Cellular and Molecular Targets of Waterbuck Repellent Blend Odors in Antennae of Glossina fuscipes fuscipes Newstead, 1910.
Insects that transmit many of the world's deadliest animal diseases, for instance trypanosomosis, find their suitable hosts and avoid non-preferred hosts mostly through olfactory cues. The waterbuck repellent blend (WRB) comprising geranylacetone, guaiacol, pentanoic acid, and δ-octalactone derived from waterbuck skin odor is a repellent to some savannah-adapted tsetse flies and reduces trap catches of riverine species. However, the cellular and molecular mechanisms associated with detection and coding of the repellent odors remain to be elucidated. Here, we demonstrated that WRB inhibited blood feeding in both Glossina pallidipes Austen, 1903 and Glossina fuscipes fuscipes Newstead, 1910. Using the DREAM (Deorphanization of Receptors based on Expression Alterations in odorant receptor mRNA levels) technique, combined with ortholog comparison and molecular docking, we predicted the putative odorant receptors (ORs) for the WRB in G. f. fuscipes, a non-model insect. We show that exposure of G. f. fuscipes in vivo to WRB odorant resulted in up- and downregulation of mRNA transcript of several ORs. The WRB component with strong feeding inhibition altered mRNA transcript differently as compared to an attractant odor, showing these two odors of opposing valence already segregate at the cellular and molecular levels. Furthermore, molecular dynamics simulations demonstrated that the predicted ligand-OR binding pockets consisted mostly of hydrophobic residues with a few hydrogen bonds but a stable interaction. Finally, our electrophysiological response showed the olfactory sensory neurons of G. f. fuscipes tuned to the tsetse repellent components in different sensitivity and selectivity.


Levels of lipid peroxidation, superoxide dismutase, and Na+/K+ ATPase in some tissues of rats exposed to a Nigerian-like diet and cadmium.
The purpose of the present study was to examine the role of a wholly compounded Nigerian-like diet on the activities of superoxide dismutase (SOD) and Na+/K+ ATPase and level of lipid peroxidation in oral cadmium toxicity. Nine-week-old Wistar albino rats (100 +/- 2.0 g) were exposed to 100 ppm cadmium in drinking water and the Nigerian-like diet (low in protein and high in carbohydrates and fiber) for 16 wk. The results obtained indicate that cadmium reduced weight gain and increased fecal output of rats, which was further potentiated by the Nigerian-like diet. Cadmium was concentrated in the intestine, liver, and kidney, with the highest level observed in the kidney, followed by the liver. The Nigerian-like diet reduced the concentration of cadmium in these tissues. Cadmium increased lipid peroxidation and inhibited SOD and Na+/K+ ATPase in the tissues. These were also aggravated in rats fed the Nigerian-like diet. Because the Nigerian-like diet increased lipid peroxidation and inhibited SOD and Na+/K+ ATPase in the tissues, it rendered rats more susceptible to cadmium toxicity.


Clinical Benefit in Response to Palbociclib Treatment in Refractory Uterine Leiomyosarcomas with a Common CDKN2A Alteration.
Uterine leiomyosarcoma (uLMS) responds poorly to conventional chemotherapeutic agents, and personalized therapies have yet to be systematically explored. Comprehensive genomic profiling (CGP) can identify therapeutic targets and provide insight into the biology of this highly aggressive tumor. We report a case of uLMS treated with the CGP-matched therapy palbociclib, a CDK4/6 inhibitor, with sustained clinical benefit in this rare and deadly malignancy. This study analyzed 279 clinically advanced/recurrent uLMS samples. Median patient age was 54 years (range, 23-83 years). DNA was extracted from 40 µm of formalin-fixed, paraffin-embedded sections, and CGP was performed on hybridization-captured, adaptor ligation-based libraries for up to 405 cancer-related genes plus introns from up to 31 genes frequently rearranged in cancer. Sequencing data were analyzed for base pair substitutions, insertions/deletions, copy number alterations, and rearrangements. CGP shows that 97.1% of uLMS harbor at least one alteration, and approximately 57% harbor alterations in one or more therapeutically targetable pathways. CDKN2A mutations that inactivate p16INK4a were identified in 11% of uLMS. We report the first demonstration of clinical benefit in response to palbociclib treatment for a uLMS patient with a CDKN2A mutation, resulting in disease stabilization and significant symptom reduction. A patient with uLMS harboring a CDKN2A mutation experienced clinical benefit from treatment with palbociclib, and genomic analysis of 279 uLMS samples revealed that 19% of patients had mutations affecting the cyclin-dependent kinase (CDK) pathway. These observations provide a rationale for a clinical trial investigating treatment with CDK pathway inhibitors for uLMS harboring relevant genomic alterations. The Oncologist 2017;22:416-421Implications for Practice: Comprehensive genomic profiling (CGP) of individuals with uterine leiomyosarcoma (uLMS) indicates that nearly 20% of patients may harbor a mutation affecting the cyclin-dependent kinase (CDK) pathway. The case presented demonstrates that a CDK inhibitory drug may provide clinical benefit to such individuals. Given the lack of curative therapies for uLMS, CGP could be performed on all cases of advanced uLMS and a CDK inhibitor could be recommended (preferably as part of a clinical trial) for individuals harboring a mutation in the CDK pathway.


[Characteristics of human adrenal microvascular endothelial cells in morphology, phenotypes, and function].
To investigate the phenotypic and functional characteristics of human adrenal microvascular endothelial cells (AdrEC). AdrEC were isolated and purified from a sample of human adrenal tissue by sub-cell clone method. The cells identified by flow cytometry for classical endothelial markers von Willebrand factor (vWF) and CD31, uptake of Dil-labeled acetylated low density lipoprotein (Dil-Ac-LDL), as well as phenotypes. The cell fenestrations were checked by scanning electron microscopy. The expressions of endogenous vascular endothelial growth factor (VEGF) mRNA and protein were detected by reverse transcription-polymerase chain reaction (RT-PCR) and immunocytochemistry. The glucocorticoid-induced cytotoxicities in different organs-derived microvascular endothelial cells were compared. Human AdrEC expressed those classical endothelial markers such as vWF, CD31, and uptake of Dil-Ac-LDL. The phenotypic analysis indicated that alpha-1 proteinase inhibitor, tumor necrosis factor receptor p55, and intercellular adhesion molecule-1 were expressed in human AdrEC. Scanning electron microscopy demonstrated that there were many microvilli and fenestrations on cellular surface. RT-PCR and immunocytochemistry showed that there was expression of endogenous VEGF in AdrEC. In response to glucocorticoid-induced cytotoxicity, microvascular endothelial cells (MVEC) derived from human brain were highly susceptible, MVEC derived from human lung and human liver sinusoidal endothelial cells were sub-sensitive, while AdrEC were highly resistant. Human AdrEC are specially differentiated and have characteristics that are different from other organ-derived MVEC in phenotypes and functions.


Moebius syndrome: The challenge of dental management.
Moebius syndrome (MBS) is a rare disorder which involves unilateral or bilateral paralysis or lack of the VI and VII cranial nerves. This is accompanied by abnormalities affecting the head, mouth, upper and lower limbs, and chest. A distinguishing feature of this syndrome is the so-called mask-like face. A small number of publications relating to occlusal and dental bnormalities and documenting the progress of orthodontic treatment has led the authors to present the case of a patient with Moebius syndrome. A patient with Moebius syndrome was initially treated by means of removable appliances and later by means of a fixed appliance after permanent tooth extractions. As a result of the treatment, there was an improvement in the ratio of the posterior facial height to the anterior facial height: Sgo/NGn increased from 55.8% to 59.1%, which is closer to the Caucasian population norm. The aesthetic result was satisfactory both for the patient and for her parents.


Empiric antibiotic therapy in urinary tract infection in patients with risk factors for antibiotic resistance in a German emergency department.
The aim of this study was to identify clinical risk factors for antimicrobial resistances and multidrug resistance (MDR) in urinary tract infections (UTI) in an emergency department in order to improve empirical therapy. UTI cases from an emergency department (ED) during January 2013 and June 2015 were analyzed. Differences between patients with and without resistances towards Ciprofloxacin, Piperacillin with Tazobactam (Pip/taz), Gentamicin, Cefuroxime, Cefpodoxime and Ceftazidime were analyzed with Fisher's exact tests. Results were used to identify risk factors with logistic regression modelling. Susceptibility rates were analyzed in relation to risk factors. One hundred thirty-seven of four hundred sixty-nine patients who met the criteria of UTI had a positive urine culture. An MDR pathogen was found in 36.5% of these. Overall susceptibility was less than 85% for standard antimicrobial agents. Logistic regression identified residence in nursing homes, male gender, hospitalization within the last 30 days, renal transplantation, antibiotic treatment within the last 30 days, indwelling urinary catheter and recurrent UTI as risk factors for MDR or any of these resistances. For patients with no risk factors Ciprofloxacin had 90%, Pip/taz 88%, Gentamicin 95%, Cefuroxime 98%, Cefpodoxime 98% and Ceftazidime 100% susceptibility. For patients with 1 risk factor Ciprofloxacin had 80%, Pip/taz 80%, Gentamicin 88%, Cefuroxime 78%, Cefpodoxime 78% and Ceftazidime 83% susceptibility. For 2 or more risk factors Ciprofloxacin drops its susceptibility to 52%, Cefuroxime to 54% and Cefpodoxime to 61%. Pip/taz, Gentamicin and Ceftazidime remain at 75% and 77%, respectively. We identified several risk factors for resistances and MDR in UTI. Susceptibility towards antimicrobials depends on these risk factors. With no risk factor cephalosporins seem to be the best choice for empiric therapy, but in patients with risk factors the beta-lactam penicillin Piperacillin with Tazobactam is an equal or better choice compared to fluoroquinolones, cephalosporins or gentamicin. This study highlights the importance of monitoring local resistance rates and its risk factors in order to improve empiric therapy in a local environment.


Malakoplakia of the kidney--a case report.
Malakoplakia is a rare disease expressed as a special type of inflammatory reaction to infection with various bacteria and fungi. We present a case of renal malakoplakia in a 30-year-old female patient. The symptoms were not characteristic enough for making the ture diagnosis preoperatively. A preoperative diagnosis of renal cell carcinoma was made in this case.


Sleeping in the arms of cancer: a review of sleeping disorders among patients with cancer.
It is well known that cancer patients experience lack of sleep, which affects their symptoms and decrease their much needed energy, particularly while undergoing treatment. Insomnia, which is defined as a predominant complaint of dissatisfaction with sleep quantity or quality during different phases of the sleep cycle, could easily affect patients' quality of life and even cancer treatment outcomes. In this article, we review the current research on and treatments for insomnia, as well as explore cancer-related fatigue and its connections to sleep disorders.


Effect of rifampin on theophylline disposition.
The concentrations of theophylline from single 400-mg oral doses were evaluated both before and after 7 days of oral rifampin administration (600 mg/day) in six healthy, nonsmoking adults. The mean oral clearance of theophylline was significantly increased from 54.9 +/- 21.2 to 68.9 +/- 26.5 ml/h/kg. The elimination rate constant was significantly increased in five of the six subjects, with a mean increase of approximately 25%. Although intersubject variability was large, these data indicate the potential need to increase theophylline doses in some patients receiving rifampin.


Diffuse panbronchiolitis in a Samoan man.
Diffuse panbronchiolitis (DPB) is an idiopathic inflammatory disease which is predominantly recognised in the Japanese population with only isolated case reports in Western populations. This is the first reported case of DPB in a Samoan man with typical radiological and histopathological features. He had an excellent response to long-term erythromycin and this case highlights the importance of recognising this rare disease.


A naturally occurring mutation in the human androgen receptor of a subject with complete androgen insensitivity confers binding and transactivation by estradiol.
The clinical phenotype of complete androgen insensitivity (CAIS) was associated with a mutation in the human androgen receptor (hAR) gene encoding the amino acid substitution, M745I, in the hAR protein. Transcriptional activation of hAR(M745I) by the synthetic androgen, methyltrienolone (R1881), was reduced compared to wild-type (wt) hAR. The transcriptional co-activator, androgen receptor associated protein 70 (ARA70), failed to enhance transactivation of hAR(M745I) at lower concentrations of R1881 (0.01-0.1 nM), whereas the p160 co-activators, SRC-1 and TIF2, stimulated activity. Transcriptional activity of hAR(M745I) was stimulated by 1 or 10 nM R1881 and activity was further enhanced by co-expression of ARA70 similar to that of the hAR(wt). Transcriptional activity of hAR(wt) was minimally stimulated by estradiol (E2) without or with co-expression of ARA70, whereas 10 or 100 nM E2 increased transactivation by hAR(M745I) of the androgen-responsive MMTV-luciferase reporter gene by 10-fold and activity was further enhanced by ARA70. Increasing concentrations of E2 competed more effectively for binding of R1881 to hAR(M745I) than to hAR(wt), indicative of the preferential binding of E2 to the mutant hAR. Partial tryptic digestion of hAR wt and M745I revealed that activation of the mutant protein was reduced in the presence of R1881. By contrast, tryptic digestion showed that the mutant hAR was activated by the binding of E2. In conclusion, the clinical phenotype of CAIS resulted from a hAR gene mutation encoding hAR(M745I) with reduced binding and transactivation by androgens, but the novel properties of enhanced affinity for and increased transactivation by estradiol.


Gastric microcirculatory changes of portal-hypertensive rats can be attenuated by long-term estrogen-progestagen treatment.
It has been suggested that estrogen-progestagen therapy may be useful in preventing bleeding from gastric angiodysplasia, a vascular lesion similar to that described in portal-hypertensive gastropathy. In this study we assessed the effects of estrogen-progestagen therapy on gastric microcirculation and systemic and splanchnic hemodynamics in portal-hypertensive and sham-operated rats. One week after the surgical procedure (partial portal vein ligation or sham surgery), animals were given an intramuscular injection of a slow-release preparation of estrogen-progestagen or its vehicle. Two weeks later, gastric mucosal blood flow was measured by means of hydrogen gas clearance, a morphometrical analysis of gastric mucosal blood vessels was performed and systemic and splanchnic hemodynamics were evaluated with a radiolabeled-microspheres technique. In portal-hypertensive rats, estrogen-progestagen therapy induced a significant reduction in gastric mucosal blood flow, number of blood vessels and relative area of vessels. Similar changes, although of lesser magnitude, were achieved with estrogen or progestagen given separately and with the low dose of combined estrogen-progestagen. Estrogen-progestagen treatment also induced significant reductions in portal pressure and porto-collateral resistance without changing systemic or splanchnic hemodynamics. In contrast, estrogen-progestagen treatment did not induce changes in any of the parameters studied in sham-operated rats. We conclude that long-term estrogen-progestagen therapy reduces the gastric hyperemia, increased mucosal vessel density and portal pressure in portal-hypertensive rats.


Cancer Cell Invasion of Mammary Organoids with Basal-In Phenotype.
This paper describes mammary organoids with a basal-in phenotype where the basement membrane is located on the interior surface of the organoid. A key materials consideration to induce this basal-in phenotype is the use of a minimal gel scaffold that the epithelial cells self-assemble around and encapsulate. When MDA-MB-231 breast cancer cells are co-cultured with epithelial cells from day 0 under these conditions, cells self-organize into patterns with distinct cancer cell populations both inside and at the periphery of the epithelial organoid. In another type of experiment, the robust formation of the basement membrane on the epithelial organoid interior enables convenient studies of MDA-MB-231 invasion in a tumor progression-relevant direction relative to epithelial cell-basement membrane positioning. That is, the study of cancer invasion through the epithelium first, followed by the basement membrane to the basal side, is realized in an experimentally convenient manner where the cancer cells are simply seeded on the outside of preformed organoids, and their invasion into the organoid is monitored. Interestingly, invasion is more prominent when tumor cells are added to day 7 organoids with less developed basement membranes compared to day 16 organoids with more defined ones.


Sex-Specific Glucose Homeostasis and Anthropometric Responses to Sleeve Gastrectomy in Obese Patients.
Bariatric surgery rapidly and effectively treats obesity and its comorbidities like dysregulated glucose homeostasis. Despite the sex-balanced incidence of obesity in most human populations, women have sought this intervention more frequently than men. However, as the number of bariatric surgeries rapidly rises, it is increasingly urgent to understand how sex-specific differences may emerge in metabolic and anthropometric parameters. Hundred fifty-four obese patients (47% men and 53% women) from the Bialystok Bariatric Surgery Study underwent sleeve gastrectomy and were measured for 25 parameters at baseline (immediately prior to surgery) and at four follow-up visits over one year. We used generalized linear mixed models to detect sex-specific differences in the time series of responses parameters. Unlike most previous studies with older cross-sections of men than women, our cohort was age-matched, and men were less healthy at baseline. Of parameters that showed a significant cohort-wide (across-sex) response, 14 (56%) also showed sex-specific responses with men improving more than women. In particular, men remitted in diabetes symptoms more strongly, rapidly, and durably than women. Taken together, our results indicate that men may benefit more from sleeve gastrectomy and that this difference in improvement may be related to more progressed morbidity prior to surgery independent of age.


[Separation of ofloxacin enantiomers by high performance capillary electrophoresis(HPCE)].
An analytical method for separation of ofloxacin enantiomers by HPCE using bovine serum albumin(BSA) as the chiral selector and isopropanol as the modifier was established. The effects of BSA concentration, pH of running buffer, isopropanol concentration, applied voltage and column temperature on the resolution of the enantiomers have been studied. The experimental results indicated that the BSA concentration and pH of the running buffer were the vital factors for the separation of the enantiomers. The concentration of isopropanol showed strong influence on the peak shape of enantiomers. Lower voltage and column temperature were favorable to improve the efficiency for the separation of the enantiomers. Optimum performance was achieved in a fused-silica capillary(45 cm x 30 microns ID, effective length 32 cm) at 30 degrees C and applied voltage of +15 kV with a pH 6.0 phosphate buffer containing 50 mg.ml-1 BSA and 5% isopropanol as running buffer and detected at 293 nm. The precision of this method was evaluated by repeated measurement of the migration times and peak areas for 0.45 mg.ml-1 ofloxacin standard solution. The RSD(n = 8) for migration times and peak areas were 1.6% and 1.1% for (-)-ofloxacin and were 1.8% and 2.8% for (+)-ofloxacin, respectively. The method was simple and fast and has been applied to separate enantiomers of ofloxacin products. The experimental results showed that the ratio of peak area of (-)-ofloxacin to that of (+)-ofloxacin was within the range of 0.995-0.998 with RSD(n = 6) of measurement between 1.8% and 2.0%.


Diagnostic assessment of traumatic brain injury by vacuum extraction in newborns: overview on forensic perspectives and proposal of operating procedures.
Traumatic brain injury (TBI) during birth constitutes one of the most relevant causes of mortality and morbidity in newborns worldwide. Although improvements in obstetrical management and better indications for caesarean section have led to a consistent decrease in the incidence of perinatal mechanical injury, vacuum extraction is still associated with a high complications rate leading to several forensic issues in the evaluation of healthcare professional management. Vacuum-associated lesions may be topographically distinguished as extracranial or intracranial injuries. In order to achieve a correct assessment, diagnostic procedure should include post-mortem computed tomography and magnetic resonance imaging, autopsy examination, brain sampling and histological/immunohistochemical examination. Post-mortem imaging represents a valid aid to guarantee preliminary evidence and direct subsequent investigations. An appropriate autopsy sampling must include several areas of cortex and underlying white matter; moreover, any visceral hemorrhages or other lesions should be sampled for the histological and immunohistochemical assessment of vitality and timing. This study aimed to promote a validated step-by-step procedure to be adopted in order to standardize and to make easier the post-mortem framing and timing of vacuum-associated pediatric brain injuries.


Meta-analysis of interleukin 6, 8, and 10 between off-pump and on-pump coronary artery bypass groups.
This study aimed to evaluate the role of off-pump coronary artery bypass (CAB) surgery on the decrease of postoperative inflammatory responses in patients. We systematically searched databases of PubMed and Embase to select the related studies. Interleukin (IL) 6, 8, and 10 were used as outcomes and pooled analysis was performed using R 3.12 software. Standardized mean differences (SMDs) and their 95% confidence intervals (95% CIs) were considered as effect estimates. A total of 27 studies, including 1340 participants, were recruited in this meta-analysis. The pooled analyses showed that postoperative concentration of IL-10 at 12 hours was significantly lower in off-pump CAB group compared to on-pump CAB group (SMD = -1.3640, 95% CI = -2.0086--0.7193). However, no significant differences were found in pre and postoperative concentrations of IL-6 and 8 between off-pump and on-pump CAB groups. These results suggest that there is no advantage of off-pump CAB surgery in the reduction of inflammation compared to on-pump CAB surgery.


A subpopulation of cerebellar granule neurons in culture expresses a functional mGluR1 metabotropic glutamate receptor: effect of depolarizing growing conditions.
Homogeneous neuronal cultures of cerebellar granule neurons express different levels of metabotropic glutamate receptor mGluR1 mRNA depending on the concentration of KCl present during the culture period. We have studied the effect of KCl on mGluR1 expression at the single neuron level by measuring: i) the effect of mGluR agonist 1S,3R-aminocyclopentane-1,3-dicarboxylic acid, tACPD, on intracellular free calcium concentration, [Ca2+]i; ii) the immunocytochemical quantitation of mGluR1 alpha protein. tACPD-induced increases in cytoplasmic free Ca2+ were pertussis toxin-sensitive. The number of tACPD-responding and mGluR1 alpha-positive neurons was higher in cultures grown in the presence of 15 mM than 25 mM KCl, but it never exceeded 50% of the cells. The measurement of basal intracellular free Ca2+ under the respective growing condition revealed a bigger subpopulation of cells with high basal Ca2+ concentration in neurons maintained in 25 mM KCl respect to 15 mM KCl. Hence, in primary cultures of cerebellar granule neurons, depolarization (possibly via Ca(2+)-regulated mechanisms) modulates the expression of a functional mGluR1 only in a subpopulation of cells and thus may account for a functional heterogeneity of morphologically similar cells.


Impact of Technological Advances on Vascular Surgery in the 1990s.
'All change is a miracle to contemplate; but it is a miracle which is taking place every instant.' Henry David Thoreau, Walden, 1854. Progress in vascular surgery is fuelled by technology. Every advance in modern vascular surgery has been preceded by a technological development which, though apparently amazing, soon became a commonplace. Those who do not believe in change in vascular surgery or that technological advances described in this volume will have any place in the treatment of vascular disease, reflect an attitude described best by Lord Moynihan, then President of the Royal College of Surgeons of England. He said, 'surgery ... has now almost reached its limit...we can surely never hope to see the craft of surgery made much more perfect than it is today.' Changes which have occurred since that statement are a cascade of advances including antibiotics, anticoagulants, prostheses, sutures, needles, and a variety of scopes which have become as common as aseptic technique.


Does HOXA9 Gene Expression in Egyptian Chronic Myelogenous Leukemia Patients Affect Disease Progression? A Retrospective Cohort Study.
Chronic myelogenous leukemia (CML) is a clonal stem cell disease and is consistently associated with the BCR-ABL fusion gene. The chronic phase of the disease tends to pass into an accelerated phase and eventually leads to acute leukemia if left untreated. Oncoproteins necessary for leukemic transformation are both fundamentally and clinically relevant to identify as they might be new molecular targets for the development of specific anti-leukemic drugs. This study is an initial step to define the proportion of HOXA9 gene expression in some Egyptians with chronic-phase CML at diagnosis and to evaluate its relation with BCR-ABL expression and its clinical significance. Sixty-two newly diagnosed CML patients (56 in chronic phase, 1 in accelerated phase, and 5 in blastic crises) were enrolled in the study. HOXA9 and BCR-ABL gene expressions were detected by one-step RT-PCR. ABL was chosen as a control gene to calculate HOXA9/ABL and BCR-ABL/ABL ratios from densitometric values of PCR product intensities. HOXA9 expression was encountered in 25/56 (44.6%) of newly diagnosed CML patients in the chronic phase. The median expression was 0.31 (range: 0.08-1.37) in relation to the ABL gene, with a higher frequency of expression in CML patients presenting with splenomegaly (p<0.001), high Sokal score (p<0.001), and BCR-ABL expression from the first round (p=0.004). No association could be detected with other clinical parameters, overall survival, or disease-free survival. HOXA9 expression is closely related to poor prognostic factors, but we could not demonstrate its relationship to patient survival. None declared.


Photoperiodic control of gonadotrophin secretion in the ram: a detailed study of the temporal changes in plasma levels of follicle-stimulating hormone, luteinizing hormone and testosterone following an abrupt switch from long to short days.
Six adult Soay rams were housed under artificial lighting conditions of long days (16 h light:8 h darkness) for 4 months and this caused the animals to lapse into a state of reproductive quiescence with low levels of gonadotrophins in the circulation and regressed testes secreting very low amounts of testosterone. The photoperiod was changed abruptly to short days (8 h light:16 h darkness) to induce a resurgence of sexual activity, and a detailed study was made of the pituitary and testicular responses over the first 100 days. Plasma levels of LH and FSH first began to increase between days 6 and 12 of short days, and rose progressively until days 33-54 before declining again. Testicular growth of the rams began on days 19-26 and continued for most of the remaining period of study. Plasma testosterone levels rose in parallel with the growth of the testes, and were greatly increased by day 100 when gonadotrophin levels were reduced. At most stages there were short-term fluctuations in the plasma levels of FSH, LH and testosterone indicative of episodic secretion. Peaks in plasma levels of LH were especially conspicuous and from the changes in frequency and amplitude of these peaks it was possible to predict the way in which photoperiod influenced gonadotrophin secretion by its effect on hypothalamic LH-RH secretion. A slight 24 h rhythm in the plasma levels of all three hormones was observed, and the significance of this in relation to the photoperiodic response is discussed.


Left ventricular failure complicating acute myocardial infarction--problems and potential of nonthrombolytic therapy.
Despite recent advances, problems in the treatment of acute myocardial infarction still remain. In the earliest stages of the syndrome thrombolysis holds substantial if not absolute promise but many patients present too late for it to be effective. In these latter individuals and those in whom thrombolysis was not successful, the major mortality risk is concentrated in those with left ventricular failure. Many drugs, including diuretics, vasodilators, ACE inhibitors and positive inotropes, singly or in combination, may be used to manipulate the circulation and correct partially or completely the abnormal circulatory profile. Despite such haemodynamic efficacy the impact of drug therapy on the high morbidity and mortality risk of patients with acute myocardial infarction complicated by left ventricular failure is still unknown.


The effects of benzoate and fluoride on dental caries in intact and desalivated rats.
The decline in prevalence of dental caries in some segments of the population has been attributed mainly to extensive exposure to fluoride. Over the past decades, the use of fluoridated products has increased. During the same period, the consumption of food preservatives such as benzoates and sorbates has also increased substantially. Benzoates, in vitro, possess antibacterial properties similar to those of fluoride and in combination with fluoride could affect caries development. In the present study we explored the effects of sodium benzoate and fluoride in combination and alone on dental caries in our animal model. The results showed a combination of benzoate and fluoride reduced caries activity more effectively in rodents fed a cariogenic diet ad libitum than fluoride alone (p = 0.038).


Training creative cognition: adolescence as a flexible period for improving creativity.
Creativity commonly refers to the ability to generate ideas, solutions, or insights that are novel yet feasible. The ability to generate creative ideas appears to develop and change from childhood to adulthood. Prior research, although inconsistent, generally indicates that adults perform better than adolescents on the alternative uses task (AUT), a commonly used index of creative ideation. The focus of this study was whether performance could be improved by practicing alternative uses generation. We examined the effectiveness of creative ideation training in adolescents (13-16 years, N = 71) and adults (23-30 years, N = 61). Participants followed one of three types of training, each comprising eight 20-min practice sessions within 2 week time: (1) alternative uses generation (experimental condition: creative ideation); (2) object characteristic generation (control condition: general ideation); (3) rule-switching (control condition: rule-switching). Progression in fluency, flexibility, originality of creative ideation was compared between age-groups and training conditions. Participants improved in creative ideation and cognitive flexibility, but not in general ideation. Participants in all three training conditions became better in fluency and originality on the AUT. With regard to originality, adolescents benefitted more from training than adults, although this was not specific for the creative ideation training condition. These results are interpreted in relation to (a) the different underlying processes targeted in the three conditions and (b) developmental differences in brain plasticity with increased sensitivity to training in adolescents. In sum, the results show that improvement can be made in creative ideation and supports the hypothesis that adolescence is a developmental stage of increased flexibility optimized for learning and explorative behavior.


Testicular alterations and semen quality in a selected group of breeding buffaloes.
Testicular ultrasound enables the evaluation of changes in the testicular parenchyma. This study aimed to report the occurrence of hypoechogenic testicular alterations and their relationship with semen quality in five breeding buffaloes. Two buffaloes presented with hyperechoic points characteristic of fibrosis and anechoic density content between the parietal and visceral tunica. The two bulls without ultrasonographic changes showed higher average trajectory speed, linear velocity, curvilinear velocity, amplitude of lateral displacement of the spermatic head, total motility, progressive motility, fast speed, and acrosomal membrane values within the normal range. The number of spermatozoa with major and total defects was higher in the group of animals without alterations. The three buffaloes that presented with testicular alterations produced semen within established freezing standards.


Use of ceftaroline after glycopeptide failure to eradicate meticillin-resistant Staphylococcus aureus bacteraemia with elevated vancomycin minimum inhibitory concentrations.
Elevated minimum inhibitory concentrations (MICs) of vancomycin against meticillin-resistant Staphylococcus aureus (MRSA) and the emergence of heteroresistant S. aureus strains have led to increased use of anti-MRSA antibiotics other than vancomycin. Ceftaroline fosamil is a novel cephalosporin with activity against MRSA, but there are limited clinical data on its use for MRSA bacteraemia (MRSAB) and against strains exhibiting high vancomycin MICs (2-4 μg/mL). This multicentre, retrospective, case-control study compared the microbiological and clinical effectiveness of ceftaroline used after vancomycin failure with that of vancomycin-treated controls for the treatment of MRSA with vancomycin MICs ≥ 2 μg/mL. In total, 32 patients were matched 1:1 with respect to vancomycin MIC, age and origin of bacteraemia. In the ceftaroline group, patients received prior MRSA therapy for a median of 5 days [interquartile range (IQR), 3-15.8 days] prior to switching to ceftaroline. Median time to eradication of MRSA was significantly less after treatment with ceftaroline compared with vancomycin [4 days (IQR, 3-7.5 days) vs. 8 days (IQR, 5.8-19.5 days); P=0.02]. Both clinical success at the end of treatment and recurrence of MRSA at Day 7 were trending towards being inferior in the vancomycin group, although the results did not attain statistical significance [81% vs. 44% (P=0.06) and 6% vs. 38% (P=0.08), respectively]. Ceftaroline added at the point of vancomycin failure resolves MRSAB more rapidly and with a higher rate of clinical success, therefore ceftaroline should be considered as an alternative for these difficult-to-treat infections.


Decreased levels of N-acetylaspartate in dorsolateral prefrontal cortex in a case of intractable severe sympathetically mediated chronic pain (complex regional pain syndrome, type I).
In our previous in vivo proton magnetic resonance spectroscopy ((1)H MRS) study we found reduced levels of N-acetylaspartate in dorsolateral prefrontal cortex of chronic back pain patients. This study tests whether these chemical abnormalities can be detected in other pain states. Using (1)H MRS, we measured levels for N-acetylaspartate and other identifiable chemicals relative to creatine in four bilateral brain regions, including dorsolateral prefrontal cortex, orbitofrontal cortex, cingulate, and thalamus, in a case of intractable severe sympathetically mediated chronic pain [complex regional pain syndrome (CRPS) type I]. The subject's chemical variations in the brain were compared to the same regional chemicals in 10 normal subjects (age- and sex-matched). Univariate statistics showed reduced levels of N-acetylaspartate in bilateral dorsolateral prefrontal cortex and increased levels of myo-inositol in left orbitofrontal cortex of the patient with intractable severe CRPS type I. These data support our original hypothesis that depletion of N-acetylaspartate in dorsolateral prefrontal cortex is a chemical marker of chronic pain, indicating for neuronal degeneration. Unpredicted changes of orbitofrontal myo-inositol may be related to the specific mood/affective state in an extreme pain perception. This is the first report, which identifies chemical markers in the prefrontal cortex for objective measurement and monitoring of CRPS type I. This information might lead to valuable insights into diagnosis and future effective interventions of CRPS type I (e.g., prefrontal brain stimulation).


Experiences of carers of youth, adult children and spouses with ME/CFS.
The debilitating nature of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) means that family members often take on a caring role. This study compared the experiences of people caring for three groups: youth, young adults, spouses. An opportunistic sample of 36 carers completed an online survey of open-ended questions asking about their experiences. Thematic analysis was used to consider the three sets of responses separately and Thematic Comparison was used to identify points of connection and disconnection across the sets. The themes identified were very similar to those identified in past studies. Two super-ordinate themes were identified: "Lack of knowledge and understanding" and "Holistic Impact". Though most sub-ordinate themes were evident across all three groups, important differences were found. The sub-ordinate themes "Caring Blindly", "Emotional and physical health cost", and "Impact on the whole family" were more evident amongst carers of youth while the theme "Worry for the future" was more evident from carers of young adults and spouses. Differences seemed to be related to both the time since diagnosis and the life stage. A longitudinal study would help to understand how carer experiences change over the life course of caring for someone with ME/CFS.


Long-term outcomes in radically treated synchronous vs. metachronous oligometastatic non-small-cell lung cancer.
Radical treatment for oligometastatic non-small-cell lung cancer (NSCLC) has a curative potential for selected patients. The present retrospective study was designed to examine the relevance of synchronous vs. metachronous manifestations as a potential prognostic factor when ablative treatments are performed in oligometastatic disease. Seventy-five patients with radically treated oligometastatic NSCLC were identified, of whom 39 presented with synchronous and 36 with metachronous metastatic manifestations. For patients with synchronous metastases, an additional therapy of the thoracic locoregional disease with a curative intent (either surgery or radiochemotherapy) was required. All patients with metachronous metastases had a documented remission of the primary tumor. Ablative treatment of the complete extent of oligometastatic disease consisted (as a minimum requirement) of either complete surgical resection or definitive ablative stereotactic radiotherapy. A comparative survival analysis of two groups of patients with oligometastatic NSCLC (synchronous vs. metachronous) and a complementary analysis of prognostic factors for the whole group of patients (by means of Cox regression analysis) was performed. Endpoints were median overall and progression-free survival (OS, PFS, respectively). Of the 75 patients, 57 presented with a solitary metastasis, in only 7 patients metastastatic lesions were present in ≥2 organs and 66 patients had a Karnofsky performance score (KPS) of 80 % or 90 %. The median follow-up was 54.0 months (95 % CI 28-81), the median OS 21.8 months (16.1-27.6) and the median PFS 13.7 months (9.7-17.6). In univariable Cox regression analysis, no single clinical factor was significantly associated with OS. For PFS both 'metastatic involvement of ≥2 organs vs. 1 organ' (hazard ratio (HR) 0.43, 0.23-0.83, p = 0.012) and a 'KPS of 90 % vs. 70-80 %' (HR 4.32, 1.73-10.89, p = 0.02) were significant prognostic factors as calculated by multivariable analysis. Comparing the cohorts with synchronous (n = 39) vs. metachronous oligometastases (n = 36), no differences in median OS and PFS were found. Both cohorts were well-balanced except for the KPS, which was significantly superior in patients with synchronous oligometastases. Radical treatment of oligometastatic NSCLC was associated with acceptable long-term survival rates in patients with good KPS and it was equally effective for synchronous and metachronous manifestations.


Migration and substance use: evidence from the U.S. National Health Interview Survey.
Representative data from the U.S. National Health Interview Survey are used to investigate the substance use patterns of immigrants and compare them to those of the native born populations. The information examined is from the 1991 supplementary Drug and Alcohol Use Data File, which examined the self-reported substance use behaviors of approximately 21,000 adults aged 18-44. Findings indicate that immigrants to the U.S. in the late twentieth century are less likely to use alcohol and other drugs than are native born citizens. Additional findings suggest assimilation processes by which exposure to mainstream American society leads to patterns of alcohol and illicit drug use among long term immigrants that approximates that of the native born population. The patterns of substance use observed among immigrants, however, are not consistent with acculturative stress mechanisms. These findings provide an important and representative profile of the substance use patterns of one of the largest international migration streams of the past one hundred years.


Anxiety, pain experience, and pain report: a signal-detection study.
The effect of experimentally induced anxiety on pain perception was examined using a signal detection discrimination experiment. The experimental condition consisted in unsignalled application of very painful stimuli which substantially raised state anxiety. The discrimination task included the total range of painful stimuli. The results indicated a range-specific effect of anxiety on pain, particularly on increased sensitivity in the upper range of intensities. The importance of testing the effect of anxiety over the whole range of intensities is stressed. That prior work considered only one intensity level may be the main reason why previous signal detection studies about pain and anxiety showed contradictory results.


Bioaccumulation of organochlorine contaminants in bowhead whales (Balaena mysticetus) from Barrow, Alaska.
Bowhead whale (Balaena mysticetus) blubber (n = 72) and liver (n = 23) samples were collected during seven consecutive subsistence harvests (1997-2000) at Barrow, Alaska, to investigate the bioaccumulation of organochlorine contaminants (OCs) by this long-lived mysticete. The rank order of OC group concentrations (geometric mean, wet weight) in bowhead blubber samples were toxaphene (TOX; 455 ng/g) > polychlorinated biphenyls (SigmaPCBs; 410 ng/g) > dichlorodiphenyltrichloroethane-related compounds (SigmaDDT; 331 ng/g) >or= hexachlorocyclohexane isomers (SigmaHCHs; 203 ng/g) >or= chlordanes and related isomers (SigmaCHLOR; 183 ng/g) > chlorobenzenes (SigmaCIBz; 106 ng/g). In liver, SigmaHCH (9.5 ng/g; wet weight) was the most abundant SigmaOC group, followed by SigmaPCBs (9.1 ng/g) >or= TOX (8.8 ng/g) > SigmaCHLOR (5.5 ng/g) > SigmaCIBz (4.2 ng/g) >or= SigmaDDT (3.7 ng/g). The dominant analyte in blubber and liver was p,p'-DDE and alpha-HCH, respectively. Total TOX, SigmaPCBs, SigmaDDT, and SigmaCHLOR concentrations in blubber generally increased with age of male whales (as interpreted by body length), but this relationship was not significant for adult female whales. Biomagnification factor (BMF) values (0.1-45.5) for OCs from zooplankton (Calanus sp.) to bowhead whale were consistent with findings for other mysticetes. Tissue-specific differences in OC patterns in blubber and liver may be attributed to variation of tissue composition and the relatively low capacity of this species to biotransform various OCs. Principal component analysis of contaminants levels in bowhead blubber samples suggest that proportions of OCs, such as beta-HCH, fluctuate with seasonal migration of this species between the Bering, Chukchi, and Beaufort Seas.


Recent Advances in Luminescence Imaging of Biological Systems Using Lanthanide(III) Luminescent Complexes.
The use of luminescence in biological systems allows one to diagnose diseases and understand cellular processes. Molecular systems, particularly lanthanide(III) complexes, have emerged as an attractive system for application in cellular luminescence imaging due to their long emission lifetimes, high brightness, possibility of controlling the spectroscopic properties at the molecular level, and tailoring of the ligand structure that adds sensing and therapeutic capabilities. This review aims to provide a background in luminescence imaging and lanthanide spectroscopy and discuss selected examples from the recent literature on lanthanide(III) luminescent complexes in cellular luminescence imaging, published in the period 2016-2020. Finally, the challenges and future directions that are pointing for the development of compounds that are capable of executing multiple functions and the use of light in regions where tissues and cells have low absorption will be discussed.


[Bronchiolitis: new pathogenetic aspects and personal cases].
The etiological, epidemiological and pathogenetical features of bronchiolitis and some clinical and biochemical data concerning seventy nine cases were discussed. It has been underlined the possible pathogenetical role of immunoallergic mechanism (immunoreactions type II, III, IV and VI), and of alterations of humoral immunocompetence (rise of IgM and deficit of IgA). Moreover it has been pointed out that hereditary, socioeconomical and environmental factors could play an important role in determining the seriousness of the clinical picture. The relationship between bronchiolitis and the respiratory diseases of the following years have been examinated.


Mean-field theory for inhomogeneous electrolytes.
We calculate the free energy density for inhomogeneous electrolytes based on the mean-field Debye-Hückel theory. Derived are the contributions of (1) the differential term for the electrolyte density being slow varying in one direction and (2) the boundary term for an electrolyte confined to one side of a planar interface. These contributions are shown to cause an electrolyte depletion near the air-water interfaces, which makes the surface tension increase, to be significantly larger than those predicted by previous theories. Nonuniform electrolyte densities are also computed near the water-electrolyte and electrolyte-electrolyte interfaces. Finally we calculate the interaction of two uncharged macrospheres due to the electrolyte depletion.


Crystalline-Amorphous Permalloy@Iron Oxide Core-Shell Nanoparticles Decorated on Graphene as High-Efficiency, Lightweight, and Hydrophobic Microwave Absorbents.
The exploration of high-efficiency microwave absorption materials with lightweight and hydrophobic features is highly expected to reduce or eliminate the electromagnetic pollution. Graphene-based nanocomposites are universally acknowledged as promising candidates for absorbing microwaves due to their remarkable dielectric properties and lightweight characteristic. However, the hydrophilicity of graphene may reduce their stability and restrict the applications in moist environment. Herein, a well-designed heterostructure composed of crystalline permalloy core and amorphous iron oxide shell was uniformly adhered on oleylamine-modified graphene nanosheets by a one-pot thermal decomposition method. Compared with the recognized hydrophilic graphene-based hybrid materials, the permalloy@iron oxide/graphene nanocomposites show excellent hydrophobic and water-resistant features with a water contact angle of 136.5°. Besides, the nanocomposites show high-efficiency microwave absorption performance, benefiting from the tunneling effect, polarization, interface interaction, impedance matching condition, and synergistic effect between core-shell permalloy@iron oxide nanoparticles and graphene nanosheets. A broad effective absorption bandwidth with reflection loss (RL) value exceeding -10 dB can be obtained from 4.25 to 18 GHz, covering about 86% measured frequency range when the absorber thickness is 2.0-5.0 mm. Also, the microwave absorption performance of nanocomposites can be tuned by changing the amount of graphene. More importantly, a greatly improved microwave absorption effectiveness of -71.1 dB can be achieved for the nanocomposites in comparison with the bare permalloy@iron oxide nanoparticles (-5.6 dB) and oleylamine-modified GO nanosheets (-3.56 dB). The lightweight and hydrophobic permalloy@iron oxide/graphene nanocomposites with high-efficiency microwave absorption performance are highly promising to improve the environmental adaptability of electric devices, especially in the wet environment.


Modulation of polyamine metabolic flux in adipose tissue alters the accumulation of body fat by affecting glucose homeostasis.
The continued rise in obesity despite public education, awareness and policies indicates the need for mechanism-based therapeutic approaches to help control the disease. Our data, in conjunction with other studies, suggest an unexpected role for the polyamine catabolic enzyme spermidine/spermine-N1-acetyltransferase (SSAT) in fat homeostasis. Our previous studies showed that deletion of SSAT greatly exaggerates weight gain and that the transgenic overexpression suppresses weight gain in mice on a high-fat diet. This discovery is substantial but the underlying molecular linkages are only vaguely understood. Here, we used a comprehensive systems biology approach, on white adipose tissue (WAT), to discover that the partition of acetyl-CoA towards polyamine catabolism alters glucose homeostasis and hence, fat accumulation. Comparative proteomics and antibody-based expression studies of WAT in SSAT knockout, wild type and transgenic mice identified nine proteins with an increasing gradient across the genotypes, all of which correlate with acetyl-CoA consumption in polyamine acetylation. Adipose-specific SSAT knockout mice and global SSAT knockout mice on a high-fat diet exhibited similar growth curves and proteomic patterns in their WAT, confirming that attenuated consumption of acetyl-CoA in acetylation of polyamines in adipose tissue drives the obese phenotype of these mice. Analysis of protein expression indicated that the identified changes in the levels of proteins regulating acetyl-CoA consumption occur via the AMP-activated protein kinase pathway. Together, our data suggest that differential expression of SSAT markedly alters acetyl-CoA levels, which in turn trigger a global shift in glucose metabolism in adipose tissue, thus affecting the accumulation of body fat.


Presbyterian Hospital of Dallas v. Harris: a dubious consequence of piecemeal health care legislation.
For almost forty years, legislators have advocated comprehensive measures designed to assure Americans quality health care. Instead of implementing an integrated health care plan, Congress has intermittently enacted statutes which address specific health care delivery problems. At times the judiciary has stretched the ambit of existing health legislation in response to particular plaintiffs' urgent claims. This Case Comment examines the dilemma of piecemeal legislation and judicial policymaking as exemplified by Presbyterian Hospital of Dallas v. Harris, a Fifth Circuit Court of Appeals health care financing decision whose outcome Congress has flatly rejected.


Media audit reveals inappropriate promotion of products under the scope of the International Code of Marketing of Breast-milk Substitutes in South-East Asia.
To review regulations and to perform a media audit of promotion of products under the scope of the International Code of Marketing of Breast-milk Substitutes ('the Code') in South-East Asia. We reviewed national regulations relating to the Code and 800 clips of editorial content, 387 advertisements and 217 Facebook posts from January 2015 to January 2016. We explored the ecological association between regulations and market size, and between the number of advertisements and market size and growth of milk formula. Cambodia, Indonesia, Myanmar, Thailand and Vietnam. Regulations on the child's age for inappropriate marketing of products are all below the Code's updated recommendation of 36 months (i.e. 12 months in Thailand and Indonesia; 24 months in the other three countries) and are voluntary in Thailand. Although the advertisements complied with the national regulations on the age limit, they had content (e.g. stages of milk formula; messages about the benefit; pictures of a child) that confused audiences. Market size and growth of milk formula were positively associated with the number of newborns and the number of advertisements, and were not affected by the current level of implementation of breast-milk substitute laws and regulations. The present media audit reveals inappropriate promotion and insufficient national regulation of products under the scope of the Code in South-East Asia. Strengthened implementation of regulations aligned with the Code's updated recommendation should be part of comprehensive strategies to minimize the harmful effects of advertisements of breast-milk substitutes on maternal and child nutrition and health.


Culture of embryos and cells from platyfish and swordtails for carcinogenicity testing and studies on melanoma formation.
We introduce inbred strains of platyfish and swordtails as well as their hybrids as laboratory animals for carcinogenicity testing. We especially propose to take advantage of the platyfish-swordtail melanoma system, which permits the breeding of animals with high susceptibility to carcinogen-induced melanoma. Based on our present view that, in melanoma formation, such fundamental processes as the determination and differentiation of a specific cell type are affected, we suggest the use of embryos and embryo-derived cell cultures. In both systems, all stages of pigment cell differentiation can be followed and screened for abnormal development. The in vitro culture of the embryos of the viviparous fish and the establishment of cell cultures are described.


The Caenorhabditis elegans tmc-1 is involved in egg-laying inhibition in response to harsh touch.
The conserved family of Transmembrane channel-like (TMC) proteins has attracted significant interest since two members appear to be key components of the mammalian hair cell mechanotransducer involved in hearing. C. elegans expresses two TMC proteins, TMC-1 and TMC-2. TMC-1 is widely expressed in in both muscles and the nervous system. This wide expression pattern suggests that TMC-1 might serve different functions in the various neurons. TMC-1 has previously been shown to function in neurons, playing a role in chemosensation in the ASH neurons and mechanosensation in OLQ neurons, further supporting this hypothesis. tmc-1 is expressed in the high-threshold mechanosensory neuron, ALA. We show that tmc-1 mutants show defects in the ALA-dependent inhibition of egg-laying in response to a harsh mechanical stimulus.


Influence of nervous tendencies on oral health status and lifestyle habits.
It is presumed that people with nervous tendencies brush their teeth for long durations, and, we aimed to investigate how nervous tendencies affect oral health status and lifestyle habits. Three hundred and sixty patients who visited the Senri Dental Clinic, affiliated with the Sunstar Foundation, and were being treated for periodontal diseases between 11 January 2017 and 10 April 2017 were enrolled. A total of 323 respondents (101 men and 222 women) were considered eligible. Nervous tendencies were investigated using the Fujinami neurotic index (FNI) and its derivative, the neurotic index (NI). Patients with NIs of ≥20 were included in the 'needs caution' group, whereas those with NIs of <19 comprised the 'healthy' group. The plaque score; periodontal pocket depth; bleeding on probing degree; gingival recession; crevice defects; oral conditions, such as cervical fillings and lifestyle habits were compared between the groups. No statistically significant differences in oral status were observed between the groups. On the other hand, the needs caution group had significantly longer brushing durations and lower usage of auxiliary teeth cleaning tools than the healthy group. Sleep duration was significantly shorter in the needs caution group than in the healthy group. Patients with strong nervous tendencies had long oral brushing durations and low usage of auxiliary cleaning tools. However, these factors did not negatively affect oral health status. These results could aid in understanding patients with strong nervous tendencies and in developing appropriate dental health guidance measures.


Phytochemical characterization and toxicological activity attributed to the acetonic extract of South American Vassobia breviflora.
The particular plant species found in southern Brazil, Vassobia breviflora (Solanaceae) has only a few apparent studies examining its biological effect. Thus, the aim of the present study was to determine the activity of the acetone extract fraction derived from V. breviflora. Four compounds were identified by ESI-qTOF-MS: eucalrobusone R, aplanoic acid B, pheophorbide A, and pheophytin A. In addition, 5 compounds were identified by HPLC-PDA-MS/MS: all-trans-lutein, 15-cis-lutein, all-trans-β-carotene, 5,8-epoxy-β-carotene, and cis-β-carotene. Cell lines A549 (lung cancer), A375 (melanoma cancer) and HeLa (cervical cancer) were incubated with different concentrations of each studied extract using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), lactate dehydrogenase (LDH), and 2'-7'dichlorofluorescin diacetate (DCFH-DA) assays. The acetonic extract exhibited cytotoxic activity at a concentration of 0.03 mg/ml in the HeLa strain and 0.1 mg/ml in the others. In addition to increased production of reactive oxygen species (ROS). Antibacterial activity was assessed utilizing minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) in 9 ATCCs strains and 7 clinical isolates, as well as determination of biofilm production. Data demonstrated that MIC and MBC were approximately 256 mg/ml in most of the strains tested and antibiofilm effect at S. aureus, S. epidermidis, A. baumannii, and E. faecalis, concentrations below the MIC. Genotoxic activity on plasmid DNA did not produce significant elevated levels in breaks in the isolated genetic material.


[What do you think of Thuisarts.nl? Experiences after 3 years of www.Thuisarts.nl].
Many people need information on health and disease, but the internet is a maze of medical information. In order to offer patients reliable medical information, and to support general practitioners, the Dutch College of General Practitioners (NHG) set up the public website Thuisarts.nl in 2011, which was later followed by an app. The NHG members survey amongst general practitioners from June 2013 showed that 90% of the general practitioners used Thuisarts.nl. The number of visitors was on average 60,000 a day. Information is also available from questionnaires filled in by the NIVEL Health Care Consumer Panel (n = 2846) and participants in a study on information technology and independence (n = 25). Thuisarts.nl meets an important need and is highly valued by doctors and patients. There are plans for the further development of Thuisarts.nl including short videos, illustrations, searchable anatomical structures and information from other reliable organisations such as associations of specialist doctors.


Facilitated Unbinding via Multivalency-Enabled Ternary Complexes: New Paradigm for Protein-DNA Interactions.
Dynamic protein-DNA interactions constitute highly robust cellular machineries to fulfill cellular functions. A vast number of studies have focused on how DNA-binding proteins search for and interact with their target DNA segments and on what cellular cues can regulate protein binding, for which protein concentration is a most obvious one. In contrast, how protein unbinding could be regulated by protein concentration has evaded attention because protein unbinding from DNA is typically a unimolecular reaction and thus concentration independent. Recent single-molecule studies from multiple research groups have uncovered that protein concentration can facilitate the unbinding of DNA-bound proteins, revealing regulation of protein unbinding as another mechanistic paradigm for gene regulation. In this Account, we review these recent in vitro and in vivo single-molecule experiments that uncovered the concentration-facilitated protein unbinding by multiple types of DNA-binding proteins, including sequence-nonspecific DNA-binding proteins (e.g., nucleoid-associated proteins, NAP), sequence-specific DNA-binding proteins (e.g., metal-responsive transcription regulators CueR and ZntR), sequence-neutral single-stranded DNA-binding proteins (e.g., Replication protein A, RPA), and DNA polymerases. For the in vitro experiments, Marko's group investigated the exchange of GFP-tagged DNA-bound NAPs with nontagged NAPs in solution of increasing concentration using single-molecule magnetic-tweezers fluorescence microscopy. The faster fluorescence intensity decrease with higher nontagged NAP concentrations suggests that DNA-bound NAPs undergo faster exchange with higher free NAP concentrations. Chen's group used single-molecule fluorescence resonance energy transfer measurements to study the unbinding of CueR from its cognate oligomeric DNA. The average microscopic dwell times of DNA-bound states become shorter with increasing CueR concentrations in the surroundings, demonstrating that free CueR proteins can facilitate the unbinding of the incumbent one on DNA through either assisted dissociation or direct substitution. Greene's group studied the unbinding of RPAs from single-stranded DNA using total internal reflection fluorescence microscopy and DNA curtain techniques. The fluorescence intensity versus time traces show faster decay with higher wild-type RPA concentrations, indicating that DNA-bound RPAs can undergo a concentration-facilitated exchange when encountering excess free RPA. van Oijen's group investigated the leading/lagging-strand polymerase exchange events in the bacteriophage T7 and E. coli replication systems using a combination of single-molecule fluorescence microscopy and DNA-flow-stretching assay. The processivity was observed to have larger decrease when the concentration of the Y526F polymerase mutant increases, indicating that the unbinding of the polymerase is also concentration-dependent. Using stroboscopic imaging and single-molecule tracking, Chen's group further advanced their study into living bacterial cells. They found CueR, as well as its homologue ZntR, shows concentration-enhanced unbinding from its DNA-binding site in vivo. Mechanistic consensus has emerged from these in vitro and in vivo single-molecule studies that encompass a range of proteins with distinct biological functions. It involves multivalent contacts between protein and DNA. The multivalency enables the formation of ternary complexes as intermediates, which subsequently give rise to concentration-enhanced protein unbinding. As multivalent contacts are ubiquitous among DNA-interacting proteins, this multivalency-enabled facilitated unbinding mechanism thus provides a potentially general mechanistic paradigm in regulating protein-DNA interactions.


[Eugenics in neurology and psychiatry in Hungary between the two World Wars].
Eugenics became an organized movement in Hungary in 1914 with the establishment of the Section of Eugenics within the Association of Social Sciences (Társádalomtudományi Egyesület). Its secretary, the prominent biologist István Apáthy jr., defined the aims and the place of eugenics within the sanitation as well as the necessary steps of organization which should be taken in Hungary. It was especially some Hungarian psychiatrists: Márk Goldberger, Lajos Naményi, Gyula Donáth and László Benedek, the Hungarian Representative of the Committee of International Eugenical Organisations who after World War I urged eugenical law which envisaged voluntary sterilization. According to the opponents of eliminative eugenics--like Károly Csörsz, one of the first distinguished medical geneticists in Hungary--sterilization had not been scientifically based yet, because the ways and the probability of heredity of nervous and mental diseases, except for Huntington chorea, had not been explored yet. The outstanding neurologist, Karl Schaffer also opposed the sterilization bill worked out by Professor Benedek, so it was rejected by the National Council of Public Health in 1932 and was not discussed by the Hungarian Parliament either. In spite of its illegality, some sterilizations were executed, for example with the consent and the request of parents in the case of mentally retarded female to stop her reproduction. Only positive eugenics was legally supported by the marriage advisory bureau in the capital, but the interest in it was rather limited in interwar Hungary.


Enhanced capacitive pressure sensing performance by charge generation from filler movement in thin and flexible PVDF-GNP composite films.
This study introduces an approach to overcome the limitations of conventional pressure sensors by developing a thin and lightweight composite film specifically tailored for flexible capacitive pressure sensors, with a particular emphasis on the medium and high pressure range. To accomplish this, we have engineered a composite film by combining polyvinylidene fluoride (PVDF) and graphite nanoplatelets (GNP) derived from expanded graphite (Ex-G). A uniform sized GNPs with an average lateral size of 2.55av and an average thickness of 33.74 av with narrow size distribution was obtained with a gas-induced expansion of expandable graphite (EXP-G) combined with tip sonication in solvent. By this precisely controlled GNP within the composite film, a remarkable improvement in sensor sensitivity has been achieved, surpassing 4.18 MPa-1 within the pressure range of 0.1 to 1.6 MPa. This enhancement can be attributed to the generation of electric charge from the movement of GNP in the polymer matrix. Additionally, stability testing has demonstrated the reliable operation of the composite film over 1000 cycles. Notably, the composite film exhibits exceptional continuous pressure sensing capabilities with a rapid response time of approximately 100 milliseconds. Experimental validation using a 3 × 3 sensor array has confirmed the accurate detection of specific contact points, thus highlighting the potential of the composite film in selective pressure sensing. These findings signify an advancement in the field of flexible capacitive pressure sensors that offer enhanced sensitivity, consistent operation, rapid response time, and the unique ability to selectively sense pressure.


Criteria to detect mitral prosthetic valve dysfunction via continuous wave Doppler echocardiography.
To detect the diagnostic criteria for mitral prosthetic valve dysfunction, Doppler echocardiography was used to assess valve function following mitral valve replacement in 100 patients [50 with St. Jude Medical (SJM) valves, 50 with Björk-Shiley (B-S) valves]. Mitral valve area (MVA) was calculated by dividing a constant of 220 by pressure half time (PHT) measured via Doppler technique [220/PHT]. The relationship of MVA to left ventricular function, geometric valve area (GVA) of the prosthetic valve, body surface area (BSA), and maximum disc-opening angle (maxOA) were assessed. In the SJM valves, MVA significantly correlated with valve area index (GVA/BSA). The % area index [(MVA/valve area index) x 100] was 100.2 +/- 12.8% on the average and no patients with the SJM valve showed the %area index of less than 73%. There was no incidence of valve dysfunction in the SJM valves. We concluded from these results that if the % area index is less than 73% (mean -2SD), the SJM valve dysfunction should be diagnosed. When the B-S valves were examined, there were 19 patients in whom the maximum opening angle had decreased to under 58 degrees. These patients also had decreased MVA and % area index. Evaluation of the relationship between the maximum opening angle and the % area index revealed that the patients in whom the maximum opening angle had diminished to under 50 degrees had low % area index (of less than 70%).(ABSTRACT TRUNCATED AT 250 WORDS)


Echocardiographic assessment of myocardial infarction: comparison of a rat model in two strains.
The purpose of this study was to induce myocardial infarction (MI) and compare the echocardiographic parameters and mortality ratio of Lewis inbred and Wistar outbred strain before and after the procedure to help choose the best one for MI studies. In this study MI was induced in 46 Lewis and 34 Wistar by occlusion of left anterior descending artery (LAD). Doppler, two-dimensional (2-D) and 2-D guided M-mode images were recorded from parasternal long-axis and parasternal short-axis and apical four-chamber views. The following parameters were acquired. Interventricular septum diastolic and systolic dimension (IVSd, s), diastolic and systolic left ventricular internal diameter (LVIDd, s), diastolic and systolic left ventricular posterior wall dimension (LVPWd, s), ejection fraction (EF), and fractional shortening (FS). The significant changes were observed in systolic IVS, LVID and EF and FS before and after MI and no significant difference was detected between Lewis and Wistar. The high mortality rate of 51% was seen in the procedure, including anesthesia in Lewis compared to 34% in Wistar. As a conclusion the echocardiographic parameters of these two strains were similar, but according to mortality rate and more cardiac anatomic variation in Lewis rats, Wistar is better for MI studies.


Solubility of 92 in blood with different hemoglobin concentrations at low temperatures.
The Brunsen solubility coefficients for O2 in blood obtained from healthy nonsmoking subjects have been determined at 0, 6, and 12 degrees C for bloods of hemoglobin concentrations 5.6, 10.2, 15.7, and 22.5 g/100 ml. Direct gasometric measurements show that blood has a relative solubility (alphabeta/alphah2o) different for each hemoglobin concentration but constant for any given hemoglobin concentration at the temperatures studied (0.6, and 12 degrees C). For hemoglobin concentrations 5.6, 10.2, 15.7, and 22.5 g/100 ml alphabetao degrees C/alphabeta 12 degrees C rations were 1.36, 1.35, 1.35, and 1.35, respectively. The alpha H20(0 degrees C)/alpha H20(12 degrees C) ratio is 1.34. Consequently, it was possible to construct a table for the Brunsen solubility coefficients for O2 in blood from O to 15 degrees C of different hemoglobulin concentrations. Values from 10 to 15 degrees C published in the Biologal Hanbook, Respiration and Circulation, based on extrapolations from previous direct measurements of temperatures from 18 to 37 degrees C differ only 1% from our present results.


Dynamic complexation of solutes in capillary electrophoresis.
The analyte migration behavior in any chemical separation system can be described using a single equation that unifies all areas of separation science. This equation can be used in capillary electrophoresis (CE) to design separation systems, and to study interactions between analytes and additives. By using individual capacity factors for each analyte species present in the system, and with the knowledge of the characteristics of each interaction, one can predict the analyte migration behavior in complicated CE systems, including systems with multiple 1:1 interactions and/or higher order interactions.


Patients' Characteristics, Histopathological Findings, and Tumor Stage in Different Types of Malignant Melanoma: A Retrospective Multicenter Study.
Cutaneous malignant melanoma (CMM) is currently the most fatal of skin cancers accounting for 50000 deaths annually. Five distinct melanomas are described histopathologically: superficial spreading, lentigo maligna, nodular, acral lentiginous and mucosal melanoma. The aim of this study was to investigate the characteristics of patients with various types of malignant melanoma and evaluate histopathological findings. In this retrospective study, we obtained our data from the records of 111 patients with melanoma. Biopsied specimens were collected and re-evaluated. Demographic information and histopathological findings were noted. SPSS 16 was used for analyzing data. Chi-square and one-way ANOVA was conducted for comparing categorical and numerical variables respectively. The mean age of patients was 59.33±14.68 years old. Most common melanoma type was acral lentiginous (40.5%), followed by nodular (35.1%) and mucosal (10.8%). The highest tumor thickness was viewed in nodular melanoma followed by mucosal melanoma. The highest rate of metastasis, microsatellitosis, perineural invasion and Clark level of the invasion were reported in nodular and acral lentiginous respectively. The most frequent rate of ulceration and vascular invasion was reported in mucosal melanoma. Distribution of melanoma types varies largely in different regions. Lack of classic presentations in some types necessitate specific public education about warning signs. Histopathological and pathological characteristics in melanoma can aid in better staging and management of the tumor.


Role of α5β1 and αvβ3 integrins in relation to adhesion and spreading dynamics of prostate cancer cells interacting with fibronectin under in vitro conditions.
Interaction of cell integrins with the ECM (extracellular matrix) proteins is commonly assumed to be associated with cell dissemination and tumour metastases. Since these processes depend on the mechanism of cell-protein interaction, we have attempted to show the contribution of α5β1 and αvβ3 integrins of the prostate cancer PC-3 cells in in vitro interaction with FN (fibronectin) adsorbed on defined polystyrene surfaces. Cell adhesion, spreading and cytoskeleton organization were studied using antibodies against integrins or a GRGDSP (Gly-Arg-Gly-Asp-Ser-Pro) peptide. The results show that blocking the α5β1 integrin causes: (i) a decrease in the number of the adherent cells in the early phase of adhesion and (ii) a decrease in the dynamics of cell spreading and cell shape changes, and weaker reorganization of cytoskeletal proteins than in the control cells. Conversely, the blocking of the αvβ3 integrin: (i) causes no observable effect on the number of the adhered cells; however, (ii) causes an increase in the dynamics of cell spreading and cell shape changes, and stronger reorganization of cytoskeletal proteins than in the control cells. Interestingly, the blocking of integrins with a GRGDSP peptide strongly decreases the number of the adhered cells, and a complete inhibition of cell spreading. Our results strongly suggest that the α5β1 integrin plays the main role in the adhesion and spreading of PC-3 cells interacting with FN, whereas the αvβ3 integrin seems to regulate other receptors in the spreading process. Moreover, integrin-FN interaction through the RGD sequence evidently curbed the cell adhesion and spreading.


Fibroblast growth factor and cerebral ischaemia.
Although the cellular events that accompany brain injury have been well characterized, the factors that mediate growth and repair in the central nervous system (CNS) are only beginning to be identified. One such is fibroblast growth factor. The fibroblast growth factor (FGF) family of proteins includes, at this moment, seven structurally related polypeptides. Acidic and basic FGF (aFGF and bFGF) were the first described members of the family, and are the best characterized. Both proteins bind with high affinity to the same kind of receptor at the plasma membrane through which they induce a whole series of intracellular events that mediate their physiological functions. FGF, which displays pleiotrophic biological activities including mitogenesis, chemotaxis, and induction of differentiation is a potent angiogenic factor in vivo, tested in assays as different as the rabbit cornea, the chick chorioalantoic membrane (CAM), the rat common carotid artery, and the rat brain.


Self-association of urea in aqueous solutions: a Voronoi polyhedron analysis study.
Molecular dynamics simulation of the aqueous solutions of urea of seven different concentrations (including neat water as a reference system) has been performed on the isothermal-isobaric (N,p,T) ensemble. The ability of the urea molecules of self-association is investigated by means of the method of Voronoi polyhedra. For this purpose, all the analyses are repeated by removing one of the two components from the sample configurations and considering only the other one. In this way, the analysis of self-aggregation is reduced to the analysis of voids, a problem that can routinely be addressed by means of Voronoi analysis. The obtained results show that the urea molecules exhibit self-association behavior, which is found to be the strongest at the urea mole fraction of 0.23. However, the size of these urea aggregates is found to be rather limited; on average, they are built up by 3-4 molecules, and never exceed the size of 20-25 molecules.


Vibrio cholerae lipopolysaccharide loaded chitosan nanoparticle could save life by induction of specific immunoglobulin isotype.
The lipopolysaccharide (LPS) of Vibrio cholerae (V. cholerae) plays an important role in cholera disease and the induction of primary protection. In this study, we evaluate mice humoral immune response in intranasal and intraperitoneal administrated V. cholerae LPS. The results showed that the intranasal administration of LPS-chitosan nanoparticle induced the high level of antibodies compared to intraperitoneal injection of antigen without chitosan (P < .001). These results indicated that intranasal and intraperitoneal administration of LPS has been able to induce the high level of antibodies both in the sera and lavage fluid and confirmed our strategy for using intranasal administration of antigen.


Total flavonoids of Daphne genkwa root significantly inhibit the growth and metastasis of Lewis lung carcinoma in C57BL6 mice.
Daphne genkwa root has been traditionally used as an effective remedy to treat various tumors. However, the active constituents for its antitumor potency have not been well documented. During the screening for antitumor constituents, it was found that the total flavonoids of D. genkwa root (TFDR) were responsible for the inhibition of tumor growth and metastasis. In this study, TFDR was investigated for its chemical composition and activities against tumor growth and metastasis. HPLC indicates that daphnodorin B, containing 42.79% of the total, represents the predominant constituent in TFDR. Treatment of LLC-bearing mice with TFDR evidently protected peripheral lymphocytes from tumor-induced reduction, and increased lymphocyte proliferation potential and cytolytic activity of NK, and inhibited tumor progression and metastasis either 7 days before, or simultaneous with, or 7 days after LLC transplantation. TFDR also suggested higher cytotoxicity to a number of tumor cell lines than that to normal human kidney cell K293. TFDR also induced an enhancement on peripheral release of TNF-alpha at doses between 25 and 75 mg/kg. These results indicated that TFDR inhibited tumor growth and metastasis by protecting host immunocyte viability and its proliferation potential, and selectively inhibiting tumor cell proliferation, and improving cytolytic activity of NK cells, and enhancing TNF release in LLC-bearing mice. Daphnodorin B and its analogues in TFDR are the active constituents in the roots of D. genkwa, contributing to the inhibition of tumor growth and metastasis.


Effects of exenatide vs. metformin on endothelial function in obese patients with pre-diabetes: a randomized trial.
Glucagon like peptide-1 (GLP-1) receptor agonist treatment may improve endothelial function via direct and indirect mechanisms. We compared the acute and chronic effects of the GLP-1 receptor agonist exenatide vs. metformin on endothelial function in patients with obesity and pre-diabetes. We performed a randomized, open-label, clinical trial in 50 non-diabetic individuals (mean age 58.5 ± 10.0; 38 females) with abdominal obesity and either impaired fasting glucose, elevated HbA1c, or impaired glucose tolerance (IGT) who were randomized to receive 3-months of exenatide or metformin. Microvascular endothelial function, assessed by digital reactive hyperemia (reactive hyperemic index: RHI), C-reactive protein (CRP), circulating oxidized LDL (oxLDL), and vascular cell adhesion molecule-1 (VCAM-1) were measured at baseline and 3-months. Seven subjects with IGT participated in a sub-study comparing the effects of pre-administration of exenatide and metformin on postprandial endothelial function. There were no differences for the change in RHI (Δ exenatide: 0.01 ± 0.68 vs. Δ metformin: -0.17 ± 0.72, P = 0.348), CRP, oxLDL, or VCAM-1 between exenatide and metformin treatment. Triglycerides were reduced more with exenatide compared to metformin (Δ exenatide: -25.5 ± 45.7 mg/dL vs. Δ metformin: -2.9 ± 22.8 mg/dL, P = 0.032). In the sub-study, there was no difference in postprandial RHI between exenatide and metformin. Three months of exenatide therapy had similar effects on microvascular endothelial function, markers of inflammation, oxidative stress, and vascular activation, as metformin, in patients with obesity and pre-diabetes. This study is registered on http://www.clinicaltrials.gov/: NCT00546728.


Supportive psychological therapy can effectively treat post-stroke post-traumatic stress disorder at the early stage.
Post-traumatic stress disorder (PTSD) can develop after stroke attacks, and its rate ranges from 4 to 37% in the stroke population. Suffering from PTSD not only decreases stroke patient's quality of life, but also relates to their non-adherence of treatment. Since strokes often recur and progress, long-term medical management is especially important. However, previous studies generally focused on the epidemiological characteristics of post-stroke PTSD, while there are literally no studies on the psychological intervention. In our study, 170 patients with a first-ever stroke during the acute phase were recruited. They were randomized into Psycho-therapy group 1 and Control group 1, and were administered with preventive intervention for PTSD or routine health education, respectively. At 2-month follow-up, PTSD symptoms were evaluated. Participants who were diagnosed with post-stroke PTSD were further randomized into Psycho-therapy group 2 and Control group 2, and received supportive therapy or routine health counseling, respectively. At 6-month follow-up (1°month after the therapy was completed), PTSD symptoms were re-evaluated. Our results showed that at 2-month, the PTSD incidence in our series was 11.69%, and the severity of stroke was the only risk factor for PTSD development. The preventive intervention was not superior to routine health education for PTSD prevention. At 6-month, results indicated the supportive therapy did have a fine effect in ameliorating symptoms for diagnosed PTSD patients, superior to routine health counseling. Thus, our study was the first to provide evidence that the supportive therapy was effective in treating post-stroke PTSD early after its diagnosis. This clinical trial was preregistered on www.chictr.org.cn (ChiCTR2100048411).


Physiochemical and Microbial Analysis of Tibetan Yak Milk Yogurt in Comparison to Locally Available Yogurt.
Yak yogurt, which is rich in microorganisms, is a naturally fermented dairy product prepared with ancient and modern techniques by Chinese herdsmen in the Qinghai-Tibet Plateau. The objective of this research was to assess the impact of Lactobacillus bulgaricus and Streptococcus thermophilus starter cultures on the quality and shelf life of yak yogurt, as well as the genetic stability across multiple generations, in comparison to commercially available plain yogurt and peach oat flavor yogurt. Following that, the samples were evenly divided into four treatment groups denoted as T1 (treatment 1), T2, T3, and T4, with each group employing a distinct source of yogurt formulation. T1 included L. bulgaricus, T2 comprised S. thermophilus, T3 consisted of plain yogurt, and T4 represented peach oat yogurt flavor. The findings indicate that T1 yogurt consistently presents a lower pH and higher acidity compared to the other three yogurt types throughout the entire generation process. Moreover, the fat content in all generations of the four yogurt types exceeds the national standard of 3.1 g/100 g, while the total solid content shows a tendency to stabilize across generations. The protein content varies significantly among each generation, with T1 and T4 yogurt indicating higher levels compared to the T2 and T3 yogurt groups. In terms of overall quality, T1 and T4 yogurt are superior to T2 and T3 yogurt, with T1 yogurt being the highest in quality among all groups. The findings revealed that the inclusion of L. bulgaricus led to enhanced flavor, texture, and genetic stability in yak yogurt. This study will serve as a valuable source of data, support, and methodology for the development and screening of compound starters to be utilized in milk fermentation in future research and applications.


Tryptophan-scanning mutagenesis in the S1 domain of mammalian HCN channel reveals residues critical for voltage-gated activation.
Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are essential regulators in rhythmic activity, membrane excitability and synaptic transmission. There are four subtypes in mammals (HCN1-4); HCN4 has the slowest activation kinetics and HCN1 the fastest. Although voltage gating originates with the voltage-dependent motion of the S4 segment, the different activation kinetics between HCN1 and HCN4 are generated mainly by S1 and the S1-S2 loop. In this study, we investigate the structural basis of the ability of S1 to affect activation kinetics by replacing each individual S1 residue in HCN1 with a tryptophan (Trp) residue, a Trp perturbation scan. Robust currents were generated in 11 out of 19 Trp mutants. Hyperpolarization-activated currents were not detected in four mutants, and two other mutants generated only small currents. Presence or absence of current reflected the predicted alpha-helical structure of the S1 transmembrane segment. Tryptophan replacements of residues responsible for the different kinetics between HCN1 and HCN4 made the activation kinetics slower than the wild-type HCN1. Tryptophan mutations introduced in the middle of S1 (L139W and V143W) prevented normal channel closure. Furthermore, a negatively charged residue at position 139 (L139D) induced a positive voltage shift of activation by 125 mV. Thus, L139 and V143 probably face a mobile part of the S4 voltage sensor and may interact with it. These results suggest that the secondary structure of S1 is alpha-helical and profoundly affects the motion of the voltage sensor.


Investigating capillary electrophoresis-mass spectrometry for the analysis of common post-translational modifications.
Capillary electrophoresis coupled to mass spectrometry is a very efficient analytical method for the analysis of post-translational modifications because of its high separation efficiency and high detection sensitivity. Here we applied CE-MS using three differently coated separation capillaries for in-depth analysis of a set of 70 synthetic post-translationally modified peptides (including phosphorylation, acetylation, methylation, and nitration). We evaluated the results in terms of peptide detection and separation characteristics and found that the use of a neutrally coated capillary resulted in highest overall signal intensity of singly modified peptides. In contrast, the use of a bare-fused silica capillary was superior in the identification of multi-phosphorylated peptides (12 out of 15 were identified). Fast separations of approximately 12 min could be achieved using a positively coated capillary, however, at the cost of separation efficiency. A comparison to nanoLC-MS revealed that multi-phosphorylated peptides interact with the RP material very poorly so that these peptides were either washed out or elute as very broad peaks from the nano column which results in a reduced peptide identification rate (7 out of 15). Moreover, the methods applied were found to be very well suited for the analysis of the acetylated, nitrated and methylated peptides. All 36 synthetic peptides, which exhibit one of those modifications, could be identified regardless of the method applied. As a final step in this study and as a proof of principle, the phosphoproteome enriched from PC-12 pheochromocytoma cells was analyzed by CE-MS resulting in 5686 identified and 4088 quantified phosphopeptides. We compared the characterized analytes to those identified by a nanoLC-MS proteomics study and found that less than one third of the phosphopeptides were identical, which demonstrates the benefit by combining different approaches quite impressively.


Whole-exome sequencing implicates DGKH as a risk gene for panic disorder in the Faroese population.
The demographic history of the isolated population of the Faroe Islands may have induced enrichment of variants rarely seen in outbred European populations, including enrichment of risk variants for panic disorder (PD). PD is a common mental disorder, characterized by recurring and unprovoked panic attacks, and genetic factors have been estimated to explain around 40% of the risk. In this study the potential enrichment of PD risk variants was explored based on whole-exome sequencing of 54 patients with PD and 211 control individuals from the Faroese population. No genome-wide significant associations were found, however several single variants and genes showed strong association with PD, where DGKH was found to be the strongest PD associated gene. Interestingly DGKH has previously demonstrated genome-wide significant association with bipolar disorder as well as evidence of association to other mental disorders. Additionally, we found an enrichment of PD risk variants in the Faroese population; variants with otherwise low frequency in more outbreed European populations. © 2016 Wiley Periodicals, Inc.


Segmentally arranged seborrhoeic keratoses with impending atypia and squamous cell carcinoma in an elderly woman.
Epidermal naevi (EN) are considered mosaic disorders. Postzygotic mutations are thought to occur during early embryogenesis. They are usually arranged along Blaschko's lines and tend to be noted either at birth or shortly thereafter. Skin tumours arising on EN are occasionally reported, with ongoing discussion as to whether these are collision tumours or a malignant transformation of the EN. We describe a 76-year-old woman with segmentally arranged seborrhoeic keratoses that showed impending atypia and, in one lesion, even overt malignant transformation. In biopsies from various lesions we found FGFR3 and PIK3CA hotspot mutations but there was no consistent pattern of mutations explaining the premalignant or malignant growth. So far it is unclear whether the precancerous changes as noted in this elderly patient can be taken as an unusual manifestation of one of the established types of EN, or whether this may represent a separate disorder that could be called 'SASKIA naevus'. The acronym would stand for segmentally arranged seborrhoeic keratoses with impending atypia.


Consistency of Eye Coloration Across Different Relationship Partners.
Studies have indicated that people are attracted to partners who resemble themselves or their parents, in terms of physical traits including eye color. We might anticipate this inclination to be relatively stable, giving rise to a sequential selection of similar partners who then represent an individual's "type". We tested this idea by examining whether people's sequential partners resembled each other at the level of eye color. We gathered details of the eye colors of the partners of participants (N = 579) across their adult romantic history (N = 3250 relationships), in three samples, comprising two samples which made use of self-reports from predominantly UK-based participants, and one which made use of publicly available information about celebrity relationship histories. Recorded partner eye colors comprised black (N = 39 partners), dark brown (N = 884), light brown (N = 393), hazel (N = 224), blue (N = 936), blue green (N = 245), grey (N = 34), and green (N = 229). We calculated the proportion of identical eye colors within each participant's relationship history, and compared that to 100,000 random permutations of our dataset, using t-tests to investigate if the eye color of partners across an individual's relationship history was biased relative to chance (i.e., if there was greater consistency, represented by higher calculated proportions of identical eye colors, in the original dataset than in the permutations). To account for possible eye color reporting errors and ethnic group matching, we ran the analyses restricted to White participants and to high-confidence eye color data; we then ran the analyses again in relation to the complete dataset. We found some limited evidence for some consistency of eye color across people's relationship histories in some of the samples only when using the complete dataset. We discuss the issues of small effect sizes, partner-report bias, and ethnic group matching in investigating partner consistency across time.


The Roles of Protein Tyrosine Phosphatases in Hepatocellular Carcinoma.
The protein tyrosine phosphatase (PTP) family is involved in multiple cellular functions and plays an important role in various pathological and physiological processes. In many chronic diseases, for example cancer, PTP is a potential therapeutic target for cancer treatment. In the last two decades, dozens of PTP inhibitors which specifically target individual PTP molecules were developed as therapeutic agents. Hepatocellular carcinoma (HCC) is one of the most common malignant tumors and is the second most lethal cancer worldwide due to a lack of effective therapies. Recent studies have unveiled both oncogenic and tumor suppressive functions of PTP in HCC. Here, we review the current knowledge on the involvement of PTP in HCC and further discuss the possibility of targeting PTP in HCC.


A Simple and Rapid HPLC-PDA MS Method for the Profiling of Citrus Peels and Traditional Italian Liquors.
A chromatographic method for the qualitative and quantitative characterization of peels and preparations based on different species of Citrus was developed in order to obtain a complete profile of the constituents, including flavonoids and protoalkaloids. Commercial peels of sweet orange, lemon, mandarin, and grapefruit were analyzed. Seventeen constituents including flavanones, flavones, polymethoxyflavones, and protoalkaloids were identified by HPLC-PDA, HPLC-MS, and HPLC-MS/MS using a comparison of retention times and UV-Vis and MS spectra with reference standards and literature data. The total amount of flavanones [neoeriocitrin (5), naringin (8) and hesperidin (9)] and polymethoxflavones [sinensetin (12), nobiletin (14), 3,5,6,7,8,3',4'-heptamethoxyflavone (15), and tangeretin (16)] was determined and expressed as naringin (8) or hesperidin (9), and sinensetin (12), respectively. The protoalkaloid synephrine was detected in all samples, except in grapefruit, but its content was lower than the limit of quantification. Qualitative and quantitative chemical profiles of three different Italian aromatic liquors ("Limoncello", "Arancello", and "Mandarinetto"), prepared according to traditional recipes, were also analyzed.


Hormesis: a fundamental concept in biology.
This paper assesses the hormesis dose response concept, including its historical foundations, frequency, generality, quantitative features, mechanistic basis and biomedical, pharmaceutical and environmental health implications. The hormetic dose response is highly generalizable, being independent of biology model (i.e. common from plants to humans), level of biological organization (i.e. cell, organ and organism), endpoint, inducing agent and mechanism, providing the first general and quantitative description of plasticity. The hormetic dose response describes the limits to which integrative endpoints (e.g. cell proliferation, cell migration, growth patterns, tissue repair, aging processes, complex behaviors such as anxiety, learning, memory, and stress, preconditioning responses, and numerous adaptive responses) can be modulated (i.e., enhanced or diminished) by pharmaceutical, chemical and physical means. Thus, the hormesis concept is a fundamental concept in biology with a wide range of biological implications and biomedical applications.