Functional Connectivity of Nucleus Accumbens Is Associated with Lifelong Premature Ejaculation in Male Adults : A Resting-state fMRI Study.
Ejaculation represents a crucial component of sexual behavior in men, which is involved in reward functions of certain brain areas including the nucleus accumbens (NAcc). Lifelong premature ejaculation (PE) is one of the most prevalent sexual dysfunctions in men. It is suggested to be related to abnormal brain function. This study aimed to explore changes of the functional connectivity patterns of NAcc and possible correlations of the neuroimaging abnormalities with clinical features in lifelong PE patients. The sample consisted with 42 lifelong PE patients and 30 healthy controls. All participants underwent functional magnetic resonance imaging scans and clinical symptoms. The functional connectivity (FC) approach was applied to investigate differences of NAcc-seed intrinsic connectivity between two groups and correlation analysis was used to access possible relationships between the imaging findings and clinical features, such as premature ejaculation diagnostic tool (PEDT) or intravaginal ejaculatory latency time (IELT). Results showed that lifelong PE patients had decreased FC between the NAcc and thalamus, superior temporal pole, superior temporal cortex (STC), inferior frontal gyrus (IFG), orbitofrontal cortex, caudate and putamen. A significantly negative correlation between the PEDT score and NAcc-STC connectivity (r = -0.46) was found in lifelong PE patients, while IELT score positively correlated with the NAcc-IFG connectivity (r = 0.48) and NAcc-thalamus connectivity (r = 0.46). The findings may facilitate a more sophisticated understanding of neural mechanisms of lifelong PE, particularly associated with the NAcc-related intrinsic connectivity during the resting state.


A new method for molecular weight determination using polyacrylamidegel electrophoresis in a linear gel-concentration-gradient (3-20 degrees ) is described. Plotting the log of molecular weights of several standard proteins against distance of migration or against 3 log of rate of n-dgration reveal linear relationships in ranges of 50.000 - 200.000 or 100.000 - 400.000 Daltons respectively. On this basis, a simple method for molecular weight determination of proteins (accuracy +/- 5 degrees ) has been devised. The method can also be applied for an individual protein in protein mixtures using specific staining procedures.


Thermal ecology of the smooth snake, Coronella austriaca Laurenti, during spring.
Thermo sensitive transmitters were used in a study on free-ranging smooth snakes (Coronella austriaca). Except on cold cloudy days, this snake shows a daily tripartite pattern of body temperatures. The pattern consists of a quick rise in body temperature in the morning, a subsequent stable phase during which body temperatures vary between 29 and 33° C, and finally a drop of body temperatures in the evening. The, consistency of the stable phase over the study period indicates that this range represents the thermal preferendum of this species. During the succesive study months a time shift in daily activity pattern was observed.


Effect of doxazosin gastrointestinal therapeutic system on patients with uncontrolled hypertension: the ASOCIA Study.
To evaluate extended-release doxazosin gastrointestinal therapeutic system (GITS) as add-on therapy in patients with treated, but uncontrolled hypertension. A 16-week, open, noncomparative, multicenter, prospective study of patients with hypertension (> or = 140/> or = 90 mm Hg). Doxazosin GITS 4 mg/d was added to entry medication and increased to 8 mg/d at Week 4 in cases of inadequate blood pressure (BP) control. A total of 3631 patients (40% women) with mean age of 62.4 +/- 0.2 years were included. Proportion of patients reaching goal (< 140/< 90 mm Hg) after 4 weeks of add-on therapy with doxazosin GITS was 39% and increased to 61% at Week 16. Systolic and diastolic BP (mean +/- SEM) decreased, respectively, from 161.6 +/- 0.2 and 95.1 +/- 0.1 mm Hg at baseline to 142.2 +/- 0.2 and 84.1 +/- 0.1 mm Hg at Week 4 (P < 0.0001) and 136.8 +/- 0.2 and 80.6 +/- 0.2 mm Hg at Week 16 (P < 0.0001). Adverse events occurred in 108 patients (3.0%), with 57 (1.6%) related to the study treatment. In 17 patients (0.5%), serious adverse events were described, but only one was related to the study drug. Doxazosin GITS as add-on therapy achieved target blood pressure and was well tolerated in patients with hypertension uncontrolled by previous regimens. Doxazosin GITS efficacy and tolerability was achieved in combination with all classes of antihypertensives tested.


Edoxaban Versus Dual Antiplatelet Therapy for Leaflet Thrombosis and Cerebral Thromboembolism After TAVR: The ADAPT-TAVR Randomized Clinical Trial.
It is unknown whether the direct oral anticoagulant edoxaban can reduce leaflet thrombosis and the accompanying cerebral thromboembolic risk after transcatheter aortic valve replacement. In addition, the causal relationship of subclinical leaflet thrombosis with cerebral thromboembolism and neurological or neurocognitive dysfunction remains unclear. We conducted a multicenter, open-label randomized trial comparing edoxaban with dual antiplatelet therapy (aspirin plus clopidogrel) in patients who had undergone successful transcatheter aortic valve replacement and did not have an indication for anticoagulation. The primary end point was an incidence of leaflet thrombosis on 4-dimensional computed tomography at 6 months. Key secondary end points were the number and volume of new cerebral lesions on brain magnetic resonance imaging and the serial changes of neurological and neurocognitive function between 6 months and immediately after transcatheter aortic valve replacement. A total of 229 patients were included in the final intention-to-treat population. There was a trend toward a lower incidence of leaflet thrombosis in the edoxaban group compared with the dual antiplatelet therapy group (9.8% versus 18.4%; absolute difference, -8.5% [95% CI, -17.8% to 0.8%]; P=0.076). The percentage of patients with new cerebral lesions on brain magnetic resonance imaging (edoxaban versus dual antiplatelet therapy, 25.0% versus 20.2%; difference, 4.8%; 95% CI, -6.4% to 16.0%) and median total new lesion number and volume were not different between the 2 groups. In addition, the percentages of patients with worsening of neurological and neurocognitive function were not different between the groups. The incidence of any or major bleeding events was not different between the 2 groups. We found no significant association between the presence or extent of leaflet thrombosis with new cerebral lesions and a change of neurological or neurocognitive function. In patients without an indication for long-term anticoagulation after successful transcatheter aortic valve replacement, the incidence of leaflet thrombosis was numerically lower with edoxaban than with dual antiplatelet therapy, but this was not statistically significant. The effects on new cerebral thromboembolism and neurological or neurocognitive function were also not different between the 2 groups. Because the study was underpowered, the results should be considered hypothesis generating, highlighting the need for further research. URL: https://www. gov. Unique identifier: NCT03284827.


Anti-glomerular basement membrane glomerulonephritis concurrent with membranous nephropathy and acute tubular interstitial nephritis in a lung cancer patient treated with pembrolizumab.
Immune checkpoint inhibitors (ICIs) have become the standard treatment for many types of cancer and have improved patient prognosis. However, ICIs upregulate the immune system against tumors, leading to immune-related adverse events (irAEs). Kidney irAEs are less common, and most of them are acute tubulointerstitial nephritis (ATIN). However, there has been a recent increase in recognition of glomerular disease related to ICI therapies. We report the case of a 65-year-old man with lung adenocarcinoma who was treated with pembrolizumab (a monoclonal antibody targeting programmed cell death protein-1 [PD-1]). Pembrolizumab was discontinued after seven cycles due to the development of destructive thyroiditis. Within three months of discontinuing the pembrolizumab treatment, the patient developed rapid progressive glomerulonephritis (RPGN), liver dysfunction, and dysgeusia. The patient underwent renal biopsy and was diagnosed with crescentic glomerulonephritis due to anti-glomerular basement membrane (GBM) antibodies complicated with membranous nephropathy (MN) and ATIN. Treatment with systemic corticosteroids resulted in a favorable clinical response. Various ICI-associated glomerular diseases have been described; however, this is the first reported case of anti-GBM glomerulonephritis associated with MN and ATIN following ICI treatment.


Changes in Tumor Characteristics in Kidney Transplanted Patients Over the Last 40 Years.
Post-transplantation tumors (PTTs) are the greatest limiting factor for patient survival following organ transplantation. To describe the incidence and main characteristics of malignancies developed in patients who underwent kidney transplantation in Budapest between 1973 and 2014. During this period, the essential data for PTTs were repeatedly evaluated. In this study, the results from 1990, 1995, 2000, 2006, and 2013 were evaluated. Incidence of PTTs increased from 2.3% to 11.1%. Male/female ratio was 2:1. Skin, native kidney, and lung cancers were the most common tumors during the entire observation period. Lymphoma was seen rarely at the beginning and became common in 2013. The same was observed in the most frequent general population tumors (colorectal, breast, hepatic, prostate, gastric cancer, and malignant melanoma) where the occurrence increased in the last 10 years. Mean age of patients increased from 35.7 to 56.5 years. During the last 20 years, age of recipients increased: above 50 years from 22.9% to 40.5%, and above 60 years from 8.2% to 23.1%. Patient survival was different according to tumor stage at discovering, i.e. renal cell carcinoma was usually discovered in stage I. resulting in a 66.1% 5-year survival rate, whereas 43.5% of colorectal cancers were diagnosed in stage IV, with a 13.9% 5-year survival rate. The frequency of PTTs and proportion of elderly persons undergoing transplants are continuously increasing. Tumor stage is a determining factor for patient survival. Recognition of precancerous conditions, diagnosis of tumors in early stage, and oncological screening can improve survival time.


Aspects of humoral immunity in a prospective study of Type I (insulin-dependent) diabetic subjects treated with insulins of different purity.
In 41 Type 1 (insulin-dependent) diabetic patients, islet cell antibodies, anti-insulin antibodies, and immune complexes measured by two different methods (the C1q solid phase assay and the conglutinin binding test) were studied at diagnosis, and the influence of treatment with insulins of different purity was investigated during the first year of treatment. Twenty subjects were treated with conventional insulins (group 1) while 21 were treated with monocomponent porcine insulins (group 2). The prevalence of islet cell antibodies significantly decreased during the 12-month study period in the 41 patients. From the first month anti-insulin antibodies were always significantly higher in group 1 than in group 2. At diagnosis the prevalence of both types of immune complexes in the 41 patients was higher than in normal subjects. The immune complexes measured by the C1q solid phase method showed a significant and progressive reduction during the follow-up period, whereas the immune complexes assayed by conglutinin showed no significant variation in the same period. The presence of C1q immune complexes was found to correlate with the occurrence of islet cell antibodies both at diagnosis and during the follow-up period. The presence of conglutinin immune complexes, on the other hand, tended to parallel the increase of anti-insulin antibody levels.


Co-expression of ILT4/HLA-G in human non-small cell lung cancer correlates with poor prognosis and ILT4-HLA-G interaction activates ERK signaling.
Non-small cell lung cancer (NSCLC) is the most common malignant tumor in the world, of which prognosis is generally poor due to insufficient mechanistic understanding. To explore the molecular pathogenesis of NSCLC, the co-expression of immunoglobulin-like transcript 4 (ILT4) and its ligand human leukocyte antigen G (HLA-G) in NSCLC tissues and cells were investigated. Here, we detected the expression of ILT4 and HLA-G in 81 tumor specimens from primary NSCLC patients, and we found that co-expression of ILT4/HLA-G was significantly associated with regional lymph node involvement, advanced stages, and the overall survival of patients. In NSCLC cell lines, HLA-G expression increased/decreased accordingly when ILT4 was up-/down-regulated, and ILT4 expression increased in a concentration-dependent manner via the stimulation of HLA-G fusion protein. Interestingly, HLA-G fusion protein could also up-regulate the phospho-ERK1/2 expression, which means the activation of extracellular signal-regulated kinase (ERK) signaling. All in all, our results indicate that the ILT4-HLA-G interaction might play an important role in NSCLC progression. Identification of ILT4 and HLA-G expression may provide an indicator to predict prognosis and guide prevention and treatment of NSCLC.


Construct validity of language independent functional evaluation as used by Spanish-speaking clinicians to evaluate persons with developmental delays.
This study aimed to establish the utility of Language Independent Functional Evaluation (LIFE) as used by clinicians. This study was a prospective trial involving 100 Spanish-speaking rehabilitation clients between the ages of 9 and 45 yrs with cognitive disability and 2 rehabilitation clinicians who cared for them at a Colombian inpatient and outpatient rehabilitation facility. Clinicians who had worked with clients for more than 2 mos rated their function using the LIFE and the Spanish-translated Barthel index. Overall LIFE scores correlated well with Barthel scores (r[98] = 0.793, P < 0.0001) and also on an item-to-item basis in all activities except grooming, bowel continence, and bladder continence. The LIFE is a reliable tool for clinicians to use in the assessment of persons with cognitive disability, regardless of the clinician's language.


Supero-Septum Pedicle Mammaplasty: A New Modification for Reduction Mammaplasty.
Many techniques have been introduced for reduction mammaplasty and are utilized in diverse frequencies by different surgeons according to patient needs. Each technique is evaluated based on the aesthetic result, longevity, complication rate, and preservation of the nipple-areola complex (NAC) sensation. The authors sought to introduce the new modified technique of supero-septum pedicle mammaplasty (SSPM) that utilizes both the septum and superior pedicle and is suitable for macromastia and gigantomastia cases. Between 2015 and 2018, 60 women who underwent SSPM were evaluated in a prospective study after undergoing superior pedicle deepithelialization and resection of the inferior, lateral, and medial segments. In the lateral pillar, a tongue of tissue was preserved for fixation to the medial pectoral fascia through a window created in the superior pedicle at the third intercostal space. Finally, septum pedicle was sutured to the fascia and muscle at the upper border of the sixth rib somewhat medially. Patients were followed up for a minimum of 13 months. The mean nipple-to-sternal notch (N-SN) distance was 33.05 cm, and the mean NAC elevation was 10.92 cm. Breast reductions varied from 270 to 2800 g per breast. Complications included wound dehiscence (5%), wound infection (2.5%), and partial NAC necrosis (2.5%). At 6 months postoperation, the NAC sensation was significantly better compared with preoperative values (P < 0.005). SSPM is a relatively safe method of reduction mammaplasty, even for very large breasts, that leads to good aesthetic form along with preserving circulation and sensation of the NAC.


Quantitative evaluation of two distinct cell populations expressing HLA-DR antigens in normal human epidermis.
HLA-DR antigens are expressed only by Langerhans cells (LC) and indeterminate cells (IC) in normal human epidermis. Indirect immunofluorescence and ultrastructural immunogold labelling were used to study the HLA-DR expression by means of two anti-DR monoclonal antibodies (MCA). Freshly dispersed DR-positive epidermal cells expressed different densities of DR antigens on their membrane surface. Approximately 25% of DR-positive cells were strongly labelled by anti-DR-MCA and 75% were weakly stained. After 18 h in complete culture medium before labelling no significant difference in these percentages was observed. The lymphoid-like LC-enriched cells obtained by Ficoll-Hypaque centrifugation also had two populations of DR-positive cells: strongly labelled cells (30.8%) and weakly labelled cells (69.2%). DR-positive cells may be divided into two types according to the density of DR sites on their cell membrane: (I) type DR+ shows weak surface labelling by gold particles (8.8 +/- 3.0 gold particles/micron) and has cytoplasmic Birbeck granules, identifying such cells as typical Langerhans cells; (2) type DR shows strong membrane immunogold labelling (38.9 +/- 4.6 gold particles/micron) and may or may not contain Birbeck granules. The gold particles bound to the cell membrane were used to quantify the number of HLA-DR sites expressed on each cell type: 1 X 10(5) sites on DR+ cells and 5 X 10(5) on DR cells.


A close encounter with DNA.
Atomic force microscopy, associated with surface science, has the potential to resolve the secondary structure of DNA in liquid form with unusually high resolution and with unprecedented accuracy.


Correction: Tuning the morphology of sulfur-few layer graphene composites via liquid phase evaporation for battery application.
[This corrects the article DOI: 10.1039/D1NA00733E.].


Pilot study on CHCF1 genotype in a pig challenge model for enterotoxigenic Escherichia coli F4ab/ac associated post-weaning diarrhea.
Host genotype is important for enterotoxigenic E. coli (ETEC) susceptibility. We conducted two trials to evaluate the effect of CHCF1 genotype on incidence of ETEC diarrhea. In trial 1 (n = 15 pigs), pigs were inoculated with 108 CFU or 1010 CFU doses of an ETEC F4ac strain. In trial 2 (n = 33 pigs), pigs were inoculated with ETEC F4ab or F4ac. Across trials, all inoculated pigs that developed ETEC diarrhea were CHCF1 heterozygous susceptible (6/6). No inoculated CHCF1 homozygous resistant pigs developed ETEC diarrhea (0/26). Susceptibility towards ETEC F4ac/ab infection might correspond with CHCF1 genotype.


CYP17A1 T-34C polymorphism is not associated with endometrial cancer risk.
The association between CYP17A1 T-34C polymorphism and endometrial cancer risk has been inconsistent and underpowered. To clarify the effect of CYP17A1 T-34C polymorphism on the risk of endometrial cancer, a meta-analysis of all available studies relating CYP17A1 T-34C polymorphism to the risk of endometrial cancer was conducted. The authors searched PubMed, EMBASE, Scopus, and VisionCite databases updated on March 2013. Data were extracted by two independent authors and pooled odds ratio (OR) with 95 % confidence interval (CI) was calculated. Finally, seven studies with 1,570 endometrial cancer cases and 2,474 controls were included in the meta-analysis. There was no statistically significant association between CYP17A1 T-34C polymorphism and endometrial cancer under heterogeneous codominant model (OR = 0.91, 95 %CI = 0.68-1.21). Although CYP17A1 T-34C polymorphism was marginally associated with endometrial cancer risk under homogeneous codominant model (OR = 0.69, 95 %CI = 0.49-0.99), the significant association was not stable after sensitivity analysis. We concluded that CYP17A1 T-34C polymorphism might not be one risk factor in the carcinogenesis of endometrial cancer. Further large and well-designed studies are needed to confirm this association.


Altered expression of CD46 and CD59 on leukocytes in neovascular age-related macular degeneration.
To investigate the expression of the complement regulatory proteins CD46, CD55, and CD59 on peripheral leukocytes in neovascular age-related macular degeneration (AMD). Prospective, case-control study. Thirty-five unrelated patients with neovascular AMD and 30 control individuals were included in this case-control study. All participants were subjected to a structured interview and detailed imaging (autofluorescence, digital funduscopy, spectral-domain optical coherence tomography, and fluorescein and indocyanine green angiography in patients suspected of having neovascular AMD) was performed. Fresh ethylenediamine-tetraacetic acid blood was obtained and stained with monoclonal antibodies. Using flow cytometry, the percentage of CD14(+) monocytes, CD45(+) lymphocytes, and CD45(+) granulocytes positive for CD46, CD55, and CD59 was determined in patients with neovascular AMD and was compared with that of controls. We found that the expression of CD46 and CD59 was significantly lower on CD14(+) monocytes in patients with neovascular AMD compared with controls (P = .0070). A significantly lower expression of CD46 on lymphocytes was observed in patients with fibrosis compared with patients without fibrosis (P = .010). Our study suggests that neovascular AMD is associated with an inadequate regulation of the complement system, supporting current evidence on the role of complement dysregulation in the pathogenesis of AMD.


Usefulness of frequent supraventricular extrasystoles and a high CHADS2 score to predict first-time appearance of atrial fibrillation.
Frequent supraventricular extrasystoles (SVEs) are associated with the subsequent first-time appearance of atrial fibrillation (AF) and ischemic stroke. The aim of this study was to investigate the combined role of SVEs and an AF-related risk score for ischemic stroke, the CHADS2 score, on the occurrence of new AF in patients in sinus rhythm. The Shinken Database 2004-2010 lists 3,263 patients who underwent 24-hour Holter monitoring. A total of 2,589 patients were analyzed, after excluding 674 patients previously diagnosed with AF. Frequent SVEs were defined as ≥102 beats/day (the top quartile) and the presence of a clinical background for a CHADS2 score ≥2 points as a high CHADS2 score. During the mean follow-up period of 571.4 ± 606.4 days, new AF occurred in 38 patients (9.4 per 1,000 patient-years). The incidence of new AF was 2.7 and 37.7 per 1,000 patient-years for patients with nonfrequent SVEs (<102 beats/day) and low CHADS2 scores and those with frequent SVEs and high CHADS2 scores, respectively. Multivariate Cox regression analysis showed that the hazard ratio for frequent SVEs and a high CHADS2 score compared with nonfrequent SVEs and a low CHADS2 score was 9.49 (95% confidence interval 3.20 to 28.15, p <0.001), even after adjustment for gender, age, medications, and echocardiographic parameters. In conclusion, frequent SVEs and a high CHADS2 score independently and synergistically predict the first-time appearance of AF in patients in sinus rhythm, indicating an approximately 10-fold higher risk. Patients meeting these criteria should have more aggressive early intervention for preventing AF.


Quantification of Functional MR Predicts Early Response in Post-doxorubicin Drug-Eluting Beads Chemoembolization for Hepatocellular Carcinoma.
The purpose of this study was to assess the value of functional MRI (fMRI) of post-doxorubicin drug-eluting beads transcatheter arterial chemoembolization (DEB-TACE) for hepatocellular carcinoma (HCC) as an early imaging biomarker of response to therapy. This prospective analysis included 21 consecutive patients undergoing fMRI before and after DEB-TACE at a single medical center from January 2013 to December 2014. Functional MRI, including relative changes in apparent diffusion coefficient (ADC) and choline levels measured at hydrogen-1 magnetic resonance spectroscopy (MRS) of treated lesions, was recorded at baseline before DEB-TACE, and at 1, 2, and 4 weeks after DEB-TACE therapy. Assessment of tumor response was based on dynamic contrast-enhanced computer tomography imaging response according to modified response evaluation criteria in solid tumors. At post-therapy, 76% (n = 16) of patients demonstrated objective tumor response, 10% (n = 2) had stable disease, and 3 (14%) had progressive disease. Stable disease and progressive disease were designated as non-response. At week 2, the mean change in ADC value of responsive tumors was 0.35 ± 0.24 mm2/s, which was greater than that of non-response tumors (mean 0.01 ± 0.13 × 10-3 mm2/s) (P = 0.006). Significant differences were found in mean choline/water ratio between responsive (7.8 ± 4.9 × 10-3) and non-responsive (17.2 ± 4.9 × 10-3) tumors (P = 0.005). Composite scores of choline/water ratio and relative change of ADC showed significantly better diagnostic accuracy in non-responsive tumors than responsive tumors (area under the curve = 1.0; P < 0.001). Combined DWI and MRS may be used as an early imaging biomarker of therapy response in HCC patients after chemoembolization therapy.


Inhibition of acetylcholine-induced activation of extracellular regulated protein kinase prevents the encoding of an inhibitory avoidance response in the rat.
It has been demonstrated that the forebrain cholinergic system and the extracellular regulated kinase signal transduction pathway are involved in the mechanisms of learning, encoding, and storage of information. We investigated the involvement of the cholinergic and glutamatergic systems projecting to the medial prefrontal cortex and ventral hippocampus and of the extracellular regulated kinase signal transduction pathway in the acquisition and recall of the step-down inhibitory avoidance response in the rat, a relatively simple behavioral test acquired in a one-trial session. To this aim we studied by microdialysis the release of acetylcholine and glutamate, and by immunohistochemistry the activation of extracellular regulated kinase during acquisition, encoding and recall of the behavior. Cholinergic, but not glutamatergic, neurons projecting to the medial prefrontal cortex and ventral hippocampus were activated during acquisition of the task, as shown by increase in cortical and hippocampal acetylcholine release. Released acetylcholine in turn activated extracellular regulated kinase in neurons located in the target structures, since the muscarinic receptor antagonist scopolamine blocked extracellular regulated kinase activation. Both increased acetylcholine release and extracellular regulated kinase activation were necessary for memory formation, as administration of scopolamine and of extracellular regulated kinase inhibitors was followed by blockade of extracellular regulated kinase activation and amnesia. Our data indicate that a critical function of the learning-associated increase in acetylcholine release is to promote the activation of the extracellular regulated kinase signal transduction pathway and help understanding the role of these systems in the encoding of an inhibitory avoidance memory.


Natural killer cells: walking three paths down memory lane.
Immunological memory has traditionally been regarded as a unique feature of the adaptive immune response, mediated in an antigen-specific manner by T and B lymphocytes. All other hematopoietic cells, including natural killer (NK) cells, are classified as innate immune cells, which have been considered short-lived but can respond rapidly against pathogens in a manner not thought to be driven by antigen. Interestingly, NK cells have recently been shown to survive long term after antigen exposure and subsequently mediate antigen-specific recall responses. In this review, we address the similarities between, and the controversies surrounding, three major viewpoints of NK memory that have arisen from these recent studies: (i) mouse cytomegalovirus (MCMV)-induced memory; (ii) cytokine-induced memory; and (iii) liver-restricted memory cells.


Modulation of the tumor cell phenotype by IFN-gamma results in resistance of uveal melanoma cells to granule-mediated lysis by cytotoxic lymphocytes.
IFN-gamma, a pleiotropic immune regulator, is implicated in both tumor immune surveillance and selection of tumor variants resistant to immune control, i.e., immunoediting. In uveal melanoma patients, elevated serum levels of IFN-gamma correlate with the spread of metastasis and represent a negative prognostic marker. Treatment with IFN-gamma boosted the MHC class I presentation machinery in uveal melanoma cells but suppressed their MHC class I-restricted CTL lysis. Tumor cells exposed to IFN-gamma efficiently activated specific CTL but were less susceptible to permeabilization by perforin and exhibited a decreased capacity to bind and incorporate granzyme B. These results define a novel mechanism of resistance to granule-mediated CTL lysis in human tumors. Furthermore, the data suggest that immunoediting is not limited to genetic or epigenetic changes resulting in stable cellular phenotypes but also involves an inducible modulation of tumor cells in response to a microenvironment associated with immune activation.


Study of the mechanism of action of adenosylcobalamindependent glycerol dehydratase from Aerobacter aerogenes. II. The inactivation kinetics of glycerol dehydratase complexes with adenosylobalamin and its analogs.
The inactivation kinetics of vacterial glycerol dehydratase (EC 188.8.131.52) in the course of its reaction with adenosylcobalamin (AdoCbl) and its analogs were investigated. It was shown that the inactivation rate of apoenzyme complexes with AdoCbl analogs is determined by the nature of the analogs employed and probably by the rate of their conversion into hydroxycobalamins. A possible inactivation mechanism of glycerol dehydratase is discussed.


Endoscopic ureteric stone extraction. Experience with the short ureteroscope.
A modified short Storz ureteroscope is described. It was used for the extraction of ureteric stones in 56 patients with a success rate of 96%.


Anticomplementary activity in serum of women with a history of recurrent pregnancy loss.
Viral complement fixation tests on women with a history of recurrent pregnancy loss were complicated by the presence of anticomplementary activity. This activity reflects the presence of a factor(s) in a patient's serum that nonspecifically fixes complement. When all patient sera tested were compared, 64.7% of women with recurrent pregnancy loss had anticomplementary activity compared with 22.0% among normal fertile pregnant women (p less than 0.01). In delineating when anticomplementary activity developed, it was found that 41.8% of women with recurrent pregnancy loss compared with 12.9% of normal pregnant women had this activity on entry to the study (p less than 0.01). This was primarily due to the fact that among women with recurrent pregnancy loss 50.0% of the pregnant versus 33.0% of the nonpregnant women had activity (NS). However, 55.2% of the anticomplementary negative women with recurrent pregnancy loss converted to a positive status compared with 15.4% of normal women (p less than 0.05). This was directly influenced by a conversion rate of 78.6% during pregnancy among women with recurrent pregnancy loss who entered the study nonpregnant and with no known cause for loss compared with a 33.3% conversion rate in their pregnant counterparts with recurrent pregnancy loss (p less than 0.025). Conversion to positive anticomplementary status occurred primarily by 20 weeks of gestation and appeared to be transient. Overall there was no association between the presence of anticomplementary activity and cervical colonization with genital mycoplasmas. The data suggest that women with a history of recurrent pregnancy loss develop a serum factor(s), usually by 20 weeks' gestation, that fixes complement. Thus these observations describe an additional anomaly in the immune system of women who experience recurrent pregnancy loss.


Trap-nesting bees and wasps colonizing set-aside fields: succession and body size, management by cutting and sowing.
Trap-nesting bees and wasps (Hymenoptera Aculeata) colonizing crop and fallow fields in an agricultural landscape were studied using 20 sown fields (pea, barley, rye, clover-grass mixtures, Phacelia tanacetifolia) and 20 fields with naturally developed vegetation (1- and 2-year old fields, both mown and unmown, and old meadows). Fourteen species of Apoidea, 4 of Sphecidae, 1 of Eumenidae and 4 of parasitoids were reared from reed nests exposed in these 40 fields of 10 field-types. Fields with naturally developed vegetation had twice as many species as sown fields, due to the distribution pattern of the 14 bee species, whereas the 9 predatory species (wasps and parasitoids) showed a rather uniform distribution. None of the trap-nesting bees were found in Phacelia fields, despite contrasting expectations of beekeepers. Old meadows showed a particularly high abundance and species richness, since only 10% of all traps were exposed, but 32% of all bee nests were sampled in old meadows, including 4 bee species that were not found elsewhere. Accordingly, species richness of fields with naturally developed vegetation showed a significant increase with age. Variability in Hymenoptera species numbers could be explained by corresponding differences in plant species numbers. The alternative hypothesis that field size or field connectivity influenced species richness was not supported. Habitats with great floral diversity appeared to offer better and richer food resources for the flower-visiting bees, whereas food availability apparently did not influence predatory wasps. The bees Osmia caerulescens and Megachile versicolor that had colonized early-successional fields took twice as long to provision cells as those that colonized late-successional meadows characterized by a greater plant species richness. In contrast, the eumenid wasp Ancistrocerus gazella took a similar period of time to provision cells in both field types. In addition, bee and wasp species of plant-species-poor fields were on average significantly larger than those of plant-species-rich fields. Thus, body size appeared to be a good predictor of colonization ability. Management by cutting greatly increased plant species richness in early-successional set-aside fields and thus doubled species richness of bees. Cutting of early-successional habitats can be expected to benefit insects and plants in general, whereas older grassland should show the greatest insect diversity when both mown and unmown parts are present.


ABCG1: how critical for cholesterol transport?
In the current issue of Cell Metabolism, Kennedy et al. (2005) have extended our understanding of the ABCG1 transporter. Their studies demonstrate that, at least in macrophages, ABCG1 is responsible for much of the cholesterol efflux that utilizes mature HDL as an acceptor.


Development and properties of dental Ti-Zr binary alloys.
In this study, two medium Zr-containing Ti-based alloys with commercially pure titanium as control were systematically investigated to assess their potential biomedical application. After samples subjected to TMP and CR, it was found that the Zr addition significantly affected the microstructure, phase constitutions, mechanical properties and cytocompatibility. The microstructural results showed that increasing Zr concentrations resulted in more refined grains. Furthermore, Zr changed the phase constitution: CR Ti-20Zr was formed by the single α-phase while CR Ti-30Zr alloy was formed by the coexistence of α and deformation-induced FCC phases. The P-type FCC phase was dominant and more prone to occur than the B-type one. The mechanical tests demonstrated that the increasing Zr content led to a simultaneous increase in micro-hardness, strength and plasticity of CR samples due to the combined effects of solution strengthening, work hardening and the FCC phase. The SEM fractography indicated that the brittle fracture of CR Ti-20Zr due to deformation twins and ductile fracture of CR Ti-30Zr because of FCC phase. Furthermore, Ti-Zr alloys presented comparable cytocompatibility to the CP-Ti control based on cell viability, proliferation and intracellular O2- content of MSCs. Specifically, alkaline phosphatase activity in BMSCs were significantly higher for grain refined CR Ti-30Zr. Considering all these results, CR Ti-30Zr alloy exhibited the optimal comprehensive performance to be potential dental materials.


A prospective study of post-cesarean delivery hypoxia after spinal anesthesia with intrathecal morphine 150μg.
Delayed respiratory depression is a feared complication of intrathecal morphine in patients undergoing cesarean delivery. The incidence, timing and risk factors for hypoxia in this population are not known. Patients undergoing cesarean delivery under spinal anesthesia at a tertiary care center from October 2012 to March 2016 were included in the study. The Berlin sleep apnea Questionnaire was completed before surgery. Oxygen saturation was recorded every second for 24hours after the initiation of spinal anesthesia. Desaturation events were defined as a median saturation of <90% (mild) or <85% (severe) across a 30-s period. Multivariable logistic regression was used to determine predictors of a desaturation event. A total of 721 patients were included in the analysis. Within this cohort, 169 women (23%) experienced at least one mild desaturation event, 91 (13%) experienced two or more mild desaturations, and 26 (4%) suffered a severe desaturation event. After the administration of intrathecal morphine, the median times to first mild or first severe desaturation were 7.4 (IQR 4.1-13.5)h and 12.0 (IQR 5.4-19.6)h, respectively. Patients who screened positive for sleep apnea had increased odds of having a mild desaturation event (OR 2.31, 95% CI 1.40 to 3.79, P=0.001), as did patients who were obese (OR 1.80, 95% CI 1.05 to 3.09, P=0.033). Mild hypoxemia occurred frequently in women receiving intrathecal morphine 150μg for post-cesarean analgesia. Desaturations were observed most frequently 4-8hours after administration of intrathecal morphine. Obesity and a positive Berlin Questionnaire were risk factors for hypoxemic events.


IRX3/5 regulate mitotic chromatid segregation and limb bud shape.
Pattern formation is influenced by transcriptional regulation as well as by morphogenetic mechanisms that shape organ primordia, although factors that link these processes remain under-appreciated. Here we show that, apart from their established transcriptional roles in pattern formation, IRX3/5 help to shape the limb bud primordium by promoting the separation and intercalation of dividing mesodermal cells. Surprisingly, IRX3/5 are required for appropriate cell cycle progression and chromatid segregation during mitosis, possibly in a nontranscriptional manner. IRX3/5 associate with, promote the abundance of, and share overlapping functions with co-regulators of cell division such as the cohesin subunits SMC1, SMC3, NIPBL and CUX1. The findings imply that IRX3/5 coordinate early limb bud morphogenesis with skeletal pattern formation.


Chalarosthrix gen. nov., a new taxon of the Sphingothrix-Triathrix clade (Harpacticoida: Cletodidae) from the Province of Cortez, Eastern Mexican Pacific.
Seven species of four cletodid genera previously described or reported from Mexico (Cletodes, Enhydrosoma, Geehydrosoma, and Stylicletodes) and an undescribed genus presumably related to Sphingothrix and Triathrix, were found in sediment samples from a coastal system in north-western Mexico. The Bayesian analysis of 95 morphological characters of thirty-four cletodid genera revealed that the new genus, Chalarosthrix gen. nov., is closely related to Sphingothrix. The clade Sphingothrix-Chalarosthrix bears a sister group relationship with Triathrix. These three genera constitute a monophyletic group defined by the presence of a posterior chitinous extension of the cephalothorax with four sensillum-bearing socles, and the presence of a median tube-pore on the anal operculum. Other synapomorphies for Sphingothrix and Triathrix proposed by earlier researchers are re-evaluated upon the latest definition of the Cletodidae. Our analysis supports previous studies in that Sphingothrix can be objectively defined by i) the reduction of the distal outer seta of the last exopodal segment of the first swimming leg being at most as long as the subdistal outer spine, and ii) the distal inner seta of the same segment inclined outwards intersecting the distal outer element at its base. On the other hand, no (aut)apomorphies were detected for Triathrix. The new genus, Chalarosthrix gen. nov., is defined here by the apomorphic secondary loss of the inner element of the second endopodal segment of the first swimming leg. Some comments on the relationships of the new genus are given.


Long-term follow-up of the apparently normal couple with a complaint of infertility.
Ninety-one couples with no obvious cause for their infertility were followed after periods of 1 to 17 years (96% were followed until they conceived or for more than 5 years). All of the couples had been fully investigated and no specific abnormality had been demonstrated. The majority of women (88%) had primary infertility of at least 2 years' duration, although a small number (12%) had had one or more first-trimester abortions and were thus classified as having secondary infertility. Cumulative conception rates (using life tables) at the end of 7 years were 36.2% for the primary infertility group and 78.8% for the women with secondary infertility. Of those couples achieving a first pregnancy and desiring a second, only 44.3% had conceived at the end of another 4-year period. These rates are markedly lower than the published conception rates of a normal population.


Tuning selectivity of electrochemical reactions by atomically dispersed platinum catalyst.
Maximum atom efficiency as well as distinct chemoselectivity is expected for electrocatalysis on atomically dispersed (or single site) metal centres, but its realization remains challenging so far, because carbon, as the most widely used electrocatalyst support, cannot effectively stabilize them. Here we report that a sulfur-doped zeolite-templated carbon, simultaneously exhibiting large sulfur content (17 wt% S), as well as a unique carbon structure (that is, highly curved three-dimensional networks of graphene nanoribbons), can stabilize a relatively high loading of platinum (5 wt%) in the form of highly dispersed species including site isolated atoms. In the oxygen reduction reaction, this catalyst does not follow a conventional four-electron pathway producing H2O, but selectively produces H2O2 even over extended times without significant degradation of the activity. Thus, this approach constitutes a potentially promising route for producing important fine chemical H2O2, and also offers opportunities for tuning the selectivity of other electrochemical reactions on various metal catalysts.


Mirabegron Versus Solifenacin in Multiple Sclerosis Patients With Overactive Bladder Symptoms: A Prospective Comparative Nonrandomized Study.
To determine the patient-perceived effectiveness and tolerability of mirabegron compared to solifenacin in a multiple sclerosis (MS) population with overactive bladder (OAB) symptoms. MS patients with OAB symptoms who were not on medication for their urinary symptoms at enrollment were prospectively recruited. Patients enrolled in years 1-2 were prescribed mirabegron, whereas patients enrolled in years 3-4 were prescribed solifenacin. At enrollment and 6-week follow-up, patients completed several patient reported outcome measures. The primary outcome was change in OAB Questionnaire Short Form (OAB-q SF) symptom severity and minimal clinically important difference (MCID) achievement. The Patient Assessment of Constipation Symptoms (PAC-SYM) was used to assess bowel function over the treatment period. Sixty-one patients were enrolled. The majority of the mirabegron (70%) and the solifenacin (69%) group achieved the OAB-q SF symptom severity MCID. The solifenacin group had a statistically significant greater decrease in its end of study OAB-q SF score (Δ = -37.87 vs -20.43, P = .02). Constipation improved in the mirabegron group and worsened in the solifenacin group (ΔPAC-SYM = -0.38 vs +0.22; P = .02), with 30% of patients prescribed solifenacin experiencing worsening above the MCID threshold. Among MS patients, we demonstrated similar response rates to mirabegron and solifenacin, with approximately 50%-70% achieving each patient reported outcome measure's MCID. Though this small study showed some short-term evidence that improvement in urinary symptom severity was greater with solifenacin, this potential benefit must be weighed against the observed risk of worsening constipation. Further studies are needed to confirm these findings.


Immunosensing prostate-specific antigen: Faradaic vs non-Faradaic electrochemical impedance spectroscopy analysis on interdigitated microelectrode device.
This work explores Electrochemical Impedance Spectroscopy (EIS) detection for a highly-sensitive quantification of prostate-specific antigen (PSA) in Faradaic (f-EIS) and non-Faradaic modes (nf-EIS). Immobilization of monoclonal antibody specific to PSA (anti-PSA) was performed using 1-ethyl-3-dimethylaminopropylcarbodiimide hydrochloride and N-hydroxysuccinimide crosslinking agents in order to conjugate carboxylic (-COOH) terminated group of 16-Mercaptoundecanoic acid with amine (-NH3+) on anti-PSA epitope. This approach offers simple and efficient approach to form a strong, covalently bound thiol-gold (SAu) for a reliable SAM layer formation. Studies on the topographic of pristine Au-IDE surface were performed by Scanning Electron Microscopy and Energy Dispersive X-ray Spectroscopy techniques, meanwhile a 3-dimensional optical surface profiler, Atomic Force Microscopy and X-ray Photoelectron Spectroscopy techniques were used to validate the successful functionalization steps on the sensor transducer surface. Detection of PSA in f-EIS mode was carried out by measuring the response in charge transfer resistance (Rct) and impedance change (Z), meanwhile in nf-EIS mode, the changes in device capacitance was monitored. In f-EIS mode, the sensor reveals a logarithmic detection of PSA in a range of 100 ng/ml down to 0.01 ng/ml in Phosphate Buffered Saline with a recorded sensitivity of 2.412 kΩ/log10 ([PSA] ng/ml) and the limit of detection (LOD) down to 0.01 ng/ml. The nf-EIS detection mode yields a logarithmic detection range of 5000 ng/ml down to 0.5 ng/ml, with a sensitivity of 8.570 nF/log10 ([PSA] ng/ml) and an LOD of 0.5 ng/ml. The developed bio-assay yields great device stability, specificity to PSA and repeatability of detection that would pave its way for the future development into portable lab-on-chip bio-sensing system.


Melorheostosis of the tenth and eleventh thoracic vertebrae crossing the facet joint: a rare cause of back pain.
Melorheostosis affecting the axial skeleton is a rare condition. We present a case affecting a single thoracic zygoapophyseal (facet) joint that proved to be a diagnostic challenge. CT, MRI and radionuclide imaging with surgical and histopathology findings are discussed.


Cigarette smoke induces genetic instability in airway epithelial cells by suppressing FANCD2 expression.
Chromosomal abnormalities are commonly found in bronchogenic carcinoma cells, but the molecular causes of chromosomal instability (CIN) and their relationship to cigarette smoke has not been defined. Because the Fanconi anaemia (FA)/BRCA pathway is essential for maintenance of chromosomal stability, we tested the hypothesis that cigarette smoke suppresses that activity of this pathway. Here, we show that cigarette smoke condensate (CSC) inhibited translation of FANCD2 mRNA (but not FANCC or FANCG) in normal airway epithelial cells and that this suppression of FANCD2 expression was sufficient to induce both genetic instability and programmed cell death in the exposed cell population. Cigarette smoke condensate also suppressed FANCD2 function and induced CIN in bronchogenic carcinoma cells, but these cells were resistant to CSC-induced apoptosis relative to normal airway epithelial cells. We, therefore, suggest that CSC exerts pressure on airway epithelial cells that results in selection and emergence of genetically unstable somatic mutant clones that may have lost the capacity to effectively execute an apoptotic programme. Carcinogen-mediated suppression of FANCD2 gene expression provides a plausible molecular mechanism for CIN in bronchogenic carcinogenesis.


Diablo/SMAC: a novel biomarker of pollutant exposure in European flounder (Platichthys flesus).
Diablo (or SMAC) is a protein released from mitochondria following apoptotic stimuli and inhibits the actions of Inhibitors of Apoptosis (IAP) proteins. IAPs regulate the activity of caspases and NFkB, the primary executioners of apoptosis and of inflammation, respectively. Thus, Diablo is important for the regulation of cellular responses to damage. In Northern Europe, statutory governmental marine monitoring programs measure various biomarkers in flounder to indicate biological effects of pollutant exposure. More recently transcriptomic techniques have been applied in flounder to gain a more comprehensive understanding of pollutant effects, and to discover novel biomarkers. In most of these studies utilising flounder, Diablo was amongst the most highly increased transcripts identified. The aim of this study was to further examine piscine Diablo, at the gene level and mRNA level, after exposure to prototypical pollutants, and in flounder caught from polluted environments. The results show that two genes encoding Diablo exist in fish species, and in flounder one of these genes is increased in liver after exposure to polyaromatic hydrocarbons and polychlorinated biphenyls, and also in livers from fish living on contaminated estuarine sediments. Therefore, Diablo measurement has potential as a biomarker of pollutant exposure, and could indicate damaging effects of chemical contaminants.


Coronary Calcium Scoring Improves Risk Prediction in Patients With Suspected Obstructive Coronary Artery Disease.
In patients with suspected obstructive coronary artery disease (CAD), the risk factor-weighted clinical likelihood (RF-CL) model and the coronary artery calcium score-weighted clinical likelihood (CACS-CL) model improves the identification of obstructive CAD compared with basic pretest probability (PTP) models. The aim of this study was to assess the prognostic value of the new models. The incidences of myocardial infarction and death were stratified according to categories by the RF-CL and CACS-CL and compared with categories by the PTP model. We used cohorts from a Danish register (n = 41,177) and a North American randomized study (n = 3,952). All patients were symptomatic and were referred for diagnostic testing because of clinical indications. Despite substantial down-reclassification of patients to a likelihood ≤5% of CAD with either the RF-CL (45%) or CACS-CL (60%) models compared with the PTP (18%), the annualized event rates of myocardial infarction and death were low using all 3 models; RF-CL 0.51% (95% CI: 0.46-0.56), CACS-CL 0.48% (95% CI: 0.44-0.56), and PTP 0.37% (95% CI: 0.31-0.44), respectively. Overall, comparison of the predictive power of the 3 models using Harrell's C-statistics demonstrated superiority of the RF-CL (0.64 [95% CI: 0.63-0.65]) and CACS-CL (0.69 [95% CI: 0.67-0.70]) compared with the PTP model (0.61 [95% CI: 0.60-0.62]). The simple clinical likelihood models that include classical risk factors or risk factors combined with CACS provide improved risk stratification for myocardial infarction and death compared with the standard PTP model. Hence, the optimized RF-CL and CACS-CL models identify 2.5 and 3.3 times more patients, respectively, who may not benefit from further diagnostic testing.


Acute myositis and dermatitis as the initial presentation of sarcoidosis.
We report a case of a patient who presented with symptoms of acute debilitating proximal muscle weakness, which mimicked acute polymyositis, accompanied by a hypopigmented papular rash. The histology of the skin and muscle demonstrated sarcoidosis. A review of the literature of acute sarcoid myositis and the various other myopathies of sarcoidosis is presented.


Systematic review of biological therapy to accelerate orthodontic tooth movement in animals: Translational approach.
To systematically review and evaluate what is known regarding contemporary biological therapy capable of accelerating orthodontic tooth movement (OTM) in animal model. MedLine, Scopus, Web of Science and OpenGrey were searched without restrictions until June 2019. Following study retrieval and selection, relevant data was extracted using a standardized table. Risk of bias (RoB) assessment was performed using the Systematic Review Centre for Laboratory Animal Experimentation (SYRCLE) tool. Fifty-one animal studies were included. Two biological therapies were identified as capable of accelerating the OTM: chemical methods (49 studies) and gene therapy (2 studies). The main substances that increased the OTM rate were cytokines (13 studies), followed by growth factors (6 studies) and hormones (5 studies). Most studies were assessed to be at unclear or high RoB. The application protocols, measurement and reporting of outcomes varied widely and methodologies were not adequately reported. Although biological therapies to accelerate OTM have been widely tested and effective in preclinical studies, the validity of the evidence is flawed to support translational of these results. There is a need for well-designed experimental studies to translate these methods for clinical field.


Consensus Obtained for the Nephrotoxic Potential of 167 Drugs in Adult Critically Ill Patients Using a Modified Delphi Method.
The approach to evaluating nephrotoxins in studies of drug-associated acute kidney injury varies. Some studies use a list of under ten drugs for evaluation whereas others include over 100 drugs. Drugs are typically assigned a binary classification, nephrotoxic or not nephrotoxic. This oversimplifies the nephrotoxic potential of the drugs under investigation. This study aimed to assign a nephrotoxin potential for 167 drugs used in the adult critical care setting. A three-round, international, interdisciplinary, web-based modified-Delphi study was used to evaluate nephrotoxins used in adult critically ill patients. Twenty-four international experienced clinicians were identified through the Acute Disease Quality Initiative group and professional affiliations. Included individuals represented the fields of intensive care, nephrology, and pharmacy. One hundred and fifty-nine medications were identified from the literature, with eight additional medications added after the first round, for a total of 167 medications. The primary outcome was consensus achieved for nephrotoxicity ratings. Scores were evaluated each round to determine if a consensus was met. Our nephrotoxin potential index rating indicated that 20 drugs were nephrotoxicity probable or probable/definite per consensus. Nephrotoxic potential was assessed based on the standard use of medications in intensive care and the following consensus scores: 0 = no nephrotoxic potential, 1 = possible nephrotoxic potential, 2 = probable nephrotoxic potential, 3 = definite nephrotoxic potential. The nephrotoxin potential index rating allows for prioritization of targeted drugs with greater nephrotoxic potential for institutional nephrotoxin stewardship programs. Furthermore, the nephrotoxin potential index rating provides homogeneity for research and guidance on detailed assessments by severity for each drug.


Oxidative stress biomarkers in patients with untreated obstructive sleep apnea syndrome.
The pathogenic role of oxidative stress in obstructive sleep apnea syndrome (OSAS) is still a matter of debate, with different studies obtaining contrasting results. The aim of the present study was to evaluate three well-known markers of oxidative stress (advanced oxidation protein products [AOPP], ferric reducing antioxidant power [FRAP], and total glutathione [GSH]) in a cohort of 41 untreated patients with a new diagnosis of OSAS. We observed that OSAS patients showed increased protein oxidative damage and impaired antioxidant defenses. Patients with more severe OSAS had a lower total antioxidant capability. Preliminary data on a subgroup of patients (n=7) treated with CPAP show a significant increment of the FRAP values (P<0.005). Our findings indicate that such oxidative stress markers may be useful to detect and monitor redox imbalance in OSAS. Moreover, FRAP might be a new useful biomarker to monitor in vivo the oxidative response to CPAP therapy.


Sexual coloration, plasma concentrations of sex steroid hormones, and responses to courtship in the female keeled earless lizard (Holbrookia propinqua).
The reproductive condition, steroid hormone concentrations in the plasma, and behavior of bright and plain female Holbrookia propinqua were examined. Bright females performed significantly more aggressive rejection of courtship than plain females. Bright females were significantly more likely than plain females to have follicles larger than 5.0 mm or oviductal eggs; females with large follicles or oviductal eggs had significantly higher concentrations of progesterone and androgen than those with small follicles and lacking oviductal eggs. Plasma progesterone, androgen, and estradiol levels in the females studied behaviorally were significantly higher for the bright females than for the plain ones. Females undergoing rapid brightening were significantly more likely to be sexually receptive and copulate than were either plain or fully brightened females. The role of sex steroid hormones in coloration and behavior and the adaptive value of chromatic signalling by females are discussed.


Simulating the longitudinal doctor-patient relationship: experiences of simulated patients in successive consultations.
The use of simulated patients (SPs) in teaching communication and practical skills at medical schools is mostly limited to single-case use: a student has 1 consultation with an SP and receives feedback afterwards. Very little literature is available that describes consecutive consultations between the same student and SP. In this study, we explored the experiences of SPs in a new, longitudinal SP programme in which SPs met the same Year 3 students ('GP') in 4 consecutive consultations during the year. The SPs suffered from a chronic disease in their patient roles. Four focus group discussions were conducted with 23 SPs (8 men, 15 women; average age 60.9 years) who had performed in the new programme. Discussions were semi-structured and followed a pre-established interview guide. Data were categorised by 3 independent raters. The SPs described the development of a more familiar relationship with students under the new programme, compared with single-case consultations. They developed specific expectations of students' performances. The SPs enjoyed participating in the programme and felt it was more realistic than single-case consultations. Feedback changed and became more detailed as SPs were able to compare consultations; students' response to feedback could be experienced during the next consultation. Practising the development of a realistic, longitudinal doctor-patient relationship may help prepare students for real practice. Longitudinal feedback is now possible; it may be of higher quality and of benefit to SPs as well. These findings suggest new possibilities for SP-based education and research. Future studies should focus on quantitative analysis and students' perspectives.


Biochemical analysis of NSs from different tospoviruses.
Tospoviruses suppress antiviral RNA interference by coding for an RNA silencing suppressor (NSs) protein. Previously, using NSs-containing crude plant and insect cell extracts, the affinity of NSs for double-stranded (ds)RNA molecules was demonstrated by electrophoretic mobility shifts assays (EMSAs). While NSs from tomato spotted wilt virus (TSWV) and groundnut ringspot virus (GRSV) were able to bind small and long dsRNA molecules, the one from tomato yellow ring virus (TYRV), a distinct Asian tospovirus, only bound small dsRNA. Here, using bacterially expressed and purified NSs from GRSV and TYRV, it is shown that they are both able to bind to small and long dsRNA. Binding of siRNAs by NSs revealed two consecutive shifts, i.e. a first shift at low NSs concentrations followed by a second larger one at higher concentrations. When NSs of TSWV resistance inducing (RI) and resistance breaking (RB) isolates were analyzed using extracts from infected plants only a major siRNA shift was observed. In contrast, plant extracts containing the respective transiently expressed NSs proteins showed only the lower shift with NSsRI but no shift with NSsRB. The observed affinity for RNA duplexes, as well as the two-stepwise shift pattern, is discussed in light of NSs as a suppressor of silencing and its importance for tospovirus infection.


Synaptic connections between layer 4 spiny neurone-layer 2/3 pyramidal cell pairs in juvenile rat barrel cortex: physiology and anatomy of interlaminar signalling within a cortical column.
Whole-cell voltage recordings were obtained from 64 synaptically coupled excitatory layer 4 (L4) spiny neurones and L2/3 pyramidal cells in acute slices of the somatosensory cortex ('barrel' cortex) of 17- to 23-days-old rats. Single action potentials (APs) in the L4 spiny neurone evoked single unitary EPSPs in the L2/3 pyramidal cell with a peak amplitude of 0.7 +/- 0.6 mV. The average latency was 2.1 +/- 0.6 ms, the rise time was 0.8 +/- 0.3 ms and the decay time constant was 12.7 +/- 3.5 ms. The percentage of failures of an AP in a L4 spiny neurone to evoke a unitary EPSP in the L2/3 pyramidal cell was 4.9 +/- 8.8 % and the coefficient of variation (c.v.) of the unitary EPSP amplitude was 0.27 +/- 0.13. Both c.v. and percentage of failures decreased with increased average EPSP amplitude. Postsynaptic glutamate receptors (GluRs) in L2/3 pyramidal cells were of the N-methyl-D-aspartate (NMDA) receptor (NMDAR) and the non-NMDAR type. At -60 mV in the presence of extracellular Mg2+ (1 mM), 29 +/- 15 % of the EPSP voltage-time integral was blocked by NMDAR antagonists. In 0 Mg2+, the NMDAR/AMPAR ratio of the EPSC was 0.50 +/- 0.29, about half the value obtained for L4 spiny neurone connections. Burst stimulation of L4 spiny neurones showed that EPSPs in L2/3 pyramidal cells depressed over a wide range of frequencies (1-100 s(-1) ). However, at higher frequencies (30 s(-1)) EPSP summation overcame synaptic depression so that the summed EPSP was larger than the first EPSP amplitude in the train. The number of putative synaptic contacts established by the axonal collaterals of the L4 projection neurone with the target neurone in layer 2/3 varied between 4 and 5, with an average of 4.5 +/- 0.5 (n = 13 pairs). Synapses were established on basal dendrites of the pyramidal cell. Their mean geometric distance from the pyramidal cell soma was 67 +/- 34 microm (range, 16-196 microm). The results suggest that each connected L4 spiny neurone produces a weak but reliable EPSP in the pyramidal cell. Therefore transmission of signals to layer 2/3 is likely to have a high threshold requiring simultaneous activation of many L4 neurons, implying that L4 spiny neurone to L2/3 pyramidal cell synapses act as a gate for the lateral spread of excitation in layer 2/3.


Lenticular soil mounds in the Kenya highlands.
Soil mounds in moist grassland at moderate altitudes in the Kenya Highlands have recently been interpreted as being formed by burrowing molerats. Evidence is presented here that these mounds contain active nests of Odontotermes spp. and are likely to have been built by the termites.


Lower extremity ultrasound-guided interventions: tendon, ligament, and plantar fascia.
Lower extremity tendinopathy and soft tissue injury are common clinical problems that can cause significant disability. Ultrasound-guided minimally invasive treatments using orthobiologics and image-guided percutaneous treatments continue to gain relevance with an ever-growing body of literature. We review the indications, technique, risks, and benefits according to the literature of common ultrasound-guided interventions utilized in the lower extremities.


Effect of corticosteroid dose and duration of administration on colonic anastomosis.
Surgical intervention under concomitant steroid therapy can be complicated by impaired anastomotic healing. The aim of this experimental study was to investigate the effects of a corticosteroid (methylprednisolone) on healing colonic anastomoses in relation to the dose and duration of administration. Fifty male Spraque-Dawley rats weighing 200-220 g were divided into five groups each containing 10 rats. No treatment was given in the control group. Group HDST: high-dose methylprednisolone (1 mg/kg/day, intramuscular) treatment for a short term of 2 days; group HDLT: high-dose methylprednisolone treatment for a long term of 60 days; group LDST: low-dose methylprednisolone (0.28 mg/kg/day) treatment for a short term of 2 days; and group LDLT: low-dose methylprednisolone treatment for a long term of 60 days. Standard left colonic anastomosis was performed in all rats. Anastomotic bursting pressure, hydroxyproline measurement, and histopathological data were evaluated in all groups on postoperative day 4. The mean anastomotic bursting pressure value was significantly lower in the HDLT group (P < 0.05). The mean hydroxyproline levels were significantly lower in all groups (P < 0.05). Histopathological results demonstrated significant changes according to neutrophil infiltration, granulation tissue formation, presence of vascularization, and peritonitis in the HDLT, LDST, and LDLT groups (P < 0.05). High and low doses of the corticosteroid produced adverse effects on the healing of colon anastomosis in rats regardless of whether it was administered over a long or short preoperative period. However, the most prominent negative effect was associated with high-dose, long-term corticosteroid administration.


Advances in the understanding of early Huntington's disease using the functional imaging techniques of PET and SPET.
The functional imaging techniques of positron emission tomography (PET) and single photon emission tomography (SPET) have been used to study regional brain function in Huntington's disease (HD) in vivo. Reduced striatal glucose metabolism and dopamine receptor binding are evident in all symptomatic HD patients and in approximately 50% of asymptomatic adult mutation carriers. These characteristics correlate with clinical measures of disease severity. Reduced cortical glucose metabolism and dopamine receptor binding, together with reduced striatal and cortical opioid receptor binding, have also been demonstrated in symptomatic patients with HD. Repeat PET measures of striatal function have been used to monitor the progression of this disease objectively. In the future, functional imaging will provide a valuable way of assessing the efficacy of both fetal striatal cell implants and putative neuroprotective agents, such as nerve growth factors.


Strain differences of the light-dark preference in inbred rats.
The present study examined strain differences in the light-dark preference among four strains of rats. The test was done in the home-cage situation under 12L:12D cycles. Data from four strains were compared: BN/Kyo, BDIX/Nem, Wistar/Nu, and F344/NSlc. These strains differed in the light-dark preference measured by the ratio of the time spent in the field area of the home cage during the light period. BN/Kyo and BDIX/Nem spent the most time (approx. 23%) in the field during the light period, while F344/NSlc spent the least time (approx. 5%). Wistar/Nu fell between the two (approx. 12%).


Antiparasitic peptides.
: The most important parasitic diseases, malaria, leishmaniasis, trypanosomiasis, and schistosomiasis, are a great burden to mankind, threatening the life of millions of people worldwide and mostly affecting the poorest. Because drug resistance is increasing and vaccines are rarely available, novel chemotherapeutic compounds are necessary in order to treat these devastating diseases. Insects serve as vectors of many human parasitic diseases and have been shown to express a huge variety of antimicrobial peptides (AMPs). Therefore, research activity on insect-derived AMPs has been increasing in the last 40 years. This chapter summarizes the current state of research on the possible role of AMPs as potential chemotherapeutic compounds against human parasitic diseases. As a representative antimicrobial peptide with antiparasitic activity, the structure of insect defensin A is shown [PDB accession code: 1ICA]. The molecule is surrounded by schematic representations of the human pathogenic parasites Plasmodium, Leishmania and Trypanosoma.


DFT studies of COOH tip-functionalized zigzag and armchair single wall carbon nanotubes.
Structure and energy calculations of pristine and COOH-modified model single wall carbon nanotubes (SWCNTs) of different length were performed at B3LYP/6-31G* level of theory. From 1 to 9 COOH groups were added at the end of the nanotube. The differences in structure and energetics of partially and fully functionalized SWCNTs at one end of the nanotube are observed. Up to nine COOH groups could be added at one end of (9,0) zigzag SWCNT in case of full functionalization. However, for (5,5) armchair SWCNT, the full functionalization was impossible due to steric crowding and rim deformation. The dependence of substituent attachment energy on the number of substituents at the carbon nanotube rim was observed.


Morphology and responses to light of the somata, axons, and terminal regions of individual photoreceptors of the giant barnacle.
1. The median eye of the giant barnacle, B. nubilus, comprises four large photoreceptor neurones which are visible under the dissecting microscope for almost their entire length. We have studied the structure of, and the responses to light recorded in, the somata, axons, and terminal regions of these neurones.2. The photoreceptor somata, each 40-70 mum in diameter, extend numerous light-sensitive dendritic processes whose membranes form rhabdomeric microvilli. Recordings from the soma show that dim light evokes a steady, noisy depolarization; brighter light elicits a transient depolarization which decays to a maintained plateau, followed by a hyperpolarization when the light is turned off.3. Light-induced voltage changes spread decrementally along the photoreceptor axons, which average 10 mm in length and 25 mum in diameter. In distal parts of the axon, near the presynaptic terminals, depolarizations and hyperpolarizations can be as large as 50% or more of their values in the soma.4. There is no demonstrable electrical coupling between photoreceptor neurones as shown by simultaneous recordings from two receptor somata or axons.5. Each photoreceptor axon enters the mid line commissure of the supraoesophageal ganglion, bifurcates, and arborizes in a restricted zone of neuropil in each hemiganglion. The large size of the terminal processes of these neurones and their characteristic cytoplasmic inclusions enable one to trace them with the electron microscope as they branch in the neuropil.6. The terminal processes subdivide and end in 1-3 mum diameter branches which are the sites of apparently chemical synapses. Vesicle-containing, presynaptic loci on these processes of the receptor cell are invariably apposed to two post-synaptic processes from cells as yet unidentified.


Efficiency and safety of phenylephrine and tropicamide used in premature retinopathy: a prospective observational study.
To determine effects and side effects of topical application of phenylephrine 2.5% and tropicamide 0.5% combination in preterm infants. In this prospective observational study, 60 infants undergoing retinopathy of prematurity (ROP) screening were prospectively observed. Pupillary diameter, blood pressure, heart rate, and oxygen saturation were monitored before and after up to 24 h during ROP screening examinations. The mean pupillary diameter 1 h after the instillation of drops was 5.58 ± 0.75 mm for both eyes. The mean systolic and diastolic pressure and oxygen saturation of infants did not change statistically until the end of the study. The average heart rate decreased by a mean of 4.96 beats/minute from the baseline following eye drops instillation. General condition deterioration, fall in oxygen saturation and bradycardia were observed in 4 infants that already had respiratory distress syndrome. The phenylephrine 2.5% plus tropicamide 0.5% drop is effective and safe as mydriatic combination for retinopathy of prematurity screening. In infants with an additional systemic disease such as respiratory distress syndrome, the side effects of mydriatic drops may be more common. Such babies should be kept under close observation. The trial was retrospectively registered on 28 February 2018. The ClinicalTrials.gov Identifier is NCT03448640.


Clinical approach to syncope in children.
Pediatric syncope is one of the most common neurological problems in the pediatric population in both the office setting and in the emergency department. The abrupt brief loss of consciousness is usually dramatic and alarming to patients, family, onlookers, and providers. The differential diagnosis of syncope is wide but most cases are benign. A comprehensive but focused history and a thorough clinical examination are usually the cornerstones in the diagnosis of high-risk patients. It should be noted that the evaluation of syncope in children is costly and testing provides a low diagnostic yield. This chapter reviews the various types of syncope and provides a succinct clinical approach to the diagnosis, investigation, and management of syncope in children.


Is it time to rethink the typical course of low back pain?
To determine the frequency and the characteristics of low back pain (LBP) recurrences. The research questions were as follows: (1) Are LBP recurrences common? (2) Do episodes worsen with multiple recurrences? (3) Does pain change location in any recognizable pattern during an episode? Single-page self-administered questionnaire. Thirty clinical practices (primary care, physical therapy, chiropractic, and surgical spine) in North America and Europe. A convenience sample of 589 respondents with LBP. There were no exclusions based on type of LBP, history of onset, or comorbidities. The survey was distributed during patients' assessment or initial treatment at their respective clinics. The survey queried the following: (1) the severity of original versus most recent episodes based on the following: pain intensity, interference with leisure and work activities, duration of episodes, and most distal extent of pain; and (2) changes in pain location within episodes. In response to research question 1, a previous episode was reported by 73%; of those, 66.1% reported their first episode lasted ≤3 months, 54% reported ≥10 episodes, and 19.4% reported >50 episodes. In response to research question 2, of those with recurrences, 61.1% reported that at least one of the survey domains was worse in recent episodes (P < .01) and only 36.9% reported that they were better; 20.5% were worse in all domains, whereas 8.6% were better or the same. In response to research question 3, the pain location changed during the episode in 75.6%; of these, 63.2% reported that their pain first spread distally before retreating proximally during recovery; there was a strong trend toward those reporting worsening episodes also reporting proximal-to-distal-to-proximal changes in pain location during their episodes (r = 0.132, P < .06). Recurrent LBP episodes were common and numerous. Recurrences often worsened over time. It seems inappropriate to characterize the typical course of LBP as benign and favorable.


Botulinum toxin (botox) reduces pain after hemorrhoidectomy: results of a double-blind, randomized study.
Pain after hemorrhoidectomy appears to be multifactorial and dependent on individual pain tolerance, mode of anesthesia, postoperative analgesia, and surgical technique. Spasm of the internal sphincter is believed to play an important role. The aim of this study was to assess the role of botulinum toxin in reducing pain after Milligan-Morgan hemorrhoidectomy. This was a double-blind study of 50 consecutive patients undergoing Milligan-Morgan hemorrhoidectomy and assigned to an internal sphincter injection of 0.4 ml of solution containing either botulinum toxin (20 U; Botox) or normal saline. Patients were managed according to standardized perioperative analgesic and laxative regimens. Pain was assessed by use of daily visual analog scores and analgesia requirements for the first seven postoperative days. Patients randomized to receive botulinum toxin had lower daily average and maximal visual analog scores throughout the study period. The difference reached significance on both Day 6 (P < 0.05) and Day 7 (P < 0.05). There was no significant difference (P = 0.12) in morphine requirements in the first 24 hours (botulinum group, 16 (range, 6-27) mg; placebo arm, 22 (range, 13-41) mg). Patients who received Botox used 19 (range, 8-36) coproxamol tablets in the first seven days after surgery compared with 23 (range, 10-40) in the placebo arm (P = 0.63). Those patients who had botulinum toxin had significantly less pain toward the end of the first week after surgery. Reduction in spasm within the internal sphincter is the presumed mechanism of action. This is the first reported randomized, controlled trial using botulinum toxin in hemorrhoidectomy.


High ratio of pCXCR4/CXCR4 tumor infiltrating immune cells in primary high grade ovarian cancer is indicative for response to chemotherapy.
Ovarian cancer (OC) is the fifth most common malignant female cancer with a high mortality, mainly because of aggressive high-grade serous carcinomas (HGSOC), but also due to absence of specific early symptoms and effective detection strategies. The CXCL12-CXCR4 axis is considered to have a prognostic impact and to serve as potential therapeutic target. Therefore we investigated the role of pCXCR4 and CXCR4 expression of the tumor cells and of tumor infiltrating immune cells (TIC) in high-grade serous OC and their association with the recurrence-free (RFS) and overall survival (OS). A tissue microarray of 47 primary high grade ovarian serous carcinomas and their recurrences was stained with primary antibodies directed against CXCR4 and pCXCR4. Beside the evaluation of the absolute tumor as well as TIC expression in primary and recurrent cancer biopsies the corresponding ratios for pCXCR4 and CXCR4 were generated and analyzed. The clinical endpoints were response to chemotherapy, OS as well as RFS. Patients with a high pCXCR4/CXCR4 TIC ratio in primary cancer biopsies showed a significant longer RFS during the first two years (p = 0.025). However, this effect was lost in the long-term analysis including a follow-up period of 5 years (p = 0.128). Interestingly, the Multivariate Cox regression analysis showed that a high pCXCR4/CXCR4 TIC ratio in primary cancer independently predicts longer RFS (HR 0.33; 95CI 0.13 - 0.81; p = 0.015). Furthermore a high dichotomized distribution of CXCR4 positive tumor expression in recurrent cancer biopsies showed a significantly longer 6-month RFS rate (p = 0.018) in comparison to patients with low CXCR4 positive tumor expression. However, this effect was not independent of known risk factors in a Multivariate Cox regression (HR 0.57; 95CI 0.24 - 1.33; p = 0.193). To the best of our knowledge we show for the first time that a high pCXCR4/CXCR4 TIC ratio in primary HGSOC biopsies is indicative for better RFS and response to chemotherapy. • We observed a significant association between high pCXCR4/CXCR4 TIC ratio and better RFS in primary cancer biopsies, especially during the early postoperative follow-up and independent of known risk factors for recurrence. • High CXCR4 tumor expression in recurrent HGSOC biopsies might be indicative for sensitivity to chemotherapy. We found evidence that at the beginning of the disease (early follow-up) the role of the immune response seems to be the most crucial factor for progression. On the other hand in recurrent/progressive disease the biology of the tumor itself becomes more important for prognosis. • We explored for the first time the predictive and prognostic role of pCXCR4/CXCR4 TIC ratio in high-grade serous ovarian cancer.


HSP90AA1 promotes lymphatic metastasis of hypopharyngeal squamous cell carcinoma by regulating epithelial-mesenchymal transition.
Lymphatic metastasis (LM) emerges as an independent prognostic marker for hypopharyngeal squamous cell carcinoma (HSPSCC), chiefly contributing to treatment inefficacy. This study aimed to scrutinize the prognostic relevance of HSP90AA1 and its potential regulatory mechanism of concerning LM in HPSCC. In a preceding investigation, HSP90AA1, a differential gene, was discovered through transcriptome sequencing of HPSCC tissues, considering both the presence and absence of LM. Validation of HSP90AA1 expression was accomplished via qRT-PCR, western-blotting(WB), and immunohistochemistry(IHC), while its prognostic significance was assessed employing Kaplan-Meier survival analysis(KMSA), log-rank test(LR), and Cox's regression analysis(CRA). Bioinformatics techniques facilitated the prediction and analysis of its plausible mechanisms in LM, further substantiated by in vitro and in vivo experiments utilizing FaDu cell lines. HSP90AA1 is substantially up-regulated in HPSCC with LM and is identified as an independent prognostic risk determinant. The down-regulation of HSP90AA1 can achieve inhibition of tumor cell proliferation, migration and invasion. Both in vivo experiments and Bioinformatics exploration hint at promoting LM by Epithelial-mesenchymal transition (EMT), regulated by HSP90AA1. HSP90AA1, by controlling EMT, can foster LM in HPSCC.This finding sets the foundation for delving into new therapeutic targets for HPSCC.


Spinal cord extracellular microenvironment. Can the changes resulting from trauma be graded?
It is now clear that alternatives are available to the standard method of producing spinal injury with the Allen drop technique. We have shown that small groups of animals with predictably consistent mechanical injury descriptors can now be produced for studies of this type. These groups can easily be selected to have minimal or maximal injury results, depending upon this series of mechanical descriptors. In addition, important physiological variables seem to show acute recovery patterns consistent with recovery of function in chronic animals. Since marginal injuries are likely to be more responsive to pharmacological or surgical intervention, a sensible approach would be to design studies in which animals are close to, but not at, some degree of injury from which they will spontaneously recover. Shifts of the acute physiological, chronic behavioral, or histopathological recovery curves would then indicate the potential therapeutic index of different interventions. Only in this way can significant advances be made in the selection of protocols for human trials.


Effect of a single oral dose of endosulfan on intestinal uptake of nutrients and on brush-border enzymes in rats.
The effect of a single oral dose of endosulfan (5 mg/kg body weight) on the uptake of certain nutrients and brush-border enzymes has been studied in rat intestine. The uptake of glucose and alanine was elevated but that of leucine was decreased in endosulfan-fed rats. There was no change in the uptake of phenylalanine and lysine in insecticide-fed rats. The activities of brush-border sucrase and alkaline phosphatase were considerably increased while the activity of Na+ K+ ATPase was reduced in endosulfan-exposed animals. The leucine aminopeptidase activity was unaffected in pesticide-treated rats. There was a significant decrease in cellular LDH and GOT activities with no change in GPT activity. Neither was there a considerable increase in the cellular glucose-6-phosphatase activity (P less than 0.01) in the pesticide-fed rats. These results suggest that endosulfan toxicity induces certain functional changes in the intestine.


Functional drug targeting to erythrocytes in vivo using antibody bearing liposomes as drug vehicles.
Covalent attachment of anti-erythrocyte F(ab')2 to the liposome surface has recently been shown to considerably enhance the liposome binding to erythrocytes in vivo. These antibody bearing liposomes have now been found quite effective as vehicles for delivering the antimalarial drug, chloroquine, to erythrocytes in Plasmodium berghei-infected mice. This demonstrates the usefulness of antibody targeted liposomes as carriers for site-specific drug delivery.


Severe congenital neutropenia due to G6PC3 deficiency: Case series of five patients and literature review.
Glucose-6-phosphate catalytic subunit 3 (G6PC3) deficiency is characterized by severe congenital neutropenia with recurrent pyogenic infections, a prominent superficial venous pattern and cardiovascular and urogenital malformations caused by an alteration of glucose homeostasis, with increased endoplasmic reticulum stress and cell apoptosis. We reviewed our patients with G6PC3 deficiency diagnosed along the last decade in Mexico; we also searched the PubMed/Medline database for the terms ('G6PC3 deficiency' OR 'Dursun syndrome' OR 'Severe congenital neutropenia type 4'), and selected articles published in English from 2009 to 2020. We found 89 patients reported from at least 14 countries in 4 continents. We describe five new cases from Mexico. Of the 94 patients, 56% are male, 48% from Middle East countries and none of them had adverse reactions to live vaccines; all presented with at least 1 severe infection prior to age 2. Seventy-five per cent had syndromic features, mainly atrial septal defect in 55% and prominent superficial veins in 62%. With a total of 94 patients reported in the past decade, we delineate the most frequent laboratory and genetic features, their treatment and outcomes, and to expand the knowledge of syndromic and non-syndromic phenotypes in these patients.


Parathormone Levels Are Independently Associated with the Presence of Left Ventricular Hypertrophy in Patients with Coronary Artery Disease.
Abnormalities of mineral metabolism and inflammation may affect the cardiovascular system. We have assessed the relationship of left ventricular hypertrophy (LVH) with inflammation and mineral metabolism. LVH was measured in 146 outpatients with stable coronary artery disease (SCAD) using echocardiography. Calcidiol (a vitamin D metabolite), parathyroid hormone (PTH), fibroblast growth factor-23, high-sensitivity C-reactive protein, MCP-1 (monocyte chemoattractant protein-1), galectin-3, NGAL (neutrophil gelatinase-associated lipocalin), and sTWEAK (soluble TNF-related weak inducer of apoptosis) plasma levels were studied. LVH, defined as septal thickness ≥11 mm, was present in 19.9% of cases. These patients were older [75.0 (61.0-81.0) vs 64.0 (51.0-76.0) years; p=0.002], had higher prevalence of left ventricular ejection fraction (LVEF)>40%, and had higher PTH [84.7 (59.6-104.7) vs 63.2 (49.2-85.2) pg/ml; p=0.007], galectin-3 [9.6 (8.0-11.1) vs 8.3 (6.9-9.9) ng/ml; p=0.037], and NGAL (208.5±87.6 vs 173.9±73.4 ng/ml; p=0.031) plasma levels than those without LVH. Glomerular filtration rate was lower in patients with LVH than in those without it (65.1±20.0 vs 74.7±19.9 mL/min/1.73 m2; p=0.021). There were no significant differences in hypertension (79.3 vs 68.4%; p=0.363) or sex between both groups. Variables showing differences based on univariate analysis and hypertension were entered into a logistic regression analysis. Only age [odds ratio (OR) =1.052 (1.011-1.096); p=0.013], PTH plasma levels [OR=1.017 (1.003-1.031); p=0.021], and LVEF>40% [OR=7.595 (1.463-39.429); p=0.016] were independent predictors of LVH. In patients with SCAD, elevated PTH levels are independently associated with the presence of LVH. Further studies are needed to elucidate the role of PTH in the development of myocardial hypertrophy.


Genomic-based high throughput screening identifies small molecules that differentially inhibit the antiviral and immunomodulatory effects of IFN-alpha.
Multiple lines of evidence suggest that inhibition of Type I Interferons, including IFN-alpha, may provide a therapeutic benefit for autoimmune diseases. Using a chemical genomics approach integrated with cellular and in vivo assays, we screened a small compound library to identify modulators of IFN-alpha biological effects. A genomic fingerprint was developed from both ex vivo patient genomic information and in vitro gene modulation from IFN-alpha cell-based stimulation. A high throughput genomic-based screen then was applied to prioritize 268 small molecule inhibitors targeting 41 different intracellular signaling pathways. Active compounds were profiled further for their ability to inhibit the activation and differentiation of human monocytes using disease-related stimuli. Inhibitors targeting NF-kappaB or Janus Kinase/Signal Transducer and Activator of Transcription (JAK/STAT) signaling emerged as "dissociated inhibitors" because they did not modulate IFN-alpha anti-viral effects against HSV-1 but potently inhibited other immune-related functions. This work describes a novel strategy to identify small molecule inhibitors for the treatment of autoimmune disorders.


Distribution of different phosphorylated forms of RNA polymerase II in relation to Cajal and PML bodies in human cells: an ultrastructural study.
The mammalian nucleus is a highly organised organelle that contains many subcompartments with roles in DNA replication and repair, gene expression and RNA processing. Cajal and promyelocytic leukaemia (PML) bodies are discrete nuclear structures with specific molecular signatures. RNA polymerase II and many transcription factors have been identified within these compartments by immunofluorescence microscopy, suggesting a role in polymerase II assembly or transcriptional activity. Here, we have examined the presence of different phosphorylated forms of polymerase II and newly made RNA in Cajal and PML bodies using high-resolution imaging of ultrathin cryosections (approximately 120 nm thick) with fluorescence and electron microscopes. We show that Cajal bodies contain polymerase II phosphorylated on Ser5, and not the Ser2-phosphorylated (active) form or newly made RNA. The presence of polymerase II in the absence of transcriptional activity suggests that Cajal bodies have roles in polymerase assembly or transport, but not in gene transcription. PML bodies contain no detectable polymerase II or nascent RNA in HeLa cells, at the resolution achieved by electron microscopy, but are often surrounded by these markers at distances>25 nm. These results support the view that although PML bodies are present in transcriptionally active areas of the nucleus, they are not generally sites of polymerase II assembly, transport or activity.


A review of glycosaminoglycan-modified electrically conductive polymers for biomedical applications.
The application areas of electrically conductive polymers have been steadily growing since their discovery in the late 1970s. Recently, electrically conductive polymers have found their way into biomedicine, allowing the realization of many relevant applications ranging from bioelectronics to scaffolds for tissue engineering. Extracellular matrix components, such as glycosaminoglycans, build an important class of biomaterials that are heavily researched for biomedical applications due to their favorable properties. Due to their highly anionic character and the presence of sulfate groups in glycosaminoglycans, these biomolecules can be employed to functionalize conductive polymers, which enables the tailorability and improvement of cell-material interactions of conductive polymers. This review paper gives an overview of recent research on glycosaminoglycan-modified conductive polymers intended for biomedical applications and discusses the effect of different biological dopants on material characteristics, such as surface roughness, stiffness, and electrochemical properties. Moreover, the key findings of the biological characterization in vitro and in vivo are summarized, and remaining challenges in the field, particularly related to the modification of electrically conductive polymers with glycosaminoglycans to achieve improved functional and biological outcomes, are discussed. STATEMENT OF SIGNIFICANCE: The development of functional biomaterials based on electrically conductive polymers (CPs) for various biomedical applications, such as neural regeneration, drug delivery, or bioelectronics, has been increasingly investigated over the last decades. Recent literature has shown that changes in the synthesis procedure or the chosen dopant could adjust the resulting material characteristics. Hence, an interesting approach lies in using natural biomolecules as dopants for CPs to tailor the biological outcome. This review comprehensively summarizes the state of the art in the field of glycosaminoglycan-modified electrically conductive polymers for the first time, particularly highlighting the effect of the chosen dopant on material characteristics, such as surface morphology or stiffness, electrochemical properties, and consequently, cell-material interactions.


Combination of Percutaneous Rotational Thrombectomy and Drug-Coated Balloon for Treatment of Femoropopliteal Artery Nonembolic Occlusion: 12-Month Follow-up.
To evaluate safety and efficacy of percutaneous mechanical thrombectomy using the Rotarex catheter combined with drug-coated balloon (DCB) in treatment of femoropopliteal artery occlusive disease. Between January 2016 and February 2018, 81 patients with acute or subacute femoropopliteal artery occlusions were treated with the Rotarex catheter combined with DCB. Lesions were classified according to the onset of symptoms as acutely (< 14 d) or subacutely (14 d to 3 mo) occluded. The mean lesion length was 12.1 cm ± 6.7. The primary endpoint was target lesion patency at 1 year as evaluated by duplex ultrasound (peak systolic velocity ratio < 2.4) and freedom from clinically indicated target lesion revascularization. Amputation rate, major adverse events, and ankle-brachial index at 12 months were evaluated. Technical success rate was 100% (n = 81). Bailout stents were necessary in 14 patients owing to residual stenosis or flow-limiting dissection. Additional thrombolysis was applied in 10 interventions. No major adverse events occurred during hospital stay. There were 9 restenosis cases during the 12-month follow-up period. Primary patency rate was 87.3% (62/71), and freedom from target lesion revascularization rate was 90.1% (64/71). Ankle-brachial index significantly increased from 0.46 ± 0.15 to 0.77 ± 0.14 during follow-up. The amputation rate was 1.4% at 12 months. These initial data from 2 centers suggest that the combination of the Rotarex catheter and DCB may be safe and effective for treatment of acute or subacute thrombotic femoropopliteal occlusion with superior immediate and midterm results achieved.


Racial and Ethnic Disparities in the Association Between Adverse Childhood Experience, Perceived Discrimination and Body Mass Index in a National Sample of U.S. Older Adults.
The current study evaluated whether there were racial/ethnic differences in the association between childhood adverse experience (ACEs), perceived racial discrimination (PRD), and body mass index (BMI) in a sample of middle age and older adults. We used data from the 2012-2013 National Epidemiologic Survey on Alcohol and Related Conditions (N = 11,404; ≥55 years) that included ACE and past year experiences with PRD. Generalized linear models were stratified by race/ethnicity (non-Hispanic White (NHW; n = 7337), non-Hispanic Black (NHB; n = 1960), and Hispanic (n = 1249)). The prevalence of ACE and PRD was significantly greater in NHB (63.6 and 29.8%, respectively) and Hispanic (61.2 and 15.9%, respectively), relative to NHW (53.1 and 4.6%, respectively). Across race/ethnicity, exposure to ACE's was associated with significantly greater odds of reporting PRD. Surprisingly, among Hispanics, exposure to ACE's was generally associated with lower BMI; however, this association was moderated by PRD in that BMI was highest among those with no ACE's and PRD, and lowest among those without ACE's or PRD. Similar, but not significant, trends were found for NHW's and NHB's. Our findings highlight the importance of screening for psychosocial adversity across the life course as risks factors for high BMI among middle age and older adults, particularly among Hispanics.


HPLC-SPE-NMR in pharmaceutical development: capabilities and applications.
High-performance liquid chromatography-solid phase extraction-NMR spectroscopy (HPLC-SPE-NMR) has recently become commercially available and has been evaluated with regard to its applicability in a pharmaceutical environment. The addition of an automated SPE unit to an HPLC-NMR system for peak trapping results in an improved NMR signal-to-noise ratio (S/N) and also has other practical advantages. The trapping efficiency is shown to depend on compound polarity and is highest for compounds eluting late on reversed-phase HPLC systems. Multiple peak trapping further increases the S/N, again with the best results for less polar compounds. For polar compounds, multiple peak trapping resulted in no S/N gain as the amount of material retained on the SPE cartridge was equivalent to that from a single injection. When compared with conventional HPLC-NMR, a S/N gain of up to five-fold could be achieved for some compounds in a single trapping step. A major advantage of the technique is the independence of the chromatographic step from the NMR step, resulting in greater versatility than conventional HPLC-NMR in the HPLC solvents and NMR solvents that can be used. Practical applications from both drug metabolite and drug impurity identification are presented.