The effect of medical institutions on doctor-patient interaction in Costa Rica.
The nature and quality of interaction and communication between doctor and patient is an important determinant in adequacy of health care. But patient behavior and physician performance are themselves influenced by the institutional and political setting. Study of two Costan Rican medical care systems reveals how historical differences in ideology and expectation can shape institutions and their services.


Sequential self-folding of polymer sheets.
Shape plays an important role in defining the function of materials, particularly those found in nature. Several strategies exist to program materials to change from one shape to another; however, few can temporally and spatially control the shape. Programming the sequence of shape transformation with temporal control has been driven by the desire to generate complex shapes with high yield and to create multiple shapes from the same starting material. This paper demonstrates a markedly simple strategy for programmed self-folding of two-dimensional (2D) polymer sheets into 3D objects in a sequential manner using external light. Printed ink on the surface of the polymer sheets discriminately absorbs light on the basis of the wavelength of the light and the color of the ink that defines the hinge about which the sheet folds. The absorbed light gradually heats the underlying polymer across the thickness of the sheet, which causes relief of strain to induce folding. These color patterns can be designed to absorb only specific wavelengths of light (or to absorb differently at the same wavelength using color hues), thereby providing control of sheet folding with respect to time and space. This type of shape programming may have numerous applications, including reconfigurable electronics, actuators, sensors, implantable devices, smart packaging, and deployable structures.


DNA methylation and heterochromatinization in the male-specific region of the primitive Y chromosome of papaya.
Sex chromosomes evolved from autosomes. Recombination suppression in the sex-determining region and accumulation of deleterious mutations lead to degeneration of the Y chromosomes in many species with heteromorphic X/Y chromosomes. However, how the recombination suppressed domain expands from the sex-determining locus to the entire Y chromosome remains elusive. The Y chromosome of papaya (Carica papaya) diverged from the X chromosome approximately 2-3 million years ago and represents one of the most recently emerged Y chromosomes. Here, we report that the male-specific region of the Y chromosome (MSY) spans approximately 13% of the papaya Y chromosome. Interestingly, the centromere of the Y chromosome is embedded in the MSY. The centromeric domain within the MSY has accumulated significantly more DNA than the corresponding X chromosomal domain, which leads to abnormal chromosome pairing. We observed four knob-like heterochromatin structures specific to the MSY. Fluorescence in situ hybridization and immunofluorescence assay revealed that the DNA sequences associated with the heterochromatic knobs are highly divergent and heavily methylated compared with the sequences in the corresponding X chromosomal domains. These results suggest that DNA methylation and heterochromatinization play an important role in the early stage of sex chromosome evolution.


Incidence and severity of SARS-CoV-2 infection in children and young people with HIV in Europe.
We assessed incidence of SARS-CoV-2 infection and disease severity among children and young people with HIV from cohorts across nine European countries. Of 1717 included, with median duration of follow-up 20.1 months, 134 (8%) had documented SARS-CoV-2 infection, a rate of 49 [95% confidence interval (CI) 42-58] per 1000 person-years. All symptomatic cases had mild coronavirus disease 2019 (COVID-19), three were hospitalized, and no deaths were reported, which may be reassuring for clinicians and families.


The effects of copper deficiency with or without high dietary iron or molybdenum on immune function of cattle.
Two experiments were conducted to determine the effects of Cu deficiency with or without high dietary Mo or Fe on the specific immunity of calves. In Exp. 1, calves from 38 bred heifers, fed corn silage-based experimental diets from the last third of gestation until the calves were weaned, were used. Dietary treatments were control (no supplemental Fe, Mo, or Cu), 600 mg of supplemental Fe/kg of DM, 5 mg of supplemental Mo/kg of DM, and 10 mg of supplemental Cu/kg of DM. In Exp. 2, 18 Holstein bull calves were fed commercial milk replacer low in Cu for 49 d and then fed semipurified diets containing approximately 1.1 mg of Cu/kg of DM or diets supplemented with 5 mg of Mo or 10 mg of Cu per kilogram of DM for 126 d. Feeding diets not supplemented with Cu resulted in severe Cu deficiency in both experiments. During Exp. 1, control calves had higher (P < .10) secondary antibody response to pig erythrocytes than Cu-, Mo-, and Fe-supplemented calves. During Exp. 2, in vitro Cu supplementation decreased (P < .01) lymphocyte blastogenic response. In vivo cell-mediated response to phytohemagglutinin was decreased (P < .10) by Cu supplementation during Exp. 1 but was increased (P < .10) by Cu and Mo supplementation during Exp. 2. Copper deficiency and Cu deficiency coupled with high dietary Mo or Fe produced inconsistent immune function responses, indicating that Cu deficiency may not affect specific immune function of calves.


The Role of Extracellular Vesicles in Efferocytosis.
Efferocytosis is the physiological process of phagocytic clearance of apoptotic cells by both professional phagocytic cells, such as macrophages, and non-professional phagocytic cells, such as epithelial cells. This process is crucial for maintaining tissue homeostasis in normal physiology. Any defects in efferocytosis can lead to pathological consequences and result in inflammatory diseases. Extracellular vesicles (EVs), including exosomes, microvesicles (MVs), and apoptotic vesicles (ApoVs), play a crucial role in proper efferocytosis. These EVs can significantly impact efferocytosis by affecting the polarization of macrophages and impacting calreticulin (CRT), TAM receptors, and MFG-E8. With further knowledge of these effects, new treatment strategies can be proposed for many inflammatory diseases caused by efferocytosis disorders. This review article aims to investigate the role of EVs during efferocytosis and its potential clinical applications in inflammatory diseases.


Marine n-3 PUFAs modulate IKs gating, channel expression, and location in membrane microdomains.
Polyunsaturated fatty n-3 acids (PUFAs) have been reported to exhibit antiarrhythmic properties. However, the mechanisms of action remain unclear. We studied the electrophysiological effects of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) on IKs, and on the expression and location of Kv7.1 and KCNE1. Experiments were performed using patch-clamp, western blot, and sucrose gradient techniques in COS7 cells transfected with Kv7.1/KCNE1 channels. Acute perfusion with both PUFAs increased Kv7.1/KCNE1 current, this effect being greater for DHA than for EPA. Similar results were found in guinea pig cardiomyocytes. Acute perfusion of either PUFA slowed the activation kinetics and EPA shifted the activation curve to the left. Conversely, chronic EPA did not modify Kv7.1/KCNE1 current magnitude and shifted the activation curve to the right. Chronic PUFAs decreased the expression of Kv7.1, but not of KCNE1, and induced spatial redistribution of Kv7.1 over the cell membrane. Cholesterol depletion with methyl-β-cyclodextrin increased Kv7.1/KCNE1 current magnitude. Under these conditions, acute EPA produced similar effects than those induced in non-cholesterol-depleted cells. A ventricular action potential computational model suggested antiarrhythmic efficacy of acute PUFA application under IKr block. We provide evidence that acute application of PUFAs increases Kv7.1/KCNE1 through a probably direct effect, and shows antiarrhythmic efficacy under IKr block. Conversely, chronic EPA application modifies the channel activity through a change in the Kv7.1/KCNE1 voltage-dependence, correlated with a redistribution of Kv7.1 over the cell membrane. This loss of function may be pro-arrhythmic. This shed light on the controversial effects of PUFAs regarding arrhythmias.


Identification of novel T cell factor 4 (TCF-4) binding sites on the HIV long terminal repeat which associate with TCF-4, β-catenin, and SMAR1 to repress HIV transcription.
Molecular regulation of HIV transcription is a multifaceted process dictated in part by the abundance of cellular transcription factors that induce or repress HIV promoter activity. β-Catenin partners with members of the T cell factor (TCF)/LEF transcription factors to regulate gene expression. The interaction between β-catenin and TCF-4 is linked to inhibition of HIV replication in multiple cell types, including lymphocytes and astrocytes. Here, we evaluated the molecular mechanism by which β-catenin/TCF-4 repress HIV replication. We identified for the first time multiple TCF-4 binding sites at -336, -143, +66, and +186 relative to the transcription initiation site on the HIV long terminal repeat (LTR). Two of the sites (-143 and +66) were present in approximately 1/3 of 500 HIV-1 isolates examined. Although all four sites could bind to TCF-4, the strongest association occurred at -143. Deletion and/or mutation of -143, in conjunction with β-catenin or TCF-4 knockdown in cells stably expressing an LTR reporter construct, enhanced basal HIV promoter activity by 5-fold but had no effect on Tat-mediated transactivation of the HIV LTR. We also found that TCF-4, β-catenin, and the nuclear matrix binding protein SMAR1 tether at the -143-nucleotide (nt) site on the HIV LTR to inhibit HIV promoter activity. Collectively, these data indicate that TCF-4 and β-catenin at -143 associate with SMAR1, which likely pulls the HIV DNA segment into the nuclear matrix and away from transcriptional machinery, leading to repression of basal HIV LTR transcription. These studies point to novel avenues for regulation of HIV replication by manipulation of β-catenin signaling within cells.


Neoadjuvant chemotherapy for gastric cancer. Is it a must or a fake?
To investigate the neoadjuvant chemotherapy (NAC) effect on the survival of patients with proper stomach cancer submitted to D2 gastrectomy. We proceeded to a review of the literature with PubMed, Embase, ASCO and ESMO meeting abstracts as well as computerized use of the Cochrane Library for randomized controlled trials (RCTs) comparing NAC followed by surgery (NAC + S) with surgery alone (SA) for gastric cancer (GC). The primary outcome was the overall survival rate. Secondary outcomes were the site of the primary tumor, extension of node dissection according to Japanese Gastric Cancer Association (JGCA) performed in both arms, disease-specific (DSS) and disease-free survival (DFS) rates, clinical and pathological response rates and resectability rates after perioperative treatment. We identified a total of 16 randomized controlled trials comparing NAC + S (n = 1089) with SA (n = 973) published in the period from January 1993 - March 2017. Only 6 of these studies were well-designed, structured trials in which the type of lymph node (LN) dissection performed or at least suggested in the trial protocol was reported. Two out of three of the RCTs with D2 lymphadenectomy performed in almost all cases failed to show survival benefit in the NAC arm. In the third RCT, the survival rate was not even reported, and the primary end points were the clinical outcomes of surgery with and without NAC. In the remaining three RCTs, D2 lymph node dissection was performed in less than 50% of cases or only recommended in the "Study Treatment" protocol without any description in the results of the procedure really perfomed. In one of the two studies, the benefit of NAC was evident only for esophagogastric junction (EGJ) cancers. In the second study, there was no overall survival benefit of NAC. In the last trial, which documented a survival benefit for the NAC arm, the chemotherapy effect was mostly evident for EGJ cancer, and more than one-fourth of patients did not have a proper stomach cancer. Additionally, several patients did not receive resectional surgery. Furthermore, the survival rates of international reference centers that provide adequate surgery for homogeneous stomach cancer patients' populations are even higher than the survival rates reported after NAC followed by incomplete surgery. NAC for GC has been rapidly introduced in international western guidelines without an evidence-based medicine-related demonstration of its efficacy for a homogeneous population of patients with only stomach tumors submitted to adequate surgery following JGCA guidelines with extended (D2) LN dissection. Additional larger sample-size multicentre RCTs comparing the newer NAC regimens including molecular therapies followed by adequate extended surgery with surgery alone are needed.


Subchondroplasty of the Foot: Two Case Reports.
Early avascular necrosis of metatarsal heads and cuboid injuries are uncommon conditions encountered by foot and ankle specialists. Treatment options are limited and typically include long periods of offloading or non-weightbearing. There is limited published information on alternative treatment approaches for such pathologies when conservative therapies fail. Presented are 2 patient cases treated with a percutaneous calcium phosphate injection after failure of standard therapy, persistent pain, and bone marrow edema in the foot.


Erectile dysfunction after COVID-19 recovery: A follow-up study.
Several studies confirm multiple complications after COVID-19 infection, including men's sexual health, which is caused by both physical and psychological factors. However, studies focusing on long-term effects among recovered patients are still lacking. Therefore, we aimed to investigate the erectile function at three months after COVID-19 recovery along with its predicting factors. We enrolled all COVID-19 male patients, who were hospitalized from May to July 2021, and declared to be sexually active within the previous two weeks. Demographic data, mental health status, and erectile function were collected at baseline and prospectively recollected three months after hospital discharge. To determine changes between baseline and the follow-up, a generalized linear mixed effect model (GLMM) was used. Also, logistic regression analysis was used to identify the associating factors of erectile dysfunction (ED) at three months. One hundred fifty-three men with COVID-19 participated. Using GLMM, ED prevalence at three months after recovery was 50.3%, which was significantly lower compared with ED prevalence at baseline (64.7%, P = 0.002). Declination of prevalence of major depression and anxiety disorder was found, but only major depression reached statistical significance (major depression 13.7% vs. 1.4%, P < 0.001, anxiety disorder 5.2% vs. 2.8% P = 0.22). Logistic regression, adjusted for BMI, medical comorbidities, and self-reported normal morning erection, showed a significant association between ED at three months and age above 40 years and diagnosis of major depression with adjusted OR of 2.65, 95% CI 1.17-6.01, P = 0.02 and 8.93, 95% CI 2.28-34.9, P = 0.002, respectively. Our study showed a high ED prevalence during the third month of recovery from COVID-19. The predicting factors of persistent ED were age over 40 years and diagnosis of major depression during acute infection.


Exploring why "memory loss" is a misleading descriptor of people living with dementia and can lead to dysfunctional care.
Amidst goals for prevention and improved treatment for people living with dementia, much remains needed to enhance the quality of life of those currently diagnosed, especially the transfer of accurate information from professionals to the public. Although many healthcare professionals understand the various types of memory and which are likely to be more affected than others during the progression of dementia, lay persons are more frequently unaware of that important information. The terms used to describe the symptoms of dementia can have a great impact on perceptions of faculties that are absent, compromised, or preserved. Understanding the nuances of preserved memory faculties and other cognitive abilities retained by persons with dementia is important in this regard. The term "memory loss" as a descriptor of the syndrome of dementia and ascribing it to persons with dementia connotes an inability to form new memories and participate in meaningful social interactions, which is detrimental to their personhood. From a multidisciplinary approach drawn from neurology, neurobiology, psychology, and case vignettes, we aim herein to highlight the ways in which the term "memory loss" can be inaccurate, counterproductive and potentially promote dementia-related misperceptions, malignant positioning and malignant social psychology. Persons with dementia unequivocally struggle with explicit memory, or recalling on demand, but retain implicit memory, as evidenced by research and everyday actions. Therefore, we propose the use of alternative medical language to reflect accurately memory impairment and preservation of some important memory capabilities.


Visual field progression in open-angle glaucoma patients presenting with monocular field loss.
Twenty-one patients with primary open-angle glaucoma were followed an average of 4.4 years after developing monocular field loss. Nine of the undamaged fellow eyes developed field loss, while 16 of the 21 eyes presenting with field loss showed progression of field changes. In 13 patients, the presenting eye had a greater progression of field loss than the fellow eye, and asymmetry of pressure control explained this in only five patients. Eleven patients with symmetric pressure control had progressive field changes in one or both eyes, and in seven, the presenting eye showed greater progression than its fellow. This suggests that an eye with field loss may be more susceptible to progression of field changes at similar pressure levels than an eye without previous damage. Furthermore, patients with unilateral field loss have a greater incidence of field loss in the undamaged fellow eye than do patients with bilateral ocular hypertension.


Manipulation of Viral MicroRNAs as a Potential Antiviral Strategy for the Treatment of Cytomegalovirus Infection.
Cytomegalovirus (CMV) infection leads to notable morbidity and mortality in immunosuppressed patients. Current antiviral drugs are effective but seriously limited in their long-term use due to their relatively high toxicity. In the present study, we characterized the expression of murine CMV microRNAs (MCMV miRNAs) both in vitro and in vivo. Although 29 miRNAs were detectable during in vitro infection, only 11 miRNAs (classified as Group 1) were detectable during in vivo infection, and as many as 18 viral miRNAs (classified as Group 2) were less detectable (<50% of animals) in both the liver and lungs. In addition, viral miRNA profiles in the blood revealed unstable and reduced expression. We next explored the in vitro effects of viral miRNAs on MCMV replication. The inhibition of Group 1 viral miRNAs had little effect on virus production, but transfected cells overexpressing miR-m01-3-5p, miR-M23-1-5p, miR-M55-1, and miR-m107-1-5p in Group 2 showed statistically lower viral loads than those transfected with control miRNA (29%, 29%, 39%, and 43%, respectively, versus control). Finally, we performed hydrodynamic injection of viral miRNA agomirs and observed lower levels of MCMV recurrence in the livers of animals overexpressing the miR-m01-3-5p or mcmv-miR-M23-1-5p agomirs compared with those of animals transfected with control agomir, confirming the antiviral effects of viral miRNA manipulation in vivo. Therefore, the manipulation of viral miRNA expression shows great therapeutic potential and represents a novel antiviral strategy for the miRNA-based treatment of cytomegalovirus infection.


Humour as emotion regulation: the differential consequences of negative versus positive humour.
Humour is often seen as an adaptive coping strategy; however, the empirical literature is inconclusive. One possible explanation is that different types of humour have different adaptive consequences. In the present research, we predicted that positive (good-natured) humour would be more effective at regulating negative emotions than negative (mean-spirited) humour. In Study 1, participants were shown negative pictures two times. First, they simply viewed the pictures and rated their levels of positive and negative emotions. Second, they were instructed to: (a) view; (b) use positive humour; or (c) use negative humour, and then rate their reactions. Compared to negative humour, positive humour was more successful at down-regulating negative and up-regulating positive emotion. In Study 2, we replicated these findings and showed that these effects cannot be explained by differences in difficulty between the two humour conditions, participants' expectations, or social desirability. Taken together, these findings suggest that positive (but not negative) humour may be an effective form of emotion regulation.


CXCL1, but not IL-6, significantly impacts intraocular inflammation during infection.
During intraocular bacterial infections, the primary innate responders are neutrophils, which may cause bystander damage to the retina or perturb the clarity of the visual axis. We hypothesized that cytokine IL-6 and chemokine CXCL1 contributed to rapid neutrophil recruitment during Bacillus cereus endophthalmitis, a severe form of intraocular infection that is characterized by explosive inflammation and retinal damage that often leads to rapid vision loss. To test this hypothesis, we compared endophthalmitis pathogenesis in C57BL/6J, IL-6-/-, and CXCL1-/- mice. Bacterial growth in eyes of CXCL1-/-, IL-6-/-, and C67BL/6J mice was similar. Retinal function retention was greater in eyes of IL-6-/- and CXCL1-/- mice compared with that of C57BL/6J, despite these eyes having similar bacterial burdens. Neutrophil influx into eyes of CXCL1-/- mice was reduced to a greater degree compared with that of eyes of IL6-/- mice. Histology confirmed significantly less inflammation in eyes of CXCL1-/- mice, but similar degrees of inflammation in IL6-/- and C57BL/6J eyes. Because inflammation was reduced in eyes of infected CXCL1-/- mice, we tested the efficacy of anti-CXCL1 in B. cereus endophthalmitis. Retinal function was retained to a greater degree and there was less overall inflammation in eyes treated with anti-CXCL1, which suggested that anti-CXCL1 may have therapeutic efficacy in limiting inflammation during B. cereus endophthalmitis. Taken together, our results indicate that absence of IL-6 did not affect overall pathogenesis of endophthalmitis. In contrast, absence of CXCL1, in CXCL1-/- mice or after anti-CXCL1 treatment, led to an improved clinical outcome. Our findings suggest a potential benefit in targeting CXCL1 to control inflammation during B. cereus and perhaps other types of intraocular infections.


PET study of D(1) dopamine receptor binding in neuroleptic-naive patients with schizophrenia.
Postmortem studies and a positron emission tomography (PET) study have suggested that there is a disturbance of central D(1) dopamine receptor function in schizophrenia. The objective of the present PET study was to compare D(1) receptor binding in first-admission, neuroleptic-naive patients with schizophrenia and in healthy subjects. Ten healthy comparison subjects and 10 neuroleptic-naive patients with schizophrenia (diagnosed according to DSM-III-R) were examined twice by PET using (11)C-labeled SCH 23390 ([(11)C]SCH 23390) with high and low specific radioactivity, respectively. The binding potential, receptor density (B(max)), and affinity (K(d)) were determined for the caudate nucleus, the putamen, and several neocortical regions during both PET examinations. Scatchard plots from the two measurements were used to calculate regional D(1) B(max) and K(d). The regional binding values were tested for hemispheric asymmetry and for correlation to clinical symptoms measured by the Brief Psychiatric Rating Scale (BPRS). [(11)C]SCH 23390 binding to D(1) receptors did not differ significantly between subjects with schizophrenia and healthy subjects in any of the brain regions or for any of the binding measures studied. Asymmetry of the regional binding values did not differ significantly between the two groups. Scores on the BPRS negative symptom subscale correlated significantly with the B(max) in the right frontal cortex. These results do not replicate previous postmortem and PET findings of altered central dopamine D(1) receptor binding in schizophrenia. The finding of a positive correlation between frontal D(1) binding and scores on the negative symptom subscale of the BPRS is contrary to a previously reported finding of a negative correlation. These discrepancies motivate further studies using D(1) ligands with higher signals for cortical regions.


Targeting of Golgi-specific pleckstrin homology domains involves both PtdIns 4-kinase-dependent and -independent components.
Phosphoinositides are required for the recruitment of many proteins to both the plasma membrane and the endosome; however, their role in protein targeting to other organelles is less clear. The pleckstrin homology (PH) domains of oxysterol binding protein (OSBP) and its relatives have been shown to bind to the Golgi apparatus in yeast and mammalian cells. Previous in vitro binding studies identified phosphatidylinositol (PtdIns) (4)P and PtdIns(4,5)P(2) as candidate ligands, but it is not known which is recognized in vivo and whether phosphoinositide specificity can account for Golgi-specific targeting. We have examined the distribution of GFP fusions to the PH domain of OSBP and to related PH domains in yeast strains carrying mutations in individual phosphoinositide kinases. We find that Golgi targeting requires the activity of the PtdIns 4-kinase Pik1p but not phosphorylation of PtdIns at the 3 or 5 positions and that a PH domain specific for PtdIns(4,5)P(2) is targeted exclusively to the plasma membrane. However, a mutant version of the OSBP PH domain that does not bind phosphoinositides in vitro still shows some targeting in vivo. This targeting is independent of Pik1p but dependent on the Golgi GTPase Arf1p. Phosphorylation of PtdIns at the 4 position but not conversion to PtdIns(4,5)P(2) contributes to recruitment of PH domains to the Golgi apparatus. However, potential phosphoinositide ligands for these PH domains are not restricted to the Golgi, and the OSBP PH domain also recognizes a second determinant that is ARF dependent, indicating that organelle specificity reflects a combinatorial interaction.


Clinical significance of histologic chorioamnionitis with a negative amniotic fluid culture in patients with preterm labor and premature membrane rupture.
To evaluate the effect of histological chorioamnionitis (HCA) with a negative amniotic fluid (AF) culture on adverse pregnancy and neonatal outcomes and inflammatory status in the AF compartment in women with preterm labor or preterm premature rupture of membranes (PPROM). This is a retrospective cohort study of 153 women diagnosed as having a preterm labor or PPROM (20-34 weeks) who delivered singleton gestations within 48 hours of amniocentesis. AF obtained through amniocentesis was cultured, and interleukin (IL)-6, IL-8, and metalloproteinase-9 (MMP-9) levels were determined. The placentas were examined histologically. The prevalence of HCA with negative AF culture was 23.5% (36/153). The women with HCA but with a negative AF culture (group 2) and those with a positive AF culture (group 3) had a significantly lower mean gestational age at amniocentesis and delivery than those with a negative AF culture and without HCA (group 1). Women in group 3 had the highest levels of AF IL-6, IL-8, and MMP-9, followed by those in group 2, and those in group 1. Composite neonatal morbidity was significantly higher in groups 2 and 3 than in group 1, but this was no longer significant after adjusting for confounders caused mainly by the impact of gestational age. In the women who delivered preterm neonates, HCA with a negative AF culture was associated with increased risks of preterm birth, intense intra-amniotic inflammatory response, and prematurity-associated composite neonatal morbidity, and its risks are similar to the risk posed by positive AF culture.


Technical note on microcatheter implantation for local inner ear drug delivery: surgical technique and safety aspects.
Despite its invasiveness, the temporary implantation of a microcatheter into the middle ear cavity is an appropriately safe method for providing continuous drug delivery to the inner ear. For the application of drugs to the inner ear, different delivery strategies are available ranging from intratympanic injections to temporarily implanted microcatheters. It has recently been demonstrated that the choice of the drug delivery system influences the pharmacokinetics in the inner ear. If a continuous drug application over several weeks is required, a secure placement of the delivery device (i.e., the microcatheter) is necessary to guarantee efficient drug delivery and to avoid unwanted side effects. Retrospective chart review. During 2000 to 2005, 25 patients with acute unilateral severe-to-profound hearing loss or anacusis and failure of systemic high-dose glucocorticoid and rheological therapy were offered an intratympanic delivery of glucocorticoids via a temporarily implanted catheter and an external pump for up to 4 weeks as a salvage treatment option. The standardized surgical implantation and fixation technique developed for the microcatheter were characterized by six elements: 1) a medial and a lateral tunnel connected by a groove in the posterior wall of the bony ear canal, 2) stabilization of the catheter with bone wax and soft tissue plugs in the tunnels, 3) an ear canal packing, 4) a series of fixating sutures along the catheter, 5) an adhesive dressing, and 6) additional tapes at the connecting line between pump and catheter. At the end of the implantation period, the catheter was removed by a second surgical procedure allowing for evaluation of the catheter position and the condition of the middle ear space. Adverse events included catheter dislocation, catheter obstruction, formation of mild granulation tissue in the middle ear cavity, tympanic membrane defects, and ear canal skin defects. With introduction of an improved implantation and fixation technique, the number of catheter dislocations could be significantly reduced. No complications were observed on long-term follow-up. If the pharmacokinetics or pharmacodynamics of a specific local inner ear therapy approach requires a continuous intratympanic drug application (e.g., to restore hearing in patients with severe or profound hearing loss), the temporary implantation of a microcatheter by a standardized surgical technique is a feasible and appropriately safe method for providing continuous drug delivery to the inner ear.


Image processing, diagnostic information extraction and quantitative assessment in pathology.
As we enter the information age we hold strong beliefs in the benefits of digital technology applied to pathology: numerical representation offers objectivity. Digital knowledge may indeed lead to significant information discovery, and, processing systems might be designed to allow a true evolution of capabilities. Questions arise whether the methodology underlying quantitative analysis provides the information that we need and whether it is appropriate for some of the problems encountered in diagnostic and prognostic histopathology. While one certainly would not dispute the value of statistical procedures, the clinical needs call for individual patient targeted prognosis.


Common marmoset as a new model animal for neuroscience research and genome editing technology.
The common marmoset (Callithrix jacchus) is a small New World primate; it originally comes from the Atlantic coastal forests in northeastern Brazil. It has been attracting much attention in the biomedical research field because of its size, availability, and unique biological characteristics. Its endocrinological and behavioral similarity to humans, comparative ease in handling, and high reproductive efficiency are very advantageous for neuroscience research. Recently, we developed transgenic common marmosets with germline transmission, and this technological breakthrough provides a potential paradigm shift by enabling researchers to investigate complex biological phenomena using genetically-modified non-human primates. In this review, we summarize recent progress in marmoset research, and also discuss a potential application of genome editing tools that should be useful toward the generation of knock-out/knock-in marmoset models.


In vivo insulin effect on ATPase activities in erythrocyte membrane from insulin-dependent diabetics.
Na+-K+-dependent ouabain-sensitive ATPase and Mg2+-ATPase have been assayed in the erythrocyte membranes of control subjects and in uncontrolled type I (insulin-dependent) diabetics. A decrease in Na+-K+-ATPase activity was observed in the patients that was significantly correlated with glycemia. The Mg2+-ATPase was increased moderately, and no correlation with glycemia was found. To study the in vivo effect of insulin, ATPase activities were measured in uncontrolled diabetics before and after a 24-h continuous insulin perfusion administered by means of an artificial pancreas. ATPase activities were corrected after normalization of glycemia. It therefore seems that glycemia and/or insulinemia are involved in the regulation of erythrocyte Na+-K+ ouabain-sensitive ATPase and to a lesser extent in that of Mg2+-dependent ATPase.


Knockdown of human telomerase reverse transcriptase induces apoptosis in cervical cancer cell line.
: Human telomerase reverse transcriptase (hTERT) is the catalytic subunit of telomerase enzyme that maintains telomere ends by the addition of telomeric repeats to the ends of chromosomal DNA, and that may generate immortal cancer cells. Hence, the activity of telomerase is raised in cancer cells including cervical cancer. The present study aimed to validate the unique siRNA loaded chitosan coated poly-lactic-co-glycolic acid (PLGA) nanoparticle targeting hTERT mRNA to knock down the expression of hTERT in HeLa cells. : The siRNA loaded chitosan coated polylactic-co-glycolic acid (PLGA) nanoparticles were synthesized by double emulsion solvent diffusion method. The characterization of nano-formulation was done to determine efficient siRNA delivery. MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay, reverse transcriptase-polymerase chain reaction (RT-PCR) and Western blot were performed to evaluate silencing efficiency of nano-formulation. :Size, zeta potential and encapsulation efficiency of nanoparticles were 249.2 nm, 12.4 mV and 80.5 per cent, respectively. Sustained release of siRNA from prepared nanoparticle was studied for 72 h by ultraviolet method. Staining assays were performed to confirm senescence and apoptosis. Silencing of hTERT mRNA and protein expression were analyzed in HeLa cells by RT-PCR and Western blot. : The findings showed that biodegradable chitosan coated PLGA nanoparticles possessed an ability for efficient and successful siRNA delivery. The siRNA-loaded PLGA nanoparticles induced apoptosis in HeLa cells. Further studies need to be done with animal model.


[Robotic radiotherapy for prostate cancer with CyberKnife].
After 3D conformal radiation therapy without and with modulated intensity, image-guided radiation therapy represents a new technological step. Should prostate cancer treatment using radiotherapy with the CyberKnife robotic system be considered as a new treatment and then investigated through classical clinical research procedure rather than a technical improvement of an already validated treatment? After a general presentation of the CyberKnife , the authors focused on prostate cancer treatment assuming that, according to dosimetric and biological considerations, the treatment by robotic system appears comparable to high dose rate brachytherapy. For prostate cancer treatment are discussed: biological rational for hypofractionated treatment, high dose rate brachytherapy boost and interest of dose escalation. A comparison is presented between CyberKnife and other validated treatment for prostate cancer (radical prostatectomy, 3D conformal radiation therapy and low and high dose rate brachytherapy). In summary, CyberKnife treatment could be considered as a technical improvement of an already validated treatment in order to deliver a prostate boost after pelvic or peri-prostatic area irradiation. However, the clinical, biological and economical results must be precisely analyzed and could be assessed in the frame of a National Observatory based on shared therapeutic program.


Photoinduced C(sp3)-H Functionalization of Glycine Derivatives: Preparation of Unnatural α-Amino Acids and Late-Stage Modification of Peptides.
ConspectusPeptides are essential components of living systems and contribute to critical biological processes, such as cell proliferation, immune defense, tumor formation, and differentiation. Therefore, peptides have attracted considerable attention as targets for the development of therapeutic products. The incorporation of unnatural amino acid residues into peptides can considerably impact peptide immunogenicity, toxicity, side effects, water solubility, action duration, and distribution and enhance the peptides' druggability. Typically, the direct modification of natural amino acids is a practical and effective approach for promptly obtaining unnatural amino acids. However, selective functionalization of multiple C(sp3)-H bonds with comparable chemical reactivities in the peptide side chains remains a formidable challenge. Furthermore, chemical modifications aimed at highly reactive (nucleophilic and aromatic) groups on peptide side chains can interfere with the biological activity of peptides.In recent years, the rapid advancement of photoinduced radical reactions has made photoredox radical-radical cross-coupling a practical approach for constructing C(sp3)-C(sp3) bonds under mild conditions. Glycine, a naturally occurring amino acid and the fundamental skeleton of all α-amino acids, provides a basis for the alkylated modification of its own α-C(sp3)-H bond under mild conditions. This Account describes our recent research endeavors for systematically investigating the photocatalytic α-C(sp3)-H alkylation of glycine derivatives via radical-radical coupling between N-aryl glycinate-derived radicals and various alkyl radicals. In 2018, we disclosed the photoinduced Cu-catalyzed decarboxylative α-C(sp3)-H alkylation of glycine derivatives. Subsequently, we developed a catalyst-free method for alkylating glycine derivatives and glycine residues in peptides via electron donor-acceptor (EDA)-complex-promoted single electron transfer. Moreover, we developed a photoinduced method for the radical alkylation of N-aryl glycinate α-C(sp3)-H bonds using unactivated alkyl chlorides (iodides) under photocatalyst-free conditions. Notably, by building on racemic alkylations of glycine derivatives and glycine-residue-containing peptides, we recently stereoselectively alkylated the N-aryl glycinate α-C(sp3)-H bond using a dual-functional Cu catalyst generated in situ for synthesizing a series of unnatural chiral α-amino and C-glycoamino acids.We have developed a series of methods for synthesizing unnatural amino acids through the α-C(sp3)-H alkylation of glycine derivatives using photoredox-promoted radical coupling as a key strategy. These methods are efficient and versatile and can be used for the late-stage modification of peptides in various contexts. Our work builds on the fundamental importance of glycine as the basic scaffold of all α-amino acids and highlights the potential of radical-based chemistry for developing chemical transformations in peptide synthesis. These findings have broad implications for chemical biology and may open doors for discovering peptide drugs and developing therapeutics.


Copper-catalysed chemoselective C-OH bond activation of N-benzoyl cytosine: facile access to 2-(dimethylamino)pyrimidine.
A novel method for the direct amination of N-benzoyl cytosine has been developed, giving access to 2-(dimethylamino)pyrimidine derivatives. A copper(II) catalyst and tert-butyl hydroperoxide easily promote the selective amination process that proceeds via C-OH bond activation. This practical approach can utilize different formamide molecules, N,N-dimethylformamide and N,N-diethylformamide, as efficient amino (-NMe2, -NEt2) sources. Moreover, the facile nature of the procedure, its broad tolerance of aliphatic and aromatic substrates, the high yields and ease of separation of the products, and the fact that it can be conducted under aerobic conditions are all notable advantages of the present protocol.


A selective inhibitor of the immunoproteasome subunit LMP2 induces apoptosis in PC-3 cells and suppresses tumour growth in nude mice.
Although the proteasome is a validated anticancer target, the clinical application of its inhibitors has been limited because of inherent systemic toxicity. To broaden clinical utility of proteasome inhibitors as anticancer agents, it is critical to develop strategies to selectively target proteasomes in cancer cells. The immunoproteasome is an alternative form of the constitutive proteasome that is expressed at high levels in cancer tissues, but not in most normal cells in the body. To validate the immunoproteasome as a chemotherapeutic target, an immunoproteasome catalytic subunit LMP2-targeting inhibitor and siRNA were used. The sensitivity of PC-3 prostate cancer cells to these reagents was investigated using viability assays. Further, a xenograft model of prostate cancer was studied to test the in vivo effects of LMP2 inhibition. A small molecule inhibitor of the immunoproteasome subunit LMP2, UK-101, induced apoptosis of PC-3 cells and resulted in significant inhibition (~50-60%) of tumour growth in vivo. Interestingly, UK-101 did not block degradation of IκBα in PC-3 cells treated with TNF-α, suggesting that its mode of action may be different from that of general proteasome inhibitors, such as bortezomib, which block IκBα degradation. These results strongly suggest that the immunoproteasome has important roles in cancer cell growth and thus provide a rationale for targeting the immunoproteasome in the treatment of prostate cancer.


[Evaluation and analysis of cognitive function in chronic renal failure patients].
To explore the characteristics of cognitive impairment and correlation analysis in patients with chronic renal failure (CRF). The Addenbrooke's cognitive examination revised (ACE-R) scale was used to evaluate the cognitive function for 101 cases of chronic renal failure patients (group CRF) receiving outpatient and inpatient treatments and selected 30 individuals with normal renal function as normal controls (group NC) for cross-sectional analysis. T test, receiver operating characteristic (ROC) curve and other statistical methods were adopted for comparing differences. (1) Compared with group NC (83.4 ± 6.5), group CRF (71.9 ± 17.6) showed significantly statistical difference on Addenbrooke's cognitive examination revised (ACE-R) scale scores (P < 0.01); (2)compared with normal controls, the patients with CRF had significantly statistical difference on the scores of visual spatial ability (11.5 ± 3.2, 14.0 ± 3.0 respectively), language fluency (7.0 ± 2.6, 8.7 ± 1.9) (P < 0.01) and memory (18.1 ± 7.0, 21.5 ± 3.6 respectively) (P < 0.05); (3) the cognitive function of patients with CRF were significantly positive correlated with glomerular filtration rate (GFR) (r = 0.614, P < 0.01) and negatively correlated with the duration of illness (r = -0.492, P < 0.01); (4) From ROC curve and the area under curve (AUC), ACE-R scale (AUC = 0.680) showed a higher sensitivity than mini-mental state examination scale (AUC = 0.576) in assessing cognitive function in patients with CRF (P < 0.01). (1) Under similar basic conditions of age, level of education and background, CRF patients showed significant damage overall cognitive function, cognitive impairment in visual spatial ability, executive function, long-term memory and logical judgment ability was particularly impaired. Immediate and delayed memory, attention, orientation and language ability also manifested different degrees of decline; (2) the severity of cognitive impairment in patients with CFR was closely related with the level of GFR; (3) the ACE-R scale showed a higher sensitivity than mini-mental state examination scale in assessing cognitive function in patients with CRF.


Perceived health: age and sex comparisons in a community.
The need to find accurate and reliable indicators on which to base the planning, provision, and evaluation of health services gave impetus to the attempt to develop reliable and valid measures of the perceived health status of the consumers of health care. Subjective measures can provide an important complement to traditional statistics by giving direct access to the personal feelings of discomfort or distress that influence the use of health services. Such measures also give meaningful criteria for the evaluation of the efficacy of such services. Self assessments of health obtained from surveys and interviews have consistently found age and sex differences in the tendency to report symptoms, ill-health, disability, visits to doctors, and sickness absence. Many of these data, however, may have been misleading in using instruments of unknown or uncertain validity and reliability. Nevertheless, subjective assessments of health have been shown to have value and to add a dimension to objective measurements of health. They have been considered to be one of the better predictors of mortality and of adjustment to major episodes of illness.


Camera-based sample-position detection and control for microgravity electrostatic levitation.
This paper presents a method for high-speed sample detection and position control in an electrostatic levitator. The algorithm uses images acquired from two charge coupled device cameras and allows for robust and reliable detection of the sample position under various process conditions. The results show improvements over position sensitive detector systems especially under harsh environments and during autonomous operation under microgravity conditions. The position of samples with a radius from 0.6 mm to 1.1 mm is detected in three dimensions with an accuracy of ±40 μm inside a 7 mm × 7 mm × 7 mm levitation area. The two orthogonally arranged cameras, recording images at a resolution of 260 px × 260 px, are used to calculate the position every 5 ms. The control model and the corresponding position controller for the three axes are presented as well. The system was successfully tested in the laboratory and under microgravity conditions at the drop tower, during parabolic flights, and on the MAPHEUS sounding rocket.


[Ultrasonics and directional Doppler. Study of superficial phlebitis of the lower extremities].
The objective of the study was to evaluate the usefulness of ultrasonic methods: ultrasonography and Doppler C.W. in the diagnosis of superficial varicose phlebitis. Especially, measurement of the venous pressure (V.P.) at the posterior tibial (P.T.) and the greater saphenous vein (G.S.V.) in clino and orthostatism, have proved to be useful. In ten cases, one patient with a varicose in the thigh, was also found to have a femoral vein thrombosis secondary to a deep thrombus entering the junction. In conclusion, these non-invasive methods are advisable, especially in patients presenting a varicose phlebitis at the thigh.


Effects of Vegetable Oil Type and Lipophilic Emulsifiers on the Induction Period of Fat Crystallization.
The induction period of crystallization, which is defined as the time required for oil to start to crystallize, is useful indicator of the freeze-thaw stability of food emulsions such as mayonnaise. We investigated the induction period of vegetable oils with low melting points, such as rapeseed and soybean oils, which are commonly employed for mayonnaise production. The induction period was measured by monitoring the temperature of a specimen during storage at low temperature. The induction period depended on the type of oil and lipophilic emulsifier, emulsifier concentration, and storage temperature. The effect of the oil type on the induction period depended on the composition of the oil. Differential scanning calorimetry (DSC) analyses of the lipophilic emulsifiers suggested that the melting trend of the emulsifier is strongly related to the induction period.


Research Review: A guide to computing and implementing polygenic scores in developmental research.
The increasing availability of genotype data in longitudinal population- and family-based samples provides opportunities for using polygenic scores (PGS) to study developmental questions in child and adolescent psychology and psychiatry. Here, we aim to provide a comprehensive overview of how PGS can be generated and implemented in developmental psycho(patho)logy, with a focus on longitudinal designs. As such, the paper is organized into three parts: First, we provide a formal definition of polygenic scores and related concepts, focusing on assumptions and limitations. Second, we give a general overview of the methods used to compute polygenic scores, ranging from the classic approach to more advanced methods. We include recommendations and reference resources available to researchers aiming to conduct PGS analyses. Finally, we focus on the practical applications of PGS in the analysis of longitudinal data. We describe how PGS have been used to research developmental outcomes, and how they can be applied to longitudinal data to address developmental questions.


[Detection of a Williams Beuren syndrome case by MLPA].
Williams-Beuren syndrome (WBS) is a rare developmental disorder characterized by distinctive facial, neurobehavioral, and cardiovascular features. WBS is caused by a heterozygous contiguous gene microdeletion of the WBS crítical region on chromosome 7q11.23. Confirmation of clinical suspicion is essential for clinical monitoring of the patient and genetic counseling of the family. Fluorescence in situ hybridization (FISH) is considered the gold standard technique for detecting WBS. Multiplex ligation-dependent probe amplification (MLPA) has been introduced into DNA diagnostic laboratories for the detection of copy number variations in several diseases including WBS. The objective of this study was to confirm, by MLPA, the clinical diagnosis of WBS in a pediatric patient. This technique allowed to detect the deletion of CYLN2, FZD9, STX1A, ELN, LIMK1 and RFC2 genes. In geographic regions were the detection by FISH is not available for this disease, the MLPA methodology allowed to confirm the clinic diagnostic of WBS. To our knowledge this is the first report demonstrating the confirmation of WBS by MLPA in Argentina.


The Impacts of miRNAs in Glioblastoma Progression.
miRNAs are short noncoding RNA sequences that cause translational repression or mRNA degradation. A growing number of studies have sought new biomarkers in GBM that will be important in disease progression and prognosis and as potential therapeutic targets. miRNA-profiling studies in glioblastoma patients have found that aberrant miRNA expression can be used as a target to develop new biomarkers for disease detection and for determining prognosis or therapeutic response. In evaluating the tumor or its therapeutic response, genetic abnormalities such as mutations, epigenetic abnormalities, and aberrant miRNA expressions can be useful markers. This review summarizes the known miRNAs according their therapeutic importance and their use as disease progression biomarkers.


Deep sternal wound complications: an overview of old and new therapeutic options.
Deep sternal wound complications represent a significant problem in current open heart surgery and still pose a tremendous challenge to surgeons. Over the years, many treatment modalities have been proposed, but only few found their way into daily clinical practice of cardiothoracic surgeons. A gold standard has not been defined yet. This review was designed to give an overview of the preferred surgical strategies.


Fluid intake and colorectal cancer risk in the Netherlands Cohort Study.
Total fluid intake, specifically water intake, has been suggested to protect against colorectal cancer. We examined the association of total fluid intake with colorectal cancer endpoints and possible effect modification by fiber intake within the Netherlands Cohort Study (N = 120,852). We also investigated intake of specific beverages. After 13.3 yr, 1,443 male and 1,040 female colorectal cancer cases with complete baseline questionnaires were available for case-cohort analyses. Multivariate analyses showed no dose-response relationship of total fluid intake and intake of specific beverages with the risk of overall colorectal, proximal, and distal colon cancer. For rectal cancer risk in men, there was a nonsignificant positive trend for total fluid intake [> 1,500 vs. </= 1,000 ml/day: HR = 1.50, 95% CI = 0.95-2.37, P trend = 0.08) and a significant positive trend for coffee intake (> 6 vs. </= 2 cups/day: HR = 1.60, 95% CI = 0.96-2.66, P trend = 0.05). However, a nonsignificant positive trend for total fluid intake was no longer observed when additionally adjusting for coffee intake. Tests for interaction were not significant. In conclusion, total fluid intake was not associated with colorectal cancer risk in either men or women. There was no evidence that fiber intake modified associations. Of the specific beverages, coffee intake was positively associated with rectal cancer risk in men.


Dual or Single Antiplatelet Therapy After Transcatheter Aortic Valve Implantation? A Systematic Review and Meta-Analysis.
Transcatheter aortic valve implantation (TAVI) has undeniably earned a prestigious post in the quiver of interventional cardiologists against symptomatic severe aortic stenosis. Cerebrovascular events are listed within the most frequent complications. We performed a systematic search of EMBASE, MEDLINE, and the Cochrane library from inception to March 2016 for the following search terms (transcatheter AND antiplatelet) OR (transcatheter AND antithrombotic) to retrieve studies of dual antiplatelet treatment (DAPT) and single antiplatelet treatment (SAPT) in patients after TAVI to study thrombotic, hemorrhagic and cardiovascular events at 30 days post procedure. From a total of 208 records 4 studies met inclusion criteria. In the included studies, 286 patients were enrolled in the DAPT group and 354 patients in the SAPT group. There was no difference in all-cause mortality, cardiovascular mortality, stroke, and myocardial infraction 30 days post TAVI between DAPT and SAPT. However, patients in the DAPT group had a significantly increased incidence of lethal and major bleeding at 30 days of follow-up and the incidence of the combined end-point of stroke, spontaneous MI, all-cause mortality and major bleeding was significantly higher in the DAPT group in comparison to the SAPT group. DAPT compared to SAPT in patients after TAVI increases incidence of hemorrhagic events with no benefits in terms of thrombotic events and cardiovascular mortality. However, these data must be interpreted cautiously and the choice of DAPT over SAPT must be based on an individual patient characteristic according to medical practice criteria.


Structural Modification of the Antidepressant Mianserin Suggests That Its Anti-inflammatory Activity May Be Independent of 5-Hydroxytryptamine Receptors.
Antidepressants are increasingly recognized to have anti-inflammatory properties in addition to their ability to treat major depressive disorders. To explore if engagement of 5-hydroxytryptamine (5-HT) receptors was required for the anti-inflammatory effect of the tetracyclic antidepressant mianserin, a series of structural derivatives were generated with the aim of reducing 5-HT receptor binding. Primary human peripheral blood mononuclear cells were used to screen for anti-inflammatory activity. The lead compound demonstrated a significant loss in 5-HT receptor binding, as assessed by non-selective 5-HT binding of radiolabelled serotonin in rat cerebral cortex. However, it retained the ability to inhibit endosomal toll-like receptor 8 signaling in primary human macrophages and spontaneous cytokine production from human rheumatoid synovial tissue equivalent to that previously observed for mianserin. These data demonstrate that the anti-inflammatory mechanism of mianserin may be independent of 5-HT receptor activity. This research offers new insights into the mechanism and structural requirements for the anti-inflammatory action of mianserin.


Pericentrosomal targeting of Rab6 secretory vesicles by Bicaudal-D-related protein 1 (BICDR-1) regulates neuritogenesis.
Membrane and secretory trafficking are essential for proper neuronal development. However, the molecular mechanisms that organize secretory trafficking are poorly understood. Here, we identify Bicaudal-D-related protein 1 (BICDR-1) as an effector of the small GTPase Rab6 and key component of the molecular machinery that controls secretory vesicle transport in developing neurons. BICDR-1 interacts with kinesin motor Kif1C, the dynein/dynactin retrograde motor complex, regulates the pericentrosomal localization of Rab6-positive secretory vesicles and is required for neural development in zebrafish. BICDR-1 expression is high during early neuronal development and strongly declines during neurite outgrowth. In young neurons, BICDR-1 accumulates Rab6 secretory vesicles around the centrosome, restricts anterograde secretory transport and inhibits neuritogenesis. Later during development, BICDR-1 expression is strongly reduced, which permits anterograde secretory transport required for neurite outgrowth. These results indicate an important role for BICDR-1 as temporal regulator of secretory trafficking during the early phase of neuronal differentiation.


Molecular biology of Fanconi anaemia--an old problem, a new insight.
Fanconi anaemia (FA) comprises a group of autosomal recessive disorders resulting from mutations in one of eight genes (FANCA, FANCB, FANCC, FANCD1, FANCD2, FANCE, FANCF and FANCG). Although caused by relatively simple mutations, the disease shows a complex phenotype, with a variety of features including developmental abnormalities and ultimately severe anaemia and/or leukemia leading to death in the mid teens. Since 1992 all but two of the genes have been identified, and molecular analysis of their products has revealed a complex mode of action. Many of the proteins form a nuclear multisubunit complex that appears to be involved in the repair of double-strand DNA breaks. Additionally, at least one of the proteins, FANCC, influences apoptotic pathways in response to oxidative damage. Further analysis of the FANC proteins will provide vital information on normal cell responses to damage and allow therapeutic strategies to be developed that will hopefully supplant bone marrow transplantation.


Transmandibular approach to the malignant neoplasms of the mouth base, tongue root and oropharynx.
Tumors of the mouth basis, tongue root and oropharynx present a challenge for surgical treatment. High recurrence rates, poor survival, and significant postoperative alterations in speech and swallowing function are common experiences for patients with malignancies in these anatomic sites. This paper reviews the evaluation of displayed patients: pathologic features, surgical approaches and postoperative complications reported in recent managing patients with these neoplasms. A modification of usual surgical techniques has been used by the author to treat 30 tumors in this region and it is presented in this paper. Out of the 30 tumors, 4 were benign lesions and 26 were malignant neoplasms. Transmandibular approach was the method of choice. The wide field of access offers a lot of advantages: wide direct and indirect visualization, better manipulation, and good control of bleeding and light insertion of free and related composites used in primary reconstruction of postoperative defects.


[Hepatopulmonary syndrome: pathogenesis, diagnosis and treatment].
The hepatopulmonary syndrome is characterized by a clinical triad consisting of: 1) hepatic disease and/or portal hypertension, 2) intrapulmonary vascular dilatations, and 3) abnormal arterial oxygenations (partial oxygen pressure <70 mm Hg or an alveolar-arterial oxygen gradient >20 mm Hg). Its frequency varies according to the diagnostic methods used. To review the literature about the pathogeny, diagnosis and treatment of the hepatopulmonary syndrome. A survey of the more relevant Brazilian and international publications on the hepatopulmonary syndrome in MEDLINE. The prevalence of the hepatopulmonary syndrome ranges from 4% to 17.5% depending on the diagnostic criteria used. The most commonly associated liver disease is cirrhosis. The alveolar-arterial oxygen gradient seems to be the best parameter for the assessment of the abnormalities of arterial oxygenation. For the detection of intrapulmonary vascular dilatations, contrast echocardiography is the method of choice because it is of easy execution and it can differentiate between the intrapulmonary and intracardiac communications. In the treatment of hepatopulmonary syndrome, it was possible to reproduce and confirm few successful reports using pharmacological therapy and/or intervention radiology. At present, liver transplantation is considered to be the main therapeutic option for these patients, with encouraging results. The hepatopulmonary syndrome is a frequent disease that requires blood gas measurements for diagnosis. Liver transplantation is the treatment of choice for patients with the syndrome.


CD95 ligand: lethal weapon against malignant glioma?
CD95 (Fas/APO-1) and its ligand (CD95L) belong to a growing cytokine and cytokine receptor family that includes nerve growth factor (NGF) and tumor necrosis factor (TNF) and their corresponding receptors. CD95 expression increases during malignant progression from low-grade to anaplastic astrocytoma and is most prominent in perinecrotic areas of glioblastoma. There is, however, no evidence that CD95 expression in malignant gliomas is triggered by hypoxia or ischemia. Agonistic antibodies to CD95, or the natural ligand, CD95L, induce apoptosis in human malignant glioma cells in vitro. Glioma cell sensitivity to CD95-mediated apoptosis is regulated by CD95 expression at the cell surface and by the levels of intracellular apoptosis-regulatory proteins, including bcl-2 family members. Several cytotoxic drugs synergize with CD95L to kill glioma cells. For as yet unknown reasons, glioma cells may co-express CD95 and CD95L in vitro without undergoing suicide or fratricide. Yet, they kill T cells via CD95/CD95L interactions and are sensitive to exogenously added CD95L. Since CD95L is expressed in gliomas in vivo, too, forced induction of CD95 expression might promote therapeutic apoptosis in these tumors. That glioma cells differ from nontransformed T cells in their sensitivity to CD95 antibodies or recombinant ligand, may allow the development of selective CD95 agonists with high antitumor activity that spare normal brain tissue. A family of death ligand/receptor pairs related to CD95L/CD95, including APO2L (TRAIL) and its multiple receptors is beginning to emerge. Although several issues regarding glioma cell sensitivity to CD95L/CD95-mediated apoptosis await elucidation, CD95 is a promising target for the treatment of malignant glioma.


Microvascular architecture of the pampiniform plexus-testicular artery system in the rat: a scanning electron microscope study of corrosion casts.
The vascular architecture of the rat pampiniform plexus was studied by scanning electron microscopy of vascular corrosion casts. The plexus consists of a thick bundle of many anastomosing veins that entirely and closely surround the convoluted segments of the testicular artery. This specially developed close contact of the pampiniform plexus with the testicular artery may allow heat exchange between the plexus and the artery to maintain the cooled condition of the testis. The epididymal arteries are also closely surrounded by the networks of the epididymal veins. It is likely that heat exchange may operate even between these epididymal vessels. The ductus deferens is provided with no vascular channels for such heat exchange. A loose or coarse capillary network is always observed between the testicular artery and the pampiniform plexus. This network is supplied by the epididymal arteries and drains into the pampiniform plexus.


Batzelline D and isobatzelline E from the indopacific sponge Zyzzya fuliginosa.
Two new pyrroloquinoline alkaloids, isobatzelline E (1) and batzelline D (2), together with the known compounds batzelline C (3), isobatzelline C (4), and makaluvamine D (5), were isolated from an Indopacific collection of the marine sponge Zyzzya fuliginosa; the known compounds makaluvamines A (9), H (10), J (7), K (8), and P (6) were obtained from Z. fuliginosa collected in Papua New Guinea. The structures were elucidated by interpretation of 1D (1)H and (13)C NMR spectra and 2D HSQC and HSQC-LR spectra. Compounds 1-10 were isolated because the crude extracts of both Zyzzya species inhibited HIV-1 envelope-mediated cell fusion. However, the inhibition profile observed for the pure compounds 1-10 mirrors that reported for the inhibition of topoisomerase II by other pyrroloquinolines, leaving open the possibility that the activity results from interactions with DNA-modifying enzymes.


Lobodontia in the primary and permanent dentition: a condition requiring individualized care.
Lobodontia is a rarely documented dental condition associated with pointed or conical cusps on premolars and canines, multitubercular occlusal surfaces on molar teeth, and irregularly shaped incisors. Information on this uncommon condition continues to be scarce, with particularly little information available on the primary dentition. The purpose of this article is to describe 6 cases of lobodontia and discuss the variability in presentation and management. Previously unreported manifestations in the primary dentition are included. The cases described in the current study demonstrate the spectrum of clinical and radiographic features of the condition, and show that a varied, individualized approach to treatment is necessary.


Antioxidant enzymatic defences in human follicular fluid: characterization and age-dependent changes.
The aim of this work was to study the antioxidant enzymatic defences in human follicular fluid and investigate their possible changes during reproductive ageing. To this end, we tested the specific activities and protein expression of enzymes involved in reactive oxygen species (ROS) scavenging and in detoxification of ROS byproducts in follicular fluid from young (range 27-32 years, n = 12) and older (range 39-45 years, n = 12) women participating in an IVF programme. Results show that all the tested enzymes [superoxide dismutase (SOD), catalase, glutathione peroxidase, glutathione transferase, glutathione reductase] were significantly expressed in human follicular fluid. However, when the two age groups were compared, we found that follicular fluid from older women exhibited a reduced level of glutathione transferase and catalase activities and a higher level of SOD activity. Immunoblot analysis revealed that ageing was associated with decreased protein expression of GST Pi isoform and did not affect SOD and catalase protein expression. Taken together, these findings indicate that reproductive ageing is accompanied by a change in the antioxidant enzymatic pattern that could impair ROS scavenging efficiency in the follicular environment.


Implementing online consultations in primary care: a mixed-method evaluation extending normalisation process theory through service co-production.
To examine patient and staff views, experiences and acceptability of a UK primary care online consultation system and ask how the system and its implementation may be improved. Mixed-method evaluation of a primary care e-consultation system. Primary care practices in South West England. Qualitative interviews with 23 practice staff in six practices. Patient survey data for 756 e-consultations from 36 practices, with free-text survey comments from 512 patients, were analysed thematically. Anonymised patients' records were abstracted for 485 e-consultations from eight practices, including consultation types and outcomes. Descriptive statistics were used to analyse quantitative data. Analysis of implementation and the usage of the e-consultation system were informed by: (1) normalisation process theory, (2) a framework that illustrates how e-consultations were co-produced and (3) patients' and staff touchpoints. We found different expectations between patients and staff on how to use e-consultations 'appropriately'. While some patients used the system to try and save time for themselves and their general practitioners (GPs), some used e-consultations when they could not get a timely face-to-face appointment. Most e-consultations resulted in either follow-on phone (32%) or face-to-face appointments (38%) and GPs felt that this duplicated their workload. Patient satisfaction of the system was high, but a minority were dissatisfied with practice communication about their e-consultation. Where both patients and staff interact with technology, it is in effect 'co-implemented'. How patients used e-consultations impacted on practice staff's experiences and appraisal of the system. Overall, the e-consultation system studied could improve access for some patients, but in its current form, it was not perceived by practices as creating sufficient efficiencies to warrant financial investment. We illustrate how this e-consultation system and its implementation can be improved, through mapping the co-production of e-consultations through touchpoints.


High-Confidence Interactome for RNF41 Built on Multiple Orthogonal Assays.
Ring finger protein 41 (RNF41) is an E3 ubiquitin ligase involved in the ubiquitination and degradation of many proteins including ErbB3 receptors, BIRC6, and parkin. Next to this, RNF41 regulates the intracellular trafficking of certain JAK2-associated cytokine receptors by ubiquitinating and suppressing USP8, which, in turn, destabilizes the ESCRT-0 complex. To further elucidate the function of RNF41 we used different orthogonal approaches to reveal the RNF41 protein complex: affinity purification-mass spectrometry, BioID, and Virotrap. We combined these results with known data sets for RNF41 obtained with microarray MAPPIT and Y2H screens. This way, we establish a comprehensive high-resolution interactome network comprising 175 candidate protein partners. To remove potential methodological artifacts from this network, we distilled the data into a high-confidence interactome map by retaining a total of 19 protein hits identified in two or more of the orthogonal methods. AP2S1, a novel RNF41 interaction partner, was selected from this high-confidence interactome for further functional validation. We reveal a role for AP2S1 in leptin and LIF receptor signaling and show that RNF41 stabilizes and relocates AP2S1.


Mechanokinetics of rapid tension recovery in muscle: the Myosin working stroke is followed by a slower release of phosphate.
Crystallographic and biochemical evidence suggests that the myosin working stroke that generates force in muscle is accompanied by the release of inorganic phosphate (Pi), but the order and relative speed of these transitions is not firmly established. To address this problem, the theory of A. F. Huxley and R. M. Simmons for the length-step response is averaged over elastic strains imposed by filament structure and extended to include a Pi-release transition. Models of this kind are applied to existing tension-recovery data from length steps at different phosphate concentrations, and from phosphate jumps upon release of caged phosphate. This body of data is simulated by the model in which the force-generating event is followed by Pi release. A version in which the Pi-release transition is slow provides a better fit than a version with rapid Pi release and a slow transition preceding force generation. If Pi is released before force generation, the predicted rate of slow recovery increases with the size of the step, which is not observed. Some implications for theories of muscle contraction are discussed.


Developing a Substance Literacy Scale for Thai Population.
To develop a substance literacy scale for Thai population. The research design was divided into 8 steps as follows: 1) devising the items, 2) exploring construct validity of each factor 3) validating reliability of each factor, 4) generating construct validity of scale, 5) testing conceptual construct ofthe scale, 6) constructing alternated rating scales, 7) conducting cognitive test, and 8) conducting pilot test. There were 15 experts involved in the content validation of scale. The research was conducted with 3,824 samples of Thai population aged between 12-65 years old from all over the country using the Stratified Three Stages Cluster sampling technique. Two substance literacy scales were developed. A standard has questionnaire of 37 items. The scale content validity index was 0.65, concurrent validity was 0.648. A short has questionnaire of 32 items. The scale content validity index was 0.86, concurrent validity was 0.667. Both scales are simple and easy to use. Scale characteristics are appropriate to assess the substance literacy of population. It can be beneficial to planners for strategic development to respond to the problem more accurately.


Does the Use of Hair Dyes Increase the Risk of Developing Breast Cancer? A Meta-analysis and Review of the Literature.
Hair dye may contain mutagenic compounds which could be associated with an increased incidence of breast cancer in women who use it. The aim of this study was to examine the association between the personal use of hair dyes and the risk of breast cancer. We conducted a literature review of epidemiological studies reporting breast cancer-specific risks among hair dye users versus non-users. The data for the incidence of breast cancer following the 'ever' use of hair dye in studies which met the inclusion criteria was analysed using a meta-analysis. The relative risk ratio (RR) and 95% confidence intervals (CI) were determined. A total of eight case-control studies published between 1980 and 2017 met the selection criteria and were included in the meta-analysis. Compared to non-users, using a random effects model and the Duval and Tweedie's trim and fill procedure to adjust for publication bias in the presence of between studies heterogeneity, the adjusted RR for women using hair dyes was 1.1885 (95% CI=1.03228-1.36835). This indicates an 18.8% increased risk of future development of breast cancer among hair dye users. Although further work is required to confirm our results and clarify potential mechanisms, our findings suggest that exposure to hair dyes may contribute to an increased breast cancer risk.


Preschool vision screening using the MTI-Photoscreener.
Amblyopia is a condition that, if detected and treated early, can improve vision for most children. Thus, both pediatric and ophthalmologic groups have acknowledged the need for preschool vision screening. However, vision screening is the exception rather than the rule for preschoolers, since traditional methods of vision screening are often inappropriate for the preschool population and almost impossible for those children who are preverbal or nonverbal, developmentally delayed, and/or have chronic illnesses or disabilities. This study evaluated the use of a photoscreener to detect vision problems in a preschool population. Fifty-one children ages 3 to 5 years were evaluated using the MTI Photoscreener. Results were compared with a complete ophthalmologic examination, including cycloplegia. The sensitivity and specificity calculated for this study was 83% and 68%, respectively. Findings conclude that the MTI Photoscreener detected a broad range of vision problems, seemed to require less time, and seemed more acceptable to preschoolers when compared with the traditional vision screening methods performed by registered nurses. Although the sensitivity and specificity rates for this study were less than desired, it is likely that both could be improved with additional photo interpretation training.


Synthesis and enzymatic ketonization of the 5-(halo)-2-hydroxymuconates and 5-(halo)-2-hydroxy-2,4-pentadienoates.
5-Halo-2-hydroxymuconates and 5-halo-2-hydroxy-2,4-pentadienoates are stable dienols that are proposed intermediates in bacterial meta-fission pathways for the degradation of halogenated aromatic compounds. The presence of the halogen raises questions about how the bulk and/or electronegativity of these substrates would affect enzyme catalysis or whether some pathway enzymes have evolved to accommodate it. To address these questions, 5-halo-2-hydroxymuconates and 5-halo-2-hydroxy-2,4-pentadienoates (5-halo = Cl, Br, F) were synthesized and a preliminary analysis of their enzymatic properties carried out. In aqueous buffer, 5-halo-2-hydroxy-2,4-pentadienoates rapidly equilibrate with the β,γ-unsaturated ketones. For the 5-chloro and 5-bromo derivatives, a slower conversion to the α,β-isomers follows. There is no detectable formation of the α,β-isomer for the 5-fluoro derivative. Kinetic parameters were also obtained for both sets of compounds in the presence of 4-oxalocrotonate tautomerase (4-OT) from Pseudomonas putida mt-2 and Leptothrix cholodnii SP-6. For 5-halo-2-hydroxymuconates, there are no major differences in the kinetic parameters for the two enzymes (following the formation of the β,γ-unsaturated ketones). In contrast, the L. cholodnii SP-6 4-OT is ≈10-fold less efficient than the P. putida mt-2 4-OT in the formation of the β,γ-unsaturated ketones and the α,β-isomers from the 5-halo-2-hydroxy-2,4-pentadienoates. The implications of these findings are discussed. The availability of these compounds will facilitate future studies of the haloaromatic catabolic pathways.


Atypical Functional Connectivity of the Amygdala in Childhood Autism Spectrum Disorders during Spontaneous Attention to Eye-Gaze.
We examined functional connectivity of the amygdala in preadolescent children with Autism Spectrum Disorders (ASDs) during spontaneous attention to eye-gaze in emotional faces. Children responded to a target word ("LEFT/RIGHT") printed on angry or fearful faces looking in a direction that was congruent, incongruent, or neutral with the target word. Despite being irrelevant to the task, gaze-direction facilitated (Congruent > Neutral) or interfered with (Incongruent > Congruent) performance in both groups. Despite similar behavioral performance, amygdala-connectivity was atypical and more widespread in children with ASD. In control children, the amygdala was more strongly connected with an emotional cognitive control region (subgenual cingulate) during interference, while during facilitation, no regions showed greater amygdala connectivity than in ASD children. In contrast, in children with ASD the amygdala was more strongly connected to salience and cognitive control regions (posterior and dorsal cingulate) during facilitation and with regions involved in gaze processing (superior temporal sulcus), cognitive control (inferior frontal gyrus), and processing of viscerally salient information (pregenual cingulate, anterior insula, and thalamus) during interference. These findings showing more widespread connectivity of the amygdala extend past findings of atypical functional anatomy of eye-gaze processing in children with ASD and challenge views of general underconnectivity in ASD.


Binding of p110 retinoblastoma protein inhibits nuclear import of simian virus SV40 large tumor antigen.
Nuclear import of the simian virus 40 large tumor antigen (T-ag) is dependent on its nuclear localization signal (NLS) within amino acids 126-132 that is recognized by the importin alpha/beta1 heterodimer, as well as a protein kinase CK2 site at serine 112 upstream of the NLS, which enhances the interaction approximately 50-fold. Here we show for the first time that T-ag nuclear import is negatively regulated by N-terminal sequences (amino acids 102-110), which represent the binding site (BS) for the retinoblastoma (Rb) tumor suppressor protein (p110(Rb)). Quantitative confocal laser scanning microscopic analysis of the transport properties of T-ag constructs with or without Rb binding site mutations in living transfected cells or in a reconstituted nuclear transport system indicates that the presence of the RbBS significantly reduces nuclear accumulation of T-ag. A number of approaches, including the analysis of T-ag nuclear import in an isogenic cell pair with and without functional p110(Rb) implicate p110(Rb) binding as being responsible for the reduced nuclear accumulation, with the Ser(106) phosphorylation site within the RbBS appearing to enhance the inhibitory effect. Immunoprecipitation experiments confirmed association of T-ag and p110(Rb) and dependence thereof on negative charge at Ser(106). The involvement of p110(Rb) in modulating T-ag nuclear transport has implications for the regulation of nuclear import of other proteins from viruses of medical significance that interact with p110(Rb), and how this may relate to transformation.


Online or In-Class: Evaluating an Alternative Online Pedagogy for Teaching Transcultural Nursing.
Online learning formats are prevalent in current higher education. Given the changing student demographics and the drive for creativity in educating a technology-savvy student, it is imperative to incorporate innovative and alternative learning modalities to engage these students. This pilot study was designed as a quality improvement program evaluation comparing the effects of an online learning module with traditional classroom delivery of transcultural nursing content using a posttest two-group survey design in associate degree nursing students. The students' perceived knowledge and confidence were investigated after receiving the lecture for both the online and in-class groups. Data analysis revealed the online cohort perceived themselves as more knowledgeable concerning the ways that cultural factors influence nursing care, but not more confident in providing culturally competent care. Due to the students' perceived knowledge gain, this pilot study supports the use of online learning modules as being more effective than the traditional classroom delivery of transcultural nursing content. [J Nurs Educ. 2017;56(6):368-372.].


Contrast ultrasound versus ultrasound elastography for diagnosis of breast lumps: A cross-sectional study.
Chinese women have dense and small breasts. Therefore, in China, contrast ultrasound and ultrasound elastography are commonly used for detection of the breast lumps. Purpose of the study was to compare the sensitivity and accuracy of ultrasound elastography with contrast ultrasound for the diagnosis of the breast lumps.A total of 1000 women with a damp in breast mass, breast pain, nipple discharge, and/or breast skin discharge were subjected to contrast ultrasound and ultrasound elastography. Women were subjected to stereotactic vacuum-assisted biopsy under B-mode ultrasonography (n = 750). The ultrasound examinations were graded on a 5-points scale method. Data were subjected to the Chi-square Independence test at 99% of confidence level.Ultrasound elastography was detected the same numbers of benign lesions (648 vs 651, P = .88), malignant lesions (90 vs 99, P = .53), and false positive lesions (5 vs 0, P = .07) as those detected by biopsies. However, diagnostic parameters for contrast ultrasound had a significant difference with those detected by biopsies (P < .0001 for all). For contrast ultrasound and ultrasound elastography, the working area to detect deformation in the image of the breast lesions at least 1 time were 0% to 45% and 5% to 100%.Ultrasound elastography is the most reliable diagnostic method for detection of the breast lumps.


Carrier-Enhanced Anticancer Efficacy of Sunitinib-Loaded Green Tea-Based Micellar Nanocomplex beyond Tumor-Targeted Delivery.
Although a few nanomedicines have been approved for clinical use in cancer treatment, that recognizes improved patient safety through targeted delivery, their improved efficacy over conventional drugs has remained marginal. One of the typical drawbacks of nanocarriers for cancer therapy is a low drug-loading capacity that leads to insufficient efficacy and requires an increase in dosage and/or frequency of administration, which in turn increases carrier toxicity. In contrast, elevating drug-loading would cause the risk of nanocarrier instability, resulting in low efficacy and off-target toxicity. This intractable drug-to-carrier ratio has imposed constraints on the design and development of nanocarriers. However, if the nanocarrier has intrinsic therapeutic effects, the efficacy would be synergistically augmented with less concern for the drug-to-carrier ratio. Sunitinib-loaded micellar nanocomplex (SU-MNC) was formed using poly(ethylene glycol)-conjugated epigallocatechin-3-O-gallate (PEG-EGCG) as such a carrier. SU-MNC specifically inhibited the vascular endothelial growth factor-induced proliferation of endothelial cells, exhibiting minimal cytotoxicity to normal renal cells. SU-MNC showed enhanced anticancer effects and less toxicity than SU administered orally/intravenously on human renal cell carcinoma-xenografted mice, demonstrating more efficient effects on anti-angiogenesis, apoptosis induction, and proliferation inhibition against tumors. In comparison, a conventional nanocarrier, SU-loaded polymeric micelle (SU-PM) comprised of PEG-b-poly(lactic acid) (PEG-PLA) copolymer, only reduced toxicity with no elevated efficacy, despite comparable drug-loading and tumor-targeting efficiency to SU-MNC. Improved efficacy of SU-MNC was ascribed to the carrier-drug synergies with the high-performance carrier of PEG-EGCG besides tumor-targeted delivery.


Thermodynamic analysis of the low frequency relaxation time in the smectic A and C phases of a liquid crystal.
Pressure-temperature-volume (pVT) measurements were carried out on 2-(4-hexyloxyphenyl)-5-octyl-pyrimidine, a substance exhibiting nematic and smectic A and C polymorphism. Analysis of the longitudinal relaxation times obtained recently for elevated pressures [Czub et al., Z. Naturforsch. A: Phys. Sci. 58, 333 (2003)] was performed for isobaric, isothermal, and isochoric conditions within the two smectic phases. Several relationships linking the dynamical and thermodynamical quantities, derived recently for isotropic glass formers [Roland et al. Rep. Prog. Phys. 68, 1405 (2005)], were found to hold for the liquid crystal, revealing a striking similarity of behaviors for these two types of materials. The parameter gamma characterizing the steepness of the interaction potential was derived in different ways. It is interesting that the liquid crystal gives relaxation time versus TV(-gamma) plots that are linear, unlike results for glass formers, implying that the dynamics of the former is thermally activated.


Waldenstrom's macroglobulinaemia: to treat or not to treat?
Waldenstrom's macroglobulinaemia (WM) is a rare lymphoproliferative disorder. It is mostly seen in the elderly population with a median age of 65 years at the time of diagnosis. The clinical presentation is variable and the patient may be entirely asymptomatic. The slow progressive nature of the disease allows many patients to survive for more than 5 years. At times it may be difficult for a clinician to determine the timing of therapy. We present an interesting case of WM that highlights the typical course of the disease and timing of its management.


Sebocytes differentially express and secrete adipokines.
In addition to producing sebum, sebocytes link lipid metabolism with inflammation at a cellular level and hence, greatly resemble adipocytes. However, so far no analysis was performed to identify and characterize the adipocyte-associated inflammatory proteins, the members of the adipokine family in sebocytes. Therefore, we determined the expression profile of adipokines [adiponectin, interleukin (IL) 6, resistin, leptin, serpin E1, visfatin, apelin, chemerin, retinol-binding protein 4 (RBP4) and monocyte chemoattractant protein 1 (MCP1)] in sebaceous glands of healthy and various disease-affected (acne, rosacea, melanoma and psoriasis) skin samples. Sebaceous glands in all examined samples expressed adiponectin, IL6, resistin, leptin, serpin E1 and visfatin, but not apelin, chemerin, RBP4 and MCP1. Confirming the presence of the detected adipokines in the human SZ95 sebaceous gland cell line we further characterized their expression and secretion patterns under different stimuli mimicking bacterial invasion [by using Toll-like receptor (TLR)2 and 4 activators], or by 13-cis retinoic acid (13CRA; also known as isotretinoin), a key anti-acne agent. With the exception of resistin, the expression of all of the detected adipokines (adiponectin, IL6, leptin, serpin E1 and visfatin) could be further regulated at the level of gene expression, showing a close correlation with the secreted protein levels. Besides providing further evidence on similarities between adipocytes and sebocytes, our results strongly suggest that sebocytes are not simply targets of inflammation but may exhibit initiatory and modulatory roles in the inflammatory processes of the skin through the expression and secretion of adipokines.


Equilibrium model for insulin-induced receptor down-regulation. Regulation of insulin receptors in differentiated BC3H-1 myocytes.
The mechanism of insulin-induced down-regulation of surface membrane insulin receptors was studied in the muscle cell line BC3H-1. Down-regulation for the differentiated myocytes is dose- and time-dependent with a half-maximum response at 0.5 nM insulin and a maximum decrease of 50% in the number of surface insulin receptors following exposure to 20 nM insulin for 18 h at 37 degrees C, as confirmed by Scatchard analysis. These receptors were fully recoverable upon lysis of the down-regulated myocyte with Triton X-100, demonstrating that down-regulation is mediated solely by insulin-induced receptor internalization without detectable receptor degradation. Phospholipase C treatment of intact down-regulated cells and Triton X-100 treatment after subcellular fractionation showed that no cryptic or masked receptors were detectable within the plasma membrane. Insulin-induced receptor internalization was dependent upon cellular energy production, protein synthesis, and endocytosis, but was insensitive to agents which primarily affect lysosomal, cytoskeletal, or transglutaminase activities. The magnitude of insulin-induced down-regulation and the kinetics of down-regulation and recovery of cell surface receptors indicate that the surface and internal receptor pools are in dynamic equilibrium with each other. The kinetic data are accommodated by separate internalization rate constants for the unoccupied (0.01 h-1) and occupied (0.11 h-1) surface receptors and a single recycling rate constant (0.11 h-1) for the internalized receptors. This model also explains the previous apparently paradoxical finding in several other systems that down-regulation is more sensitive to hormone than hormone-receptor binding under physiologic conditions. Down-regulation in BC3H-1 myocytes, therefore, appears to be mediated solely by an insulin-induced increase in the receptor internalization rate constant and a consequent shift in the dynamic equilibrium between the surface and internalized receptor pools, resulting in a 50% decrease in the number of cell surface receptors. In other systems where the internalized hormone receptor is a substrate for rapid degradation, the essential role of this shift in mediating the down-regulation process may be obscured.


Return of the lysergamides. Part III: Analytical characterization of N6 -ethyl-6-norlysergic acid diethylamide (ETH-LAD) and 1-propionyl ETH-LAD (1P-ETH-LAD).
The psychoactive properties of lysergic acid diethylamide (LSD) have fascinated scientists across disciplines and the exploration of other analogues and derivatives has been motivated by deepening the understanding of ligand-receptor interactions at the molecular level as well as by the search for new therapeutics. Several LSD congeners have appeared on the new psychoactive substances (NPS) market in the form of blotters or powders. Examples include 1-propionyl-LSD (1P-LSD), AL-LAD, and LSZ. The absence of analytical data for novel compounds is a frequent challenge encountered in clinical and toxicological investigations. Two newly emerging lysergamides, namely N6 -ethyl-6-norlysergic acid diethylamide (ETH-LAD) and 1P-ETH-LAD, were characterized by gas chromatography-mass spectrometry (GC-MS), low and high mass accuracy electrospray MS(/MS), GC solid-state infrared analysis, high performance liquid chromatography diode array detection as well as nuclear magnetic resonance spectroscopy. Limited analytical data for ETH-LAD were previously available, whereas information about 1P-ETH-LAD has not previously been encountered in the scientific literature. This study extends the characterization of lysergamides distributed on the NPS market, which will help to make analytical data available to clinicians, toxicologists, and other stakeholders who are likely to encounter these substances. The analysis of a test incubation of 1P-ETH-LAD with human serum at 37°C by LC single quadrupole MS at various time points (0-6 h, once per hour and one measurement after 24 h) revealed the formation of ETH-LAD, suggesting that 1P-ETH-LAD might serve as a pro-drug. 1P-ETH-LAD was still detectable in serum after 24 h. Copyright © 2017 John Wiley & Sons, Ltd.


Performance of Ultrasound-Guided Core Biopsy Driven by FDG-avid Supraclavicular Lymph Nodes in Patients With Suspected Lung Cancer.
Ultrasound-guided core biopsy (UGCB) for supraclavicular lymph nodes (SLNs) represents an attractive procedure to obtain tissues for lung cancer confirmation. The aim of the present study is to evaluate the performance of UGCB driven by FDG-avid SLNs, as performed by nuclear medicine physicians, in patients with suspected lung cancer. Institutional database in our hospital was searched for eligible patients between September 2019 and March 2021. A 3-12 MHz linear probe was used to guide the biopsy process and to ensure that the needle tip was being directed at the metabolically active area that had been indicated by side-by-side PET/CT images. Diagnostic yield, malignancy rate, molecular testing results, and complications were reviewed. Among the 54 patients included in this study, definite pathological diagnosis from UGCB specimens was achieved in 53 patients, reaching a diagnostic yield of 98.1% (53/54) and a malignancy rate of 96.2% (51/53). Among the 50 patients confirmed as lung cancer, thirty-eight were spared from further invasive procedures which had been planned. Molecular analyses were adequately performed on all the 38 specimens obtained from non-small cell lung cancer (NSCLS). The positive rate was 36.8% (14/38) for epidermal growth receptor (EGFR) mutation and 31.6% (12/38) for anaplastic lymphoma kinase (ALK) translocation. 28.9% (11/38) of the patients had a tumor proportion score (TPS) ≥ 50% for PD-L1 expression. No complication was observed and the average biopsy time was 15 min. Nuclear medicine physicians-performed UGCB driven by FDG-avid SLNs in suspected lung cancer patients could produce a high performance in terms of diagnostic yield, malignancy rate, and molecular analysis, which may obliviate more invasive interventional procedures and lead to fast decisions on subsequent management.


Macromineral nutrition by heat stress interactions in dairy cattle: review and original research.
This paper examines whether or not responses of dairy cattle to various dietary macromineral elements differed in hot weather compared with thermoneutral conditions. The consequences of heat stress and the interrelationships of macromineral elements on feed intake, digestive function, use of dietary buffers, mineral element uptake from the portal-drained viscera, perturbation of acid-base physiology and related mineral element nutrition, effects of dietary macromineral element concentrations on lactational performance as affected by season, and influence of mineral elements in drinking water are reviewed, and new research results are presented. Dietary mineral buffers aided in alleviation of the decline in DMI and milk yield induced by heat stress. New research results showed that portal plasma flow declined with heat stress or by restriction of DMI in a thermoneutral environment and that uptake of P from the portal-drained viscera by lactating cows was reduced 50% by heat stress compared with that of cows with the same DMI in a thermoneutral environment. Accelerated respiration rate caused respiratory alkalosis and apparently compensated metabolic acidosis, changing the demand for Na and K during heat stress. There is need to characterize more accurately the nyctohemeral pattern of acid-base physiology in the heat-stressed lactating dairy cow and to relate it to macromineral element needs. A large data set (n = 1444 cow period means) was used to compare milk yield and DMI responses to varying dietary concentrations of P, Na, K, Cl, Ca, Mg, and cation-anion difference in summer compared with those in winter. Interactions of dietary concentrations of Cl, Ca, and Mg with season on DMI and K, Ca, and Mg with season on 4% FCM yield were detected. Interactions of Na by Cl, Na by P, and Cl by P with season on DMI and of Cl by P with season on 4% FCM yield were detected. High concentrations of sulfate and chloride in drinking water jeopardized productivity of cows during hot weather.