elements of the camel immune system have been characterized. Stress and excitement induced by animal housing represent the most important environmental factors with potential modulatory effects on the immune system. The present study evaluated the impacts of a restricted-housing system on some phenotypic and functional properties of blood leukocytes in dromedary camels. Immunofluorescence and flow cytometry were used to comparatively analyze samples collected from camels during a free-ranging time and samples collected from the same camels during movement-restricted housing. In comparison to blood samples collected from the camels during the free-ranging time, samples from movement-restricted camels showed elevated serum myeloperoxidase activity, a significant shape-change in their neutrophils, and higher reactive oxygen species content in their monocytes and neutrophils, indicating increased cellular oxidative stress under movement-restricted housing. The leukogram pattern of the camels under restricted housing was characterized by leukocytosis with increased numbers of neutrophils, eosinophils, lymphocytes, and monocytes, resembling an excitement leukogram pattern. Within the lymphocyte population, only the helper T cells and B cells were expanded in animals under restricted housing. The upregulation of CD163 together with the downregulation of MHC-II on monocytes from excited camels indicate a modulatory potential of animal excitement to polarize monocytes toward an anti-inflammatory phenotype. Functional analysis of bacterial phagocytosis indicates an impaired antibacterial function of phagocytes in excited camels. The downregulation of several cell adhesion molecules on leukocytes from excited camels suggests a role for impaired cell adhesion and tissue migration and leukocyte retention in blood in the observed leukocytosis in animals under excitement. The present study identified significant changes in blood immune cell composition, phenotype, and function in dromedary camels under restricted-housing conditions. The observed changes in leukocyte composition suggest the development of an excitement leukogram pattern in camels under movement-restricted housing. To evaluate the clinical relevance of the observed changes in immune cell phenotype and function for the immune competence of camels under restricted housing, further studies are required.


Growth pattern and carbon allocation to volatile leaf terpenes under nitrogen-limiting conditions in Heterotheca subaxillaris (Asteraceae).
Rosettes of Heterotheca subaxillaris were grown at four levels of nitrate. Individual leaf volatile mono- and sesquiterpene content, leaf nitrogen content, and root and shoot dry weight were measured on individual leaves every two weeks for 18 weeks. Rosettes with the highest nitrate availability had 2.2-fold greater leaf nitrogen levels compared to plants with the lowest availability. As nitrate availability became increasingly limited, carbon allocation to both volatile leaf terpenes and root growht increased. Leaf mono- and sesquiterpene content was greatest in the young leaves of individuals growing at the lowest nitrate availability conditions. Higher levels of carbon-based herbivore-deterring chemicals in nitrate-limited plants may increase net productivity through retention of nitrogen that would otherwise be lost to herbivory.


Optical coherence tomography derived cut-off value of uncovered stent struts to predict adverse clinical outcomes after drug-eluting stent implantation.
Although the presence of uncovered struts may be associated with occurrence of stent thrombosis, the impact of uncovered struts detected routinely by optical coherence tomography (OCT) on subsequent long-term clinical outcomes remains unclear. The objective of this study was to determine the cut-off value of uncovered struts that predicted adverse clinical outcomes after drug eluting stent (DES) implantation. Major safety events (MSEs, a composite occurrence of cardiovascular death, myocardial infarction, and stent thrombosis) were evaluated in 489 DES-treated patients (535 lesions) during the median 851 days after follow-up OCT. MSEs occurred in six patients (four definite stent thrombosis and two sudden cardiac death). The best cut-off value of percentage of uncovered struts for predicting MSE was 5.9 % using the maximal χ(2) method: area under the receiver-operating characteristic curve = 0.779, 95 % confidence interval (CI) = 0.648-0.910, p = 0.019, a sensitivity of 83.3 % and a specificity of 70.3 %. Independent predictors for MSE were post-intervention minimal lumen diameter (odds ratio 0.019, 95 % CI = 0.001-0.513, p = 0.018) and percentage of uncovered struts ≥5.9 % (odds ratio 19.781, 95 % CI = 2.071-188.968, p = 0.010). A greater percentage of uncovered struts (the cut-off value of ≥5.9 % uncovered struts) might be significantly associated with occurrence of MSE after DES implantation.


Emerging nano-structured innovative materials as adsorbents in wastewater treatment.
Water supply around the globe is struggling to meet the rapidly increasing demand by the population, drastic changes in climate and degrading water quality. Even though, many large-scale methods are employed for wastewater treatment they display several negative impacts owing to the presence of pollutants. Technological innovation is required for integrated water management with different groups of nanomaterials for the removal of toxic metal ions, microbial disease, organic and inorganic solutes. The method of manipulating atoms on a nanoscale is nanotechnology. Nanomembranes are used in nanotechnology to soften water and eliminate physical, chemical and biological pollutants. The present review concentrates on various nanotechnological approaches in wastewater remedy, mechanisms involved to promote implementation, benefits and limitations in comparison with current processes, properties, barriers and commercialization research needs. Also the review identifies opportunities for further exploiting the exclusive features for green water management by following the advances in nanotechnology.


Fos protein immunoreactivity in the developing olfactory bulbs of normal and naris-occluded rats.
Immediate early genes such as c-fos may be a route through which extracellular events affect genomic expression. Expression of immediate early genes is important in the transcriptional regulation necessary for the normal development of the nervous system. Developmental patterns of Fos protein (the product of c-fos immediate early gene expression) were studied in the main olfactory bulb of the rat using immunocytochemistry. Embryonic Day 21 (E21, the last prenatal day), as well as Postnatal Day 0 (P0), P1, P5, P10, P15, P20 and P30 subjects were examined. Although staining was absent in the E21 bulb, there was a rapid onset of Fos synthesis within hours after birth. Distribution of Fos-immunoreactive (Fos-ir) nuclei corresponded to the sequence of bulb maturation: numerous mitral/tufted and granule cells were labeled on P0, followed by the appearance of Fos-ir in the nuclei of periglomerular cells and an increase in the number of stained granule cells with development. Surgical closure of an external naris on P1 resulted in a 70% reduction in the number of Fos-ir granule cell nuclei as early as 2 h after the manipulation. During the next 30 days, levels of Fos staining further diminished in experimental bulbs when compared to their contralateral controls. Nevertheless, electrical stimulation of the contralateral bulb in P20 pups resulted in a robust increase of Fos labeling in most main and accessory olfactory bulb mitral cells and in many granule and periglomerular neurons, suggesting that the experimental bulbs remain competent to express Fos protein.


Photosynthesis in epiphytic and rooted Clusia rosea Jacq.
Clusia rosea Jacq. is a hemiepiphyte having Crassulacean Acid Metabolism (CAM). In its natural habitat Clusia begins its life cycle as an epiphyte and eventually becomes a rooted tree. These two stages of the life cycle of Clusia represent markedly different water regimes. Our CO2 exchange, stomatal conductance, titratable acidity, and stable carbon isotope ratio measurements indicate that Clusia has a flexible photosynthetic mode, where CO2 is fixed mostly via CAM during its epiphytic stage, when water availability is low, and via both CAM and C3 during its rooted stage.


The application of hyaluronic acid in bone regeneration.
Hyaluronic acid (HA) exists naturally as an important component of the extracellular matrix (ECM) in the human body. In recent decades, HA has been widely used in bone regeneration, and is currently a popular topic, particularly in the craniofacial and dental fields. From maxilla augmentation to craniofacial bone trauma, there is now a large demand for bone regenerative therapy. Serving as a cell-seeding scaffold or a carrier for bioactive components, hyaluronic acid-incorporated scaffolds and carriers in bone regeneration can be fabricated into either rigid or colloidal forms. Since the type of material used is a critical factor in the biological properties of a scaffold, HA derivatives or HA-incorporated composite scaffolds have shown excellent potential for improving osteogenesis and mineralization. Furthermore, in order to better enhance osteogenesis, local delivery carriers based on hyaluronic acid derivatives, rather than specifically serving as scaffolds, can be established by loading different osteoinductive or osteogenetic components and acquiring different release patterns. Such osteoinductive carriers immobilized on implant surfaces are also effective in improving osseointegration. Thus, as such a competent biomaterial, hyaluronic acid should be considered a promising tool in bone regeneration.


MAC expanded: AD50 and AD95 values of common inhalation anesthetics in man.
Two important measures may be derived from patient responses to a range of anesthetic doses. The AD50, corresponding to MAC, estimates the median anesthetic concentration--that dose where half the patients are anesthetized and half are not. The AD95 approaches the theoretical "minimum" anesthetic concentration by estimating the dose that anesthetizes 95 per cent of a patient population. The AD50 and AD95 are logical extensions of the MAC concept and can be evaluated with current experimental methodology. Recomputed from available data , the AD50's of nine inhaled anesthetics proved to be numerically identical to their MAC values. The AD95's of nine inhaled anesthetics proved to be numerically identical to their MAC values. The AD95's were 5 to 40 per cent greater than the AD50's.)Key workd: Potency, anesthetic, MAC, AD50, AD95; Pharmacology, dose-response curves.)


Neonatal lupus erythematosus, multiple thromboses, and monoarthritis in a family with Ro antibody.
We describe a family afflicted with striking clinical and serologic autoimmune features. The mother and maternal uncle of a patient with neonatal lupus had rheumatic disease manifestations. All three had Ro antibodies (SS-A) in their sera, as well as La antibody (SS-B). The 17-year-old mother developed postpartum inflammatory monoarthritis of the right knee and had a positive lupus band test. The uncle at the age of 26 developed a fulminant disease most consistent with systemic lupus erythematosus (SLE); initial manifestations were myocardial infarction, deep vein thrombosis, and the nephrotic syndrome. Although it is known that mothers of neonatal lupus infants can develop SLE postpartum, the development of severe disease in the maternal uncle suggests the relevance of identifying seropositive relatives of individuals with neonatal lupus.


Dendritic cell vaccination in glioblastoma patients induces systemic and intracranial T-cell responses modulated by the local central nervous system tumor microenvironment.
We previously reported that autologous dendritic cells pulsed with acid-eluted tumor peptides can stimulate T cell-mediated antitumor immune responses against brain tumors in animal models. As a next step in vaccine development, a phase I clinical trial was established to evaluate this strategy for its feasibility, safety, and induction of systemic and intracranial T-cell responses in patients with glioblastoma multiforme. Twelve patients were enrolled into a multicohort dose-escalation study and treated with 1, 5, or 10 million autologous dendritic cells pulsed with constant amounts (100 mug per injection) of acid-eluted autologous tumor peptides. All patients had histologically proven glioblastoma multiforme. Three biweekly intradermal vaccinations were given; and patients were monitored for adverse events, survival, and immune responses. The follow-up period for this trial was almost 5 years. Dendritic cell vaccinations were not associated with any evidence of dose-limiting toxicity or serious adverse effects. One patient had an objective clinical response documented by magnetic resonance imaging. Six patients developed measurable systemic antitumor CTL responses. However, the induction of systemic effector cells did not necessarily translate into objective clinical responses or increased survival, particularly for patients with actively progressing tumors and/or those with tumors expressing high levels of transforming growth factor beta(2) (TGF-beta(2)). Increased intratumoral infiltration by cytotoxic T cells was detected in four of eight patients who underwent reoperation after vaccination. The magnitude of the T-cell infiltration was inversely correlated with TGF-beta(2) expression within the tumors and positively correlated with clinical survival (P = 0.047). Together, our results suggest that the absence of bulky, actively progressing tumor, coupled with low TGF-beta(2) expression, may identify a subgroup of glioma patients to target as potential responders in future clinical investigations of dendritic cell-based vaccines.


Patients undergoing liver transplantation: psychosocial characteristics, depressive symptoms, and quality of life.
Liver transplantation is the treatment of choice for patients with end-stage liver diseases to improve social rehabilitation and quality of life. Our objective was to evaluate the psychosocial characteristics, depressive symptoms, and quality of life among patients undergoing liver transplantation. Patients underwent individual assessments using a semidirected interview. Beck's Depression Inventory and SF-36 Quality of Life Questionnaire. The signal test was used with a significance level set at .05. The characteristics of the sample (n = 30) were compatible with literature data for gender (n = 20 men), age (mean age, 51.96 years), education (elementary and middle school), and etiology (viral hepatitis). A significant number of patients were not able to maintain their professional activities: prior to transplantation (n = 18) and after transplantation (n = 13) due to the adverse effects of immunosuppressants (n = 9). The analysis indicated a significant quality of life improvement after transplantation for the following domains: functional capacity (P = .047), physical aspects (P = .024), pain (P = .001), overall health status (P = .003), and social aspects (P = .021). Significant depressive symptoms (n = 6) were experienced before and after the surgery. The data indicated a significant quality of life improvement after liver transplantation. Occupational activity and surgery time had a positive influence on these results. The frequency of depressive symptoms was similar before and after transplantation, correlating with less favorable quality of life scores. The results indicated the need to provide regular psychosocial assessment and follow-up in all stages of therapy.


Lipid profile disturbances in antipsychotic-naive patients with first-episode non-affective psychosis: A systematic review and meta-analysis.
Dyslipidaemia is one of the most prevalent metabolic disturbances observed in schizophrenia patients and has been largely attributed to the effects of poor lifestyle habits and adverse effects of antipsychotic treatment. However, less is known whether patients with first-episode non-affective psychosis (FENP) present subthreshold indices of dyslipidaemia. Therefore, we tested the hypothesis whether subclinical lipid profile alterations occur already in antipsychotic-naïve FENP patients. In this systematic review and meta-analysis we adhered to the PRISMA guidelines and searched PubMed, CINAHL Complete, Academic Search Complete, ERIC and Health Source: Nursing/Academic Edition from database inception to Dec 12, 2016, for case-control studies measuring the levels of total cholesterol, low- and high-density lipoproteins (LDL and HDL) and triglycerides in patients with FENP and controls. W calculated effect size (ES) estimates as Hedges' g and pooled data using random- or fixed-effects models depending on heterogeneity. Our study was registered in the PROSPERO database (CRD42016051732). Out of 2466 records identified, 19 studies representing 1803 participants were finally included in our systematic review and meta-analysis. Pooled analysis revealed that FENP patients had significantly lower levels of total cholesterol [ES=-0.16 (95% CI: -0.27, -0.06), p=0.003], LDL [ES=-0.13 (95% CI: -0.24, -0.01), p=0.034] and HDL [ES=-0.27 (95% CI: -0.49, -0.05), p=0.018] as well as significantly higher levels of triglycerides [ES=0.22 (95% CI: 0.11, 0.32), p<0.001] compared to controls. After removing single studies in sensitivity analysis, ES estimate for LDL levels was insignificant. Antipsychotic-naïve patients with FENP present subclinical dyslipidaemia. Future studies should disentangle whether our findings reflect disease-specific mechanisms.


[The role of physicians in patient and family adherence to genetic testing].
More and more French cancer patients are offered by their physicians having their genetic characteristics analyzed (diagnosis, adaptation of treatment plans, etc.). In oncology, considering the development of personalized medicine, these analyses are commonplace. Analyses of germline (hereditary) genetic characteristics require information from patients who must sign an informed consent (article 16.10 of the Civil Code and articles L. 1131-3 and L. 1122-1-1 of the Public Health Code). However, prescribing physicians are rarely geneticists and have little training in genetics. Patients report that few are able to answer their questions and often sign a consent that is not truly informed. To identify the genetic knowledge and training needs of prescribers, we conducted an online survey of physicians prescribing genetic testing in oncology between January and March 2020. The survey consisted of 17 closed questions and 3 open questions. We obtained 35 usable questionnaires which show that 50% of the prescribing physicians questioned lack knowledge of genetics, but do not express a need for training. They were interested in the provision of a digital teaching aid for patients. We have therefore made a film for patients, available in free access, which aims to shed light on the analysis of genetic characteristics. The film helps physicians to explain the offered analyses and their consequences (https://youtu.be/5lWUSsteavs).


Amelioration of pulmonary aflatoxicosis by green tea extract: An in vivo study.
Aflatoxins (AFB1) are mycotoxins known to be associated with human and animal diseases. The lung is a at risk from AFB1exposure either via inhalation or circulation. Green tea consumption is increasing over time due to widespread popularity as antioxidants, anti-inflammatory, and cytoprotective agents. Therefore, we attempted to study the lung toxicity caused by AFB1 and the possible ameliorating effect of green tea extract. Forty adult male albino rats were divided into five groups; Group I: Untreated control group, Group II (vehicle): Each rat received 1 ml of olive oil, Group III (GTE): Each rat received Camellia sinensis, green tea extract (30 mg/kg/day), Group IV(AFB1): Each rat received (50 μg/kg/day of AFB1). Group V (AFB1+ GTE): Each rat received the same previously mentioned doses of AFB1 in addition to GTE concomitantly. All treatments were orally gavaged for 8 weeks then rats were sacrificed. Serum levels of pro-inflammatory (IL-1β, TNF-α, IL-6) and anti-inflammatory (IL-10) cytokines were measured, lung tissues' oxidative stress indices were also measured in addition to the histopathological study which was performed by using hematoxylin & eosin and Masson trichrome stains. Morphometric and statistical analyses were also performed. Oral gavage of AFB1 resulted in significant histopathological changes in the lung tissues, in the form of variable degrees of congestion, hemorrhage, interstitial inflammation with infiltration by chronic inflammatory cells, interstitial fibrosis, bronchitis, vasculitis and fibrous thickening of arterial walls. Inflammation was evident by elevated levels of pro-inflammatory cytokines and a declined level of anti-inflammatory cytokines. Also, oxidative stress was evident by increased levels of Malondialdehyde (MDA), Myeloperoxidase (MPO), and decreased levels of total glutathione (tGSH) and Catalase (CAT). The histopathological changes, inflammatory cytokines, and oxidative stress markers were significantly decreased during concomitant administration of green tea extract in (AFB1+ GTE) group. Aflatoxin B1 has deleterious effects on the lung tissue that could be minimized by concomitant administration of Green tea extract owing to its anti-inflammatory, antioxidant, and protective properties.


Dissimilar Anxiety-like Behavior in Prepubertal and Young Adult Female Rats on Acute Exposure to Aluminium.
Puberty is a developmental transition in which an estrogenic surge occurs, mediating the release of xenoestrogens, like aluminium. Aluminium's effect on anxiety in rodents at the different developmental stages is inconsistent. This study aimed at investigating the effect of the metalloestrogenic property of aluminium on anxiety-like behavioral changes in prepubertal and young adult female rats. Considering this aim, our objective was to evaluate the anxiety-like behavior by the elevated plus maze in prepubertal and young adult female rats with or without acute exposure to aluminium. To address this property of aluminium, 5mg/Kg body weight (Al-5) and 10 mg/Kg body weight (Al-10) of aluminium was administered intraperitoneally to female rats at two developmental stages, prepubertal (PP; n = 8 for each dose) and young adult (YA; n = 6 for each dose) for two weeks. Post-treatment, three days behavioral assessment of the rats was done employing elevated plus maze. Reduced escape latency was seen in Al-5, Al-10 pre-pubertal rats, and Al-5 young-adult rats on day 3. A significant reduction in open arm time was seen in the Al-5 young-adult rats. Aluminium treatment in the pre-pubertal rats reduced their head dipping and grooming. Reduced sniffing, head dipping, and stretch-attended posture in the treated young-adult female rats showed that they had impaired risk-taking tendency. Differential effect on the anxiety-like behavior in the pre-pubertal and young-adult female rats might be due to the metalloestrogenic property of aluminium, acting differently on the two age groups.


An immunohistochemical, enzymatic, and behavioral study of CD157/BST-1 as a neuroregulator.
Recent rodent and human studies provide evidence in support of the fact that CD157, well known as bone marrow stromal cell antigen-1 (BST-1) and a risk factor in Parkinson's disease, also meaningfully acts in the brain as a neuroregulator and affects social behaviors. It has been shown that social behaviors are impaired in CD157 knockout mice without severe motor dysfunction and that CD157/BST1 gene single nucleotide polymorphisms are associated with autism spectrum disorder in humans. However, it is still necessary to determine how this molecule contributes to the brain's physiological and pathophysiological functions. To gain fresh insights about the relationship between the presence of CD157 in the brain and its enzymatic activity, and aberrant social behavior, CD157 knockout mice of various ages were tested. CD157 immunoreactivity colocalized with nestin-positive cells and elements in the ventricular zones in E17 embryos. Brain CD157 mRNA levels were high in neonates but low in adults. Weak but distinct immunoreactivity was detected in several areas in the adult brain, including the amygdala. CD157 has little or no base exchange activity, but some ADP-ribosyl cyclase activity, indicating that CD157 formed cyclic ADP-ribose but much less nicotinic acid adenine dinucleotide phosphate, with both mobilizing Ca2+ from intracellular Ca2+ pools. Social avoidance in CD157 knockout mice was rescued by a single intraperitoneal injection of oxytocin. CD157 may play a role in the embryonic and adult nervous systems. The functional features of CD157 can be explained in part through the production of cyclic ADP-ribose rather than nicotinic acid adenine dinucleotide phosphate. Further experiments are required to elucidate how the embryonic expression of CD157 in neural stem cells contributes to behaviors in adults or to psychiatric symptoms.


Epigenetic and long-term effects of nicotine on biology, behavior, and health.
Tobacco and nicotine use are associated with disease susceptibility and progression. Health challenges associated with nicotine and smoking include developmental delays, addiction, mental health and behavioral changes, lung disease, cardiovascular disease, endocrine disorders, diabetes, immune system changes, and cancer. Increasing evidence suggests that nicotine-associated epigenetic changes may mediate or moderate the development and progression of a myriad of negative health outcomes. In addition, nicotine exposure may confer increased lifelong susceptibility to disease and mental health challenges through alteration of epigenetic signaling. This review examines the relationship between nicotine exposure (and smoking), epigenetic changes, and maladaptive outcomes that include developmental disorders, addiction, mental health challenges, pulmonary disease, cardiovascular disease, endocrine disorders, diabetes, immune system changes, and cancer. Overall, findings support the contention that nicotine (or smoking) associated altered epigenetic signaling is a contributing factor to disease and health challenges.


Resource planning principles for the radiotherapy process using simulations applied to a longer vacation period use case.
Radiotherapy (RT) resources need to be used wisely to balance workload and patient throughput. There are no known strategies on how to plan resource use around longer vacation periods to avoid patient waiting times. We created a simulation model over the RT workflow to evaluate different scenarios for this purpose. The simulation model mimics a large modern RT department in Sweden. It was based on real data on patient referral patterns and resource use extracted from clinical systems (3666 treatment courses). Workshops with managers and staff were held to investigate nine different scenarios for the summer vacation period including one scenario to validate the model. Different capacity reductions, vacation period lengths and timing of the vacation periods between the preparatory part of the RT workflow and the treatment part were evaluated. For an eight-week period, resource utilization was predicted to be high both before and after the vacation period regardless of timing. However, more patients would be waiting with completed preparations with simultaneous vacation periods than when the preparatory part started one-two weeks prior to the treatment part. With shorter vacation periods, treatment would require overtime during the vacation period with higher levels of patients waiting compared to an eight-week scenario. Our proposed strategy aided managers to identify a preferred scenario for the summer vacation period with the preparatory part starting one-two weeks prior to the treatment part for an eight-week vacation period. This can help other RT departments to plan for similar situations.


Mechanism of action of narcotics in the production of menstrual dysfunction in women.
The ability of morphine to block ovulation in animals prompted investigation of the frequency and mechanisms of menstrual abnormalities in women addicted to narcotic analgesics. Menstrual histories obtained from 76 former heroin addicts receiving daily methadone maintenance revealed that more than one-half of these women had experienced menstrual abnormalities while taking heroin or methadone. In order to determine the specific physiologic effects of narcotic analgesics on reproductive function, detailed endocrinologic studies were carried out in seven of these patients who complained of amenorrhea or irregular menses while receiving methadone. Four of the seven women manifested abnormalities of the control of gonadotropin secretion. Three of these four failed to exhibit cyclic gonadotropin release, as evidenced by an absence of increased levels of follicular phase follicle-stimulating hormone, midcycle gonadotropin peaks or luteal phase progesterone increments. In the fourth patient a prolonged follicular phase (30 days) of the menstrual cycle was detected. One of these four patients also had low basal gonadotropin levels and failed to exhibit luteinizing hormone increments greater than control levels in response to ethinyl estradiol (positive feedback). The remaining three women exhibited normal patterns of gonadotropin secretion during the observation period. In these women, menstrual bleeding occurred in response to withdrawal from luteal phase (10 to 20 ng/ml) progesterone levels and to exogenous ethinyl estradiol, suggesting normal uterine responsivity to progesterone and estrogen. Although not documented, it is likely that oligo-ovulation was the cause of the irregular menses in these three patients. Amenorrhea is commonly associated with methadone ingestion or heroin addiction and appears to be related to an alteration of the hypothalamic mechanisms controlling gonadotropin secretion. Tolerance to these effects of methadone may develop after chronic ingestion.