Divergence of IL-1, IL-18, and cell death in NLRP3 inflammasomopathies.
The inflammasome is a cytoplasmic multiprotein complex that promotes proinflammatory cytokine maturation in response to host- and pathogen-derived signals. Missense mutations in cryopyrin (NLRP3) result in a hyperactive inflammasome that drives overproduction of the proinflammatory cytokines IL-1β and IL-18, leading to the cryopyrin-associated periodic syndromes (CAPS) disease spectrum. Mouse lines harboring CAPS-associated mutations in Nlrp3 have elevated levels of IL-1β and IL-18 and closely mimic human disease. To examine the role of inflammasome-driven IL-18 in murine CAPS, we bred Nlrp3 mutations onto an Il18r-null background. Deletion of Il18r resulted in partial phenotypic rescue that abolished skin and visceral disease in young mice and normalized serum cytokines to a greater extent than breeding to Il1r-null mice. Significant systemic inflammation developed in aging Nlrp3 mutant Il18r-null mice, indicating that IL-1 and IL-18 drive pathology at different stages of the disease process. Ongoing inflammation in double-cytokine knockout CAPS mice implicated a role for caspase-1-mediated pyroptosis and confirmed that CAPS is inflammasome dependent. Our results have important implications for patients with CAPS and residual disease, emphasizing the need to explore other NLRP3-mediated pathways and the potential for inflammasome-targeted therapy.


Dual-energy computed tomography-based iodine concentration as a predictor of histopathological response to preoperative chemoradiotherapy for pancreatic cancer.
To explore predictors of the histopathological response to preoperative chemoradiotherapy (CRT) in patients with pancreatic cancer (PC) using dual-energy computed tomography-reconstructed images. This retrospective study divided 40 patients who had undergone preoperative CRT (50-60 Gy in 25 fractions) followed by surgical resection into two groups: the response group (Grades II, III and IV, evaluated from surgical specimens) and the nonresponse group (Grades Ia and Ib). The computed tomography number [in Hounsfield units (HUs)] and iodine concentration (IC) were measured at the locations of the aorta, PC and pancreatic parenchyma (PP) in the contrast-enhanced 4D dual-energy computed tomography images. Logistic regression analysis was performed to identify predictors of histopathological response. Univariate analysis did not reveal a significant relation between any parameter and patient characteristics or dosimetric parameters of the treatment plan. The HU and IC values in PP and the differences in HU and IC between the PP and PC (ΔHU and ΔIC, respectively) were significant predictors for distinguishing the response (n = 24) and nonresponse (n = 16) groups (P < 0.05). The IC in PP and ΔIC had a higher area under curve values [0.797 (95% confidence interval, 0.659-0.935) and 0.789 (0.650-0.928), respectively] than HU in PP and ΔHU [0.734 (0.580-0.889) and 0.721 (0.562-0.881), respectively]. The IC value could potentially be used for predicting the histopathological response in patients who have undergone preoperative CRT.


Pregnancy, Proteinuria, Plant-Based Supplemented Diets and Focal Segmental Glomerulosclerosis: A Report on Three Cases and Critical Appraisal of the Literature.
Chronic kidney disease (CKD) is increasingly recognized in pregnant patients. Three characteristics are associated with a risk of preterm delivery or small for gestational age babies; kidney function reduction, hypertension, and proteinuria. In pregnancy, the anti-proteinuric agents (ACE-angiotensin converting enzyme-inhibitors or ARBS -angiotensin receptor blockers) have to be discontinued for their potential teratogenicity, and there is no validated approach to control proteinuria. Furthermore, proteinuria usually increases as an effect of therapeutic changes and pregnancy-induced hyperfiltration. Based on a favourable effect of low-protein diets on proteinuria and advanced CKD, our group developed a moderately protein-restricted vegan-vegetarian diet tsupplemented with ketoacids and aminoacids for pregnant patients. This report describes the results obtained in three pregnant patients with normal renal function, nephrotic or sub-nephrotic proteinuria, and biopsy proven diagnosis of focal segmental glomerulosclerosis, a renal lesion in which hyperfiltration is considered of pivotal importance (case 1: GFR (glomerular filtration rate): 103 mL/min; proteinuria 2.1 g/day; albumin 3.2 g/dL; case 2: GFR 86 mL/min, proteinuria 3.03 g/day, albumin 3.4 g/dL; case 3: GFR 142 mL/min, proteinuria 6.3 g/day, albumin 3.23 g/dL). The moderately restricted diet allowed a stabilisation of proteinuria in two cases and a decrease in one. No significant changes in serum creatinine and serum albumin were observed. The three babies were born at term (38 weeks + 3 days, female, weight 3180 g-62th centile; 38 weeks + 2 days, female, weight 3300 g-75th centile; male, 38 weeks + 1 day; 2770 g-8th centile), thus reassuring us of the safety of the diet. In summary, based on these three cases studies and a review of the literature, we suggest that a moderately protein-restricted, supplemented, plant-based diet might contribute to controlling proteinuria in pregnant CKD women with focal segmental glomerulosclerosis. However further studies are warranted to confirm the potential value of such a treatment strategy.


The QKI-6 and QKI-7 RNA binding proteins block proliferation and promote Schwann cell myelination.
The quaking viable (qk(v)) mice have uncompacted myelin in their central and peripheral nervous system (CNS, PNS). The qk gene encodes 3 major alternatively spliced isoforms that contain unique sequence at their C-terminus dictating their cellular localization. QKI-5 is a nuclear isoform, whereas QKI-6 and QKI-7 are cytoplasmic isoforms. The qk(v) mice harbor an enhancer/promoter deletion that prevents the expression of isoforms QKI-6 and QKI-7 in myelinating cells resulting in a dysmyelination phenotype. It was shown that QKI regulates the differentiation of oligodendrocytes, the myelinating cells of the CNS, however, little is known about the role of the QKI proteins, or RNA binding proteins in PNS myelination. To define the role of the QKI proteins in PNS myelination, we ectopically expressed QKI-6 and QKI-7 in primary rat Schwann cell/neuron from dorsal root ganglia cocultures. We show that the QKI isoforms blocked proliferation and promoted Schwann cell differentiation and myelination. In addition, these events were coordinated with elevated proteins levels of p27(KIP1) and myelin basic protein (MBP), markers of Schwann cell differentiation. QKI-6 and QKI-7 expressing co-cultures contained myelinated fibers that had directionality and contained significantly thicker myelin, as assessed by electron microscopy. Moreover, QKI-deficient Schwann cells had reduced levels of MBP, p27(KIP1) and Krox-20 mRNAs, as assessed by quantitative RT-PCR. Our findings suggest that the QKI-6 and QKI-7 RNA binding proteins are positive regulators of PNS myelination and show that the QKI RNA binding proteins play a key role in Schwann cell differentiation and myelination.


Rapid Analysis and Authentication of Meat Using the MasSpec Pen Technology.
Food authenticity and safety are major public concerns due to the increasing number of food fraud cases. Meat fraud is an economically motivated practice of covertly replacing one type of meat with a cheaper alternative raising health, safety, and ethical concerns for consumers. In this study, we implement the MasSpec Pen technology for rapid and direct meat analysis and authentication. The MasSpec Pen is an easy-to-use handheld device connected to a mass spectrometer that employs a solvent droplet for gentle chemical analysis of samples. Here, MasSpec Pen analysis was performed directly on several meat and fish types including grain-fed beef, grass-fed beef, venison, cod, halibut, Atlantic salmon, sockeye salmon, and steelhead trout, with a total analysis time of 15 s per sample. Statistical models developed with the Lasso method using a training set of samples yielded per-sample accuracies of 95% for the beef model, 100% for the beef versus venison model, and 84% for the multiclass fish model. Predictors of meat type selected included several molecules previously reported in the skeletal muscles of animals, including carnosine, anserine, succinic acid, xanthine, and taurine. When testing the models on independent test sets of samples, per-sample accuracies of 100% were achieved for all models, demonstrating the robustness of our method for unadulterated meat authentication. MasSpec Pen feasibility testing for classifying venison and grass-fed beef samples adulterated with grain-fed beef achieved per-sample prediction accuracies of 100% for both classifiers using test sets of samples. Altogether, the results obtained in this study provide compelling evidence that the MasSpec Pen technology is a powerful alternative analytical method for meat analysis and investigation of meat fraud.


Molecular mechanisms controlling midline crossing by precerebellar neurons.
Precerebellar neurons of the inferior olive (IO) and lateral reticular nucleus (LRN) migrate tangentially from the rhombic lip toward the floor plate following parallel pathways. This process is thought to involve netrin-1 attraction. However, whereas the cell bodies of LRN neurons cross the midline, IO neurons are unable to do so. In many systems and species, axon guidance and cell migration at the midline are controlled by Slits and their receptor Robos. We showed previously that precerebellar axons and neurons do not cross the midline in the absence of the Robo3 receptor. To determine whether this signaling by Slits and the two other Robo receptors, Robo1 and Robo2, also regulates precerebellar neuron behavior at the floor plate, we studied the phenotype of Slit1/2 and Robo1/2/3 compound mutants. Our results showed that many IO neurons can cross the midline in absence of Slit1/2 or Robo1/2, supporting a role for midline repellents in guiding precerebellar neurons. We also show that these molecules control the development of the lamellation of the inferior olivary complex. Last, the analysis of Robo1/2/3 triple mutants suggests that Robo3 inhibits Robo1/2 repulsion in precrossing LRN axons but not in IO axons in which it has a dominant and distinct function.


Pressure-limited sustained inflation vs. gradual tidal inflations for resuscitation in preterm lambs.
Support of the mechanically complex preterm lung needs to facilitate aeration while avoiding ventilation heterogeneities: whether to achieve this gradually or quickly remains unclear. We compared the effect of gradual vs. constant tidal inflations and a pressure-limited sustained inflation (SI) at birth on gas exchange, lung mechanics, gravity-dependent lung volume distribution, and lung injury in 131-day gestation preterm lambs. Lambs were resuscitated with either 1) a 20-s, 40-cmH2O pressure-limited SI (PressSI), 2) a gradual increase in tidal volume (Vt) over 5-min from 3 ml/kg to 7 ml/kg (IncrVt), or 3) 7 ml/kg Vt from birth. All lambs were subsequently ventilated for 15 min with 7 ml/kg Vt with the same end-expiratory pressure. Lung mechanics, gas exchange and spatial distribution of end-expiratory volume (EEV), and tidal ventilation (electrical impedance tomography) were recorded regularly. At 15 min, early mRNA tissue markers of lung injury were assessed. The IncrVt group resulted in greater tissue hysteresivity at 5 min (P = 0.017; two-way ANOVA), higher alveolar-arterial oxygen difference from 10 min (P < 0.01), and least uniform gravity-dependent distribution of EEV. There were no other differences in lung mechanics between groups, and the PressSI and 7 ml/kg Vt groups behaved similarly throughout. EEV was more uniformly distributed, but Vt least so, in the PressSI group. There were no differences in mRNA markers of lung injury. A gradual increase in Vt from birth resulted in less recruitment of the gravity-dependent lung with worse oxygenation. There was no benefit of a SI at birth over mechanical ventilation with 7 ml/kg Vt.


Transfection of Escherichia coli spheroplasts: infectious lambda prophage DNA.
High mol. wt. DNA was extracted from Escherichia coli lambda lysogens and was shown to be infectious. Its infectivity was due to prophage DNA integrated into the host chromosome rather than to DNA released from mature phage particles, as established by the following criteria: the titre of infectious DNA exceeded by 100-fold the titre of infectious units present before DNA extraction; mild shear selectively reduced prophage DNA infectivity to 2% of the unsheared DNA while lambda phage DNA infectivity retained 50% of its infectivity; DNA extracted from an E. coli (lambda c857 tsxisam6) lysogen yielded 200 times as many plaques on sup+ than on sup- spheroplasts. Thus lambda prophage DNA infectivity depends on expression of the excision gene while the infectivity of non-integrated forms of lambda does not. About 10(4) genome equivalents of E. coli DNA yielded one infectious centre unit in this assay system; this high infectivity should make prophage DNA a useful marker in genetic transformation experiments.


Effects of cinacalcet treatment on QT interval in hemodialysis patients.
Cinacalcet is a calcimimetic drug that acts via calcium-sensing receptors (CaSRs) and increases the sensitivity of CaSRs on the parathyroid gland; thus, it lowers calcium and phosphorus levels as well as parathormone levels. Prolongation of the QT interval is recognized as a risk factor for the development of ventricular arrhythmias and sudden death. Patients with end-stage renal disease (ESRD) are sensitive for QT prolongation and torsade de pointes more than the normal population. In this study, we aimed to evaluate the effects of cinacalcet on the electrocardiogram (ECG), particularly changes in the QT interval, in patients with ESRD. Thirty-seven patients (21 males and 16 females) undergoing maintenance hemodialysis for at least 12 months were included in this retrospective study. Patients receiving cardioactive and antiarrhythmic drugs and those having a history of any cardiac or cerebrovascular events, active malignancy, and infections were excluded. Baseline ECG measurements of patients were performed over the newest ECG measurements that were obtained within 1 month before initiating the cinacalcet treatment, and the ECG measurements of patients after the cinacalcet treatment were performed according to the most recent ECG that was taken within the last 1 week in the clinic. We recorded the heart rate and QT values of patients before and after treatment and then calculated the corrected QT values (QTc). The Statistical Package for the Social Sciences (SPSS) ver. 21.0 was used for statistical analysis. The mean age of patients was 52.24±14.49 years. Prolongation of QTc was statistically significant compared with the baseline QTc value (baseline: 396.62±42.04 msec; after treatment: 404.97±43.47 msec; p=0.031). We found a positive correlation between the prolongation of QTc and treatment dose of cinacalcet (p<0.005, r=0.560). Clinicians should be very careful for life threatening cardiac side effects while increasing the dose of cinacalcet treatment in hemodialysis patients who have a borderline or prolonged QTc interval.


Sec35p, a novel peripheral membrane protein, is required for ER to Golgi vesicle docking.
SEC35 was identified in a novel screen for temperature-sensitive mutants in the secretory pathway of the yeast Saccharomyces cerevisiae (. Genetics. 142:393-406). At the restrictive temperature, the sec35-1 strain exhibits a transport block between the ER and the Golgi apparatus and accumulates numerous vesicles. SEC35 encodes a novel cytosolic protein of 32 kD, peripherally associated with membranes. The temperature-sensitive phenotype of sec35-1 is efficiently suppressed by YPT1, which encodes the rab-like GTPase required early in the secretory pathway, or by SLY1-20, which encodes a dominant form of the ER to Golgi target -SNARE-associated protein Sly1p. Weaker suppression is evident upon overexpression of genes encoding the vesicle-SNAREs SEC22, BET1, or YKT6. The cold-sensitive lethality that results from deleting SEC35 is suppressed by YPT1 or SLY1-20. These genetic relationships suggest that Sec35p acts upstream of, or in conjunction with, Ypt1p and Sly1p as was previously found for Uso1p. Using a cell-free assay that measures distinct steps in vesicle transport from the ER to the Golgi, we find Sec35p is required for a vesicle docking stage catalyzed by Uso1p. These genetic and biochemical results suggest Sec35p acts with Uso1p to dock ER-derived vesicles to the Golgi complex.


Inhibitory effects of Rubi Fructus extracts on hepatic steatosis development in high-fat diet-induced obese mice.
The present study was performed to investigate the potential effects of the unripened dried fruit of Rubus coreanus Miq., Rubi Fructus (RF), on hepatic steatosis and lipid metabolism in mice fed with a high-fat diet (HFD) known to induce obesity and hyperlipidaemia. Rubi Fructus extract (RFex) fed mice demonstrated a reduced body weight and adipose tissue weight. RFex fed mice also demonstrated decreased aminotransferase levels, lipid contents [triglyceride (TG), total cholesterol (TC) and low-density lipoprotein-cholesterol (LDL-C)], leptin content and increased high‑density lipoprotein-cholesterol (HDL‑C) contents in the plasma. These effects were accompanied by a decreased expression of lipogenic genes, including sterol regulatory element binding protein-1c, liver X receptor, fatty acid synthase (FAS), acetyl‑CoA carboxylase, cluster of differentiation 36, lipoprotein lipase and decreased lipogenic enzyme FAS and 3-hydroxy-3 methylglutamyl coenzyme reductase enzyme activities, while elevating carnitine palmitoyltrasferase-1 activity. Based on these results, the present study hypothesized that the inhibitory effect on hepatic steatosis of RFex is the result of the suppression of lipid synthesis in mice fed with HFD, suggesting that RFex may be beneficial in preventing hepatic steatosis and liver lipotoxicity.


Uptake and internalization of exogenous apolipoprotein E3 by cultured human central nervous system neurons.
Apolipoprotein E (apoE) has been confirmed as a risk factor for late-onset Alzheimer's disease (AD) and is associated with neurofibrillary tangles and senile plaques, the microscopic pathological characteristics of AD. There has been no direct evidence that human central nervous system neurons can take up and internalize exogenous apoE, which may be important in order for apoE to be involved in the development of the disease. This paper demonstrates by immunohistochemistry and confocal microscopy that cultured human brain neurons can take up and internalize exogenous recombinant human apoE3. We confirm that neurons express the low-density lipoprotein receptor-related protein (LRP) but do not express the low-density lipoprotein receptor. We also demonstrate that the LRP mediates the neuronal uptake of apoE.


[Laboratory and clinical investigation of lysis centrifugation blood culture method for fungemia].
We compared the lysis centrifugation blood culture system using Isolator (Du Pont) to the conventional blood culture bottle using BCB system (Roch), and the following results were obtained. In the investigation of experimental fungemia made by human blood and Candida albicans, the organism was detected 9/12 after 1 day and 11/12 after 3 days by Isolator, although the organism was detected 3/12 after 3 days and 11/12 after 6 days by the culture bottle system. In the experimental fungemia of Candida tropicalis, the organism was detected 12/12 after 2 days by Isolator, although it was detected 1/12 after 6 days and 4/12 after 10 days with the culture bottle system. Isolator showed faster and a more sensitive detection rate for fungemia. Clinical investigation of 94 cases (180 cultures) showed a 11.1% isolation rate with Isolator system and a 7.1% isolation rate with the culture bottle system. In 43 cases which were examined by the both systems, 7 cases were positive with Isolator, 3 positive with culture bottle. The culture bottle system isolated only Candida albicans and Candida parapsilosis, where as the Isolator isolated Candida albicans, Candida parapsilosis, Candida tropicalis, Candida krusei, and Candida spp. This investigation suggested that the Isolator system was an excellent method for the detection of fungemia.


Association of breastfeeding intensity and bottle-emptying behaviors at early infancy with infants' risk for excess weight at late infancy.
Our goal was to test the hypothesis that infants who were breastfed more intensively during early infancy (< or = 6 months) will be less likely to have excess weight during late infancy (> 6 months) and to examine the independent impact of infant-initiated bottle emptying and mothers' encouragement of bottle emptying on infants' risk for excess weight. The sample consisted of 1896 mothers who participated in postpartum surveys of the Infant Feeding Practice Study II and who provided at least 1 weight measurement of their infants during the second half of infancy. We used multiple logistic regression models to assess the association between infants' risks for excess weight during the second half of infancy and 3 self-reported feeding practices during the first half of infancy after adjusting for a series of sociodemographic characteristics. The early feeding practices examined included the percentage of all milk feedings in which infants consumed breast milk (breastfeeding intensity), the frequency of bottle feedings in which infants initiated bottle emptying, and the frequency of bottle feedings in which mothers encouraged bottle emptying. Infants fed with low (< 20% of milk feeds being breast milk) and medium (20%-80%) breastfeeding intensity in the first half of infancy were at least 2 times more likely to have excess weight during the second half of infancy than those breastfed at high intensity (> 80%). Infants who often emptied bottles in early infancy were 69% more likely than those who rarely emptied bottles to have excess weight during late infancy. However, mothers' encouragement of bottle emptying was negatively associated with their infants' risk for excess weight during the second half of infancy. Infants' risk for excess weight during late infancy was negatively associated with breastfeeding intensity but positively associated with infant-initiated bottle emptying during early infancy. These findings not only provide evidence for the potential risk of not breastfeeding or breastfeeding at a low intensity in development of childhood obesity, but they also suggest that infant-initiated bottle emptying may be an independent risk factor as well.


Anthracycline-induced cardiotoxicity in children with cancer: strategies for prevention and management.
The fact that anthracyclines are cardiotoxic seriously narrows their therapeutic index in cancer therapy. The cardiotoxic risk increases with the cumulative dose and may lead to congestive heart failure (CHF) and dilated cardiomyopathy in adults and in children. The prevention of anthracycline-induced cardiotoxicity is particularly important in children who can be expected to survive for decades after being cured of their malignancy. Attempts to reduce anthracycline cardiotoxicity have been directed towards: (i) decreasing myocardial concentrations of anthracyclines and their metabolites by dose limitation and schedule modification; (ii) developing less cardio-toxic analogs; and (iii) concurrently administering cardioprotective agents to attenuate the effects of anthracyclines on the heart. As regards schedule modification, avoidance of anthracycline peak levels may reduce the pathologic and clinical cardiotoxicity, although this has not always been observed. The analogs of doxorubicin, such as idarubicin and epirubicin, have similar cardiotoxicity to that of doxorubicin when given in amounts of equivalent myelotoxicity. Liposomal anthracyclines are a new class of agents that may permit more specific organ targeting, thereby producing less systemic and cardiac toxicity, but more studies are required to assess the advantages, if any, of these preparations over classical anthracyclines. The cardioprotective agent, dexrazoxane, an iron chelator, is highly effective and provides short-term cardioprotection to most patients receiving even the most intensive doxorubicin-containing regimens. Its long-term benefits remain to be determined. In addition, data remain insufficient to make specific recommendations regarding current use of dexrazoxane in children. It is thought that subtle abnormalities, related to anthracycline treatment in childhood, can develop into more permanent myocardial disease resulting in cardiomyopathy, which may progress to CHF. As regards the therapy of patients with anthracycline cardiotoxicity, two different situations have, therefore, to be considered: (i) if the patient presents with cardiac abnormalities, such as a reduction in fractional shortening at echocardiogram, without cardiac symptoms; and (ii) if the patient has CHF. In the presence of CHF, recovery with digitalis-diuretic therapy alone seldom occurs, and in patients who have refractory hemodynamic decompensation, heart transplantation is indicated. In patients with CHF, therapy with ACE inhibitors induces improvement in left ventricular structure and function, but this improvement is transient. Randomized clinical trials are, therefore, necessary to determine the effects of ACE inhibitors in mild-to-moderate left ventricular dysfunction. The beneficial effects of beta-adrenoceptor antagonists (beta-blockers) on cardiac function in heart failure due to anthracyclines seem comparable with those observed in other forms of heart failure with systolic dysfunction. Many drugs are available to treat children with CHF due to anthracycline treatment, but they are only palliative.


Mammary tumors that become independent of the type I insulin-like growth factor receptor express elevated levels of platelet-derived growth factor receptors.
Targeted therapies are becoming an essential part of breast cancer treatment and agents targeting the type I insulin-like growth factor receptor (IGF-IR) are currently being investigated in clinical trials. One of the limitations of targeted therapies is the development of resistant variants and these variants typically present with unique gene expression patterns and characteristics compared to the original tumor. MTB-IGFIR transgenic mice, with inducible overexpression of the IGF-IR were used to model mammary tumors that develop resistance to IGF-IR targeting agents. IGF-IR independent mammary tumors, previously shown to possess characteristics associated with EMT, were found to express elevated levels of PDGFRα and PDGFRβ. Furthermore, these receptors were shown to be inversely expressed with the IGF-IR in this model. Using cell lines derived from IGF-IR-independent mammary tumors (from MTB-IGFIR mice), it was demonstrated that PDGFRα and to a lesser extent PDGFRβ was important for cell migration and invasion as RNAi knockdown of PDGFRα alone or PDGFRα and PDGFRβ in combination, significantly decreased tumor cell migration in Boyden chamber assays and suppressed cell migration in scratch wound assays. Somewhat surprisingly, concomitant knockdown of PDGFRα and PDGFRβ resulted in a modest increase in cell proliferation and a decrease in apoptosis. During IGF-IR independence, PDGFRs are upregulated and function to enhance tumor cell motility. These results demonstrate a novel interaction between the IGF-IR and PDGFRs and highlight an important, therapeutically relevant pathway, for tumor cell migration and invasion.


Unlocking the EGFR-mediated epitranscriptome: A pathway to novel therapies.
In this issue, Lv et al.1 explore EGFR-driven epitranscriptomic reprogramming in glioblastoma, revealing the pivotal role of the EGFR-ALKBH5-GCLM axis in ferroptosis protection. Their findings offer mechanistic insight and therapeutic strategies involving novel combination targets to enhance tumor responses.


Acute exposure to GH during exercise stimulates the turnover of free fatty acids in GH-deficient men.
The secretion of growth hormone (GH) increases acutely during exercise, but whether this is associated with the concomitant alterations in substrate metabolism has not previously been studied. We examined the effects of acute GH administration on palmitate, glucose, and protein metabolism before, during, and after 45 min of moderate-intensity aerobic exercise in eight GH-deficient men (mean age = 40.8 +/- 2.9 yr) on two occasions, with (+GH; 0.4 IU GH) and without GH administered (-GH). A group of healthy controls (n = 8, mean age = 40.4 +/- 4.2 yr) were studied without GH. The GH replacement during exercise on the +GH study mimicked the endogenous GH profile seen in healthy controls. No significant difference in resting free fatty acid (FFA) flux was found between study days, but during exercise a greater FFA flux was found when GH was administered (211 +/- 26 vs. 168 +/- 28 micromol/min, P < 0.05) and remained elevated throughout recovery (P < 0.05). With GH administered, the exercise FFA flux was not significantly different from that observed in control subjects (188 +/- 14 micromol/min), but the recovery flux was greater on the +GH day than in the controls (169 +/- 17 vs. 119 +/- 11 micromol/min, respectively, P < 0.01). A significant time effect (P < 0.01) for glucose rate of appearance from rest to exercise and recovery occurred in the GH-deficient adults and the controls, whereas there were no differences in glucose rate of disappearance. No significant effect across time was found for protein muscle balance. In conclusion, 1) acute exposure to GH during exercise stimulates the FFA release and turnover in GH-deficient adults, 2) GH does not significantly impact glucose or protein metabolism during exercise, and 3) the exercise-induced secretion of GH plays a significant role in the regulation of fatty acid metabolism.


The role of autonomy needs in suicidal ideation: integrating the interpersonal-psychological theory of suicide and self-determination theory.
This study investigated the role of autonomy satisfaction in the development of suicidal ideation by integrating two theoretical models of suicide-related behaviors. The first hypothesized a direct effect of autonomy on suicidal ideation. The second hypothesized an indirect effect of autonomy on suicidal ideation via perceived burdensomeness and thwarted belongingness. This was a cross-sectional study of 449 college students, who were predominantly female (73.1%) and Hispanic (70.6%), with a mean age of 20.40 years (SD = 4.38, range 18-50 years). Participants were recruited from a psychology participant pool and completed self-report survey measures for course credit. The model of indirect effects provided the best fit to the data; relatedness, autonomy, and competence were significantly associated with higher thwarted belongingness and perceived burdensomeness, which, in turn, were significantly associated with higher suicidal ideation. Future studies should test this model longitudinally and consider autonomy as a possible avenue for the prevention of suicide-related behaviors.


Tocilizumab Is Associated with Increased Risk of Fungal Infections among Critically Ill Patients with COVID-19 and Acute Renal Failure: An Observational Cohort Study.
Does treatment with tocilizumab increase the risk of a fungal infection in critically ill patients with coronavirus-19? Numerous therapies have been evaluated as possible treatments for coronavirus-2019 caused by severe acute respiratory syndrome coronavirus-2. Tocilizumab is a humanized monoclonal antibody directed against the interleukin-6 receptor that has found a role as a therapy for patients with severe coronavirus-19 pneumonia. The immunomodulatory effects of tocilizumab may have the unintended consequence of predisposing recipients to secondary infections. We sought to assess the risk of invasive fungal disease and the therapeutic impact of tocilizumab on the hospital length of stay, duration of mechanical ventilation, and intensive-care-unit length of stay in critically ill patients with severe coronavirus-19 pneumonia. Records of critically ill patients with coronavirus-2019 admitted from March to September 2020 at our institution were reviewed. The risk for fungal infections, intensive-care-unit length of stay, hospital length of stay, and duration of mechanical ventilation in those that received tocilizumab in addition to standard coronavirus-2019 treatments was assessed. Fifty-six critically ill patients treated with dexamethasone and remdesivir for coronavirus-2019 were included, of which 16 patients also received tocilizumab. The majority of the cohort was African American, Asian, or of other ethnic minorities (53.6%). Invasive fungal infections occurred in 10.7% of all patients, and infection rates were significantly higher in the tocilizumab group than in the control group (31.2% vs. 2.5%, risk difference [RD] = 28.8%, p < 0.01). The increased risk in the tocilizumab group was strongly associated with renal replacement therapy. There was a dose-response relationship between the risk of fungal infection and number of tocilizumab doses received, with 2.5% of infections occurring with zero doses, 20% with a single dose (RD = 17.5%), and 50% with two doses (RD = 47.5%) (trend test p < 0.001). In addition, ICU LOS (23.4 days vs. 9.0 days, p < 0.01), the duration of mechanical ventilation (18.9 vs. 3.5 days, p = 0.01), and hospital length of stay (LOS) (29.1 vs. 15.5, p < 0.01) were increased in patients that received tocilizumab. Repurposed immunomodulator therapies, such as tocilizumab, are now recommended treatments for severe coronavirus-2019 pneumonia, but safety concerns remain. In this early pandemic cohort, the addition of tocilizumab to dexamethasone was associated with an increased risk of fungal infection in those that were critically ill and received renal replacement therapy. Tocilizumab use was also associated with increased ICU and hospital LOSs and duration of mechanical ventilation.


Exposure to a low pathogenic A/H7N2 virus in chickens protects against highly pathogenic A/H7N1 virus but not against subsequent infection with A/H5N1.
Recent evidences have demonstrated that the presence of low pathogenic avian influenza viruses (LPAIV) may play an important role in host ecology and transmission of avian influenza viruses (AIV). While some authors have clearly demonstrated that LPAIV can mutate to render highly pathogenic avian influenza viruses (HPAIV), others have shown that their presence could provide the host with enough immunological memory to resist re-infections with HPAIV. In order to experimentally study the role of pre-existing host immunity, chickens previously infected with H7N2 LPAIV were subsequently challenged with H7N1 HPAIV. Pre-infection of chickens with H7N2 LAPIV conferred protection against the lethal challenge with H7N1 HPAIV, dramatically reducing the viral shedding, the clinical signs and the pathological outcome. Correlating with the protection afforded, sera from chickens primed with H7N2 LPAIV reacted with the H7-AIV subtype in hemagglutination inhibition assay and specifically with the N2-neuraminidase antigen. Conversely, subsequent exposure to H5N1 HPAIV resulted in a two days-delay on the onset of disease but all chickens died by 7 days post-challenge. Lack of protection correlated with the absence of H5-hemagglutining inhibitory antibodies prior to H5N1 HPAIV challenge. Our data suggest that in naturally occurring outbreaks of HPAIV, birds with pre-existing immunity to LPAIV could survive lethal infections with HA-homologous HPAIV but not subsequent re-infections with HA-heterologous HPAIV. These results could be useful to better understand the dynamics of AIV in chickens and might help in future vaccine formulations.


Quantification of renal uric acid synthesis in the rat.
The excretion of nephrogenic uric acid in the urine of Sprague-Dawley rats was estimated by use of the isotope-dilution technique. In nonfasted rats the urine-to-plasma specific activity ratio (SAR) of [14C]uric acid was 0.93, suggesting that a minimum of 7% of the uric acid excreted in the urine is synthesized in the kidney. During hypoxanthine infusion the SAR decreased in a dose-related fashion, indicating that the rat kidney is capable of synthesizing relatively large amounts of uric acid and that circulating precursor levels may in part regulate the renal synthesis of uric acid. During allopurinol infusion the SAR increased to 1.0, demonstrating that the SAR is a valid indicator of the contribution of nephrogenic uric acid excreted into the urine. Results of perfusion studies in isolated rat kidneys suggest that uric acid is the major end product of purine catabolism in the rat kidney and that some uric acid formed in the kidney may be absorbed directly into the circulation.


Carbon efficient production of chemicals with yeasts.
Microbial metabolism offers a wide variety of opportunities to produce chemicals from renewable resources. Employing such processes of industrial biotechnology provides valuable means to fight climate change by replacing fossil feedstocks by renewable substrate to reduce or even revert carbon emission. Several yeast species are well suited chassis organisms for this purpose, illustrated by the fact that the still largest microbial production of a chemical, namely bioethanol is based on yeast. Although production of ethanol and some other chemicals is highly efficient, this is not the case for many desired bulk chemicals. One reason for low efficiency is carbon loss, which decreases the product yield and increases the share of total production costs that is taken by substrate costs. Here we discuss the causes for carbon loss in metabolic processes, approaches to avoid carbon loss, as well as opportunities to incorporate carbon from CO2 , based on the electron balance of pathways. These aspects of carbon efficiency are illustrated for the production of succinic acid from a diversity of substrates using different pathways.


Superior wood for violins--wood decay fungi as a substitute for cold climate.
Violins produced by Antonio Stradivari during the late 17th and early 18th centuries are reputed to have superior tonal qualities. Dendrochronological studies show that Stradivari used Norway spruce that had grown mostly during the Maunder Minimum, a period of reduced solar activity when relatively low temperatures caused trees to lay down wood with narrow annual rings, resulting in a high modulus of elasticity and low density. The main objective was to determine whether wood can be processed using selected decay fungi so that it becomes acoustically similar to the wood of trees that have grown in a cold climate (i.e. reduced density and unchanged modulus of elasticity). This was investigated by incubating resonance wood specimens of Norway spruce (Picea abies) and sycamore (Acer pseudoplatanus) with fungal species that can reduce wood density, but lack the ability to degrade the compound middle lamellae, at least in the earlier stages of decay. Microscopic assessment of the incubated specimens and measurement of five physical properties (density, modulus of elasticity, speed of sound, radiation ratio, and the damping factor) using resonance frequency revealed that in the wood of both species there was a reduction in density, accompanied by relatively little change in the speed of sound. Thus, radiation ratio was increased from 'poor' to 'good', on a par with 'superior' resonance wood grown in a cold climate.


Glioblastoma multiforme of the lateral ventricle: report of nine cases.
Glioblastoma multiforme is the most common lethal primary central nervous system (CNS) tumour in adults and they are rarely seen as primary intraventricular tumours. We present nine cases with lateral ventricle glioblastoma multiforme treated in our department. Seven of the nine tumours were located at the body of the lateral ventricle, whereas the other tumours were arising from septum pellicidum. Five patients were operated through an anterior transcallosal approach and four patients were operated through frontal transcortical approach. Total tumour excision was achieved only in one patient. Median survival time was 18.8 months. Three patients were alive at the end of study, and received radiotherapy and chemotherapy. Our goal was the decompressive surgery for these tumours without harming eloquent structures. In our opinion, patient's life quality is critically important in the postoperative period for these mortal tumours with rapid progression.


Disordered eating in adolescent males from a school-based sample.
The authors sought to describe a sample of adolescent males who reported disordered eating, to explore whether males with disordered eating are overweight or obese, and to determine if patterns displayed by females would be replicated with a male sample. Three school-based adolescent samples were selected. (1) 27 males reporting disordered eating (2) 27 physically matched controls, and (3) 27 randomly selected controls. Findings indicated that boys reporting disordered eating expressed greater body dissatisfaction, depression, restraint, and poorer interoceptive awareness compared to matched and randomly selected controls. Negative Emotionality and poor Interoceptive Awareness scores showed the strongest associations with eating pathology. Body mass index and Negative Emotionality scores showed the strongest relationships to restrained eating. Previous results for female adolescents were replicated, suggesting that findings for females can be generalized to males. Disordered eating appears to exist in the absence of significant weight problems in adolescent males.


Diastolic right ventricular filling vortex in normal and volume overload states.
Functional imaging computational fluid dynamics simulations of right ventricular (RV) inflow fields were obtained by comprehensive software using individual animal-specific dynamic imaging data input from three-dimensional (3-D) real-time echocardiography (RT3D) on a CRAY T-90 supercomputer. Chronically instrumented, lightly sedated awake dogs (n = 7) with normal wall motion (NWM) at control and normal or diastolic paradoxical septal motion (PSM) during RV volume overload were investigated. Up to the E-wave peak, instantaneous inflow streamlines extended from the tricuspid orifice to the RV endocardial surface in an expanding fanlike pattern. During the descending limb of the E-wave, large-scale (macroscopic or global) vortical motions ensued within the filling RV chamber. Both at control and during RV volume overload (with or without PSM), blood streams rolled up from regions near the walls toward the base. The extent and strength of the ring vortex surrounding the main stream were reduced with chamber dilatation. A hypothesis is proposed for a facilitatory role of the diastolic vortex for ventricular filling. The filling vortex supports filling by shunting inflow kinetic energy, which would otherwise contribute to an inflow-impeding convective pressure rise between inflow orifice and the large endocardial surface of the expanding chamber, into the rotational kinetic energy of the vortical motion that is destined to be dissipated as heat. The basic information presented should improve application and interpretation of noninvasive (Doppler color flow mapping, velocity-encoded cine magnetic resonance imaging, etc.) diastolic diagnostic studies and lead to improved understanding and recognition of subtle, flow-associated abnormalities in ventricular dilatation and remodeling.


Short fusion with vertebrectomy during growth in congenital spinal deformity: is early surgical intervention recommended?
This was a multi-center retrospective cohort study included consecutive pediatric patients who were admitted to 8 institutions for the treatment of congenital spinal deformity from 1991 to 2012. The purpose of this study was to compare curve corrections and balances, reoperations, and complications at 2-year follow-up between those treated early vs. late. Although early intervention has been recommended, no empirical study has examined the optimal timing of short fusion among patients with congenital spinal deformity. Patients with congenital spinal deformity with formation failure undergoing vertebrectomy with short fusion (≤ 6 fusion segments) were categorized as early (surgery at ≤ 6 years) and late (7-18 years) fusion. Outcomes included coronal and sagittal curve corrections at immediate and 2-year evaluations; loss of curve correction from immediate to 2-year follow-up; coronal and sagittal balance at 2 years; and inter-operative, major and minor short-term postoperative, and long-term postoperative complications and reoperations. Early fusion (N = 79) compared to late fusion (N = 96) was associated with greater percent curve correction at immediate (71% vs. 60%, p = 0.0046) and 2-year (63% vs. 52%, p = 0.0153) evaluations adjusting for surgeon experience and preoperative coronal balance. These associations were significant for males and those with 3-level fusions but not 4 to 6-level fusions. Early fusion compared with late fusion had more intraoperative (6% vs. 1%) and postoperative long-term complications (27% vs. 18%), as well as unplanned reoperations (13% vs. 9%). Early vs. late fusion had fewer short-term complications, both major (6% vs. 15%) and minor (6% vs. 15%). Patients who underwent early treatment achieved larger major curve correction by 10% compared to patients with late treatment when assessed at 2-year postoperative evaluation. However, early fusion should be considered with careful attention to possible increased risk of reoperations. Level III.


One-stage radical cystectomy for bladder carcinoma: operative mortality, cost/benefit analysis.
An analysis of cystectomies performed between September 1, 1969 and December 31, 1974 was conducted to determine the rates of morbidity (59 per cent) and operative mortality (4.1 per cent). Comparison of these figures for single operations with data published from other sources concerning staging of the therapeutic procedures suggests that there is no benefit for the patient relative to surgical morbidity or mortality if the latter course is followed. Conversely, prolongation of hospital experience, multiple operations, absence from productive activity and increased health care cost are associated with the staged procedures. Application of cost/benefit analysis suggests that this experience may act as a model to evaluate competing forms of therapy involving other disorders. When costs are not equivalent and benefits are the same the more expensive form of therapy should not be offered except for unusual circumstances.


Rapid and unpredictable changes of the G-matrix in a natural bird population over 25 years.
Knowledge of the genetic variances and covariances of traits (the G-matrix) is fundamental for the understanding of evolutionary dynamics of populations. Despite its essential importance in evolutionary studies, empirical tests of the temporal stability of the G-matrix in natural populations are few. We used a 25-year-long individual-based field study on almost 7000 breeding attempts of the collared flycatcher (Ficedula albicollis) to estimate the stability of the G-matrix over time. Using animal models to estimate G for several time periods, we show that the structure of the time-specific G-matrices changed significantly over time. The temporal changes in the G-matrix were unpredictable, and the structure at one time period was not indicative of the structure at the next time period. Moreover, we show that the changes in the time-specific G-matrices were not related to changes in mean trait values or due to genetic drift. Selection, differences in acquisition/allocation patterns or environment-dependent allelic effects are therefore likely explanations for the patterns observed, probably in combination. Our result cautions against assuming constancy of the G-matrix and indicates that even short-term evolutionary predictions in natural populations can be very challenging.


[Protein composition of erythrocyte membranes in patients with stomach, colon and rectal cancer].
Examinations of the protein composition of erythrocyte membrane in patients with cancer of the stomach, large intestine and rectum by using the method of disc-electrophoresis in polyacrylamide gel revealed the changing contents of protein fractions, which consisted in a lower share of high-molecular polypeptides with, simultaneously, higher quantity of low-molecular peptides. A comparison of the studied parameters of the protein spectrum of erythrocyte membrane as observed in patients with cancer of the stomach, on the one hand, and in patients with tumors of the large intestine and rectum, on the other hand, led to defining the reliable difference only for the content of the fraction-5 proteins.


A case of Chediak-Higashi syndrome presented with accelerated phase could be treated effectively by unrelated cord blood transplantation.
CHS is a rare immunodeficiency syndrome with defects in the functions of cytotoxic cells and neutrophils. Approximately 85% of patients with CHS undergo an AP within the first decade, which is similar to FHLH. Chemotherapy could induce transient remission, but only allogeneic HCT could correct the underlying genetic defect and prevent relapse. We reported a case of CHS diagnosed at 19 months, who had an elder brother who had previously succumbed to the same disease. The little girl presented with severe AP manifestations including recurrent high fever, enlarged superficial lymph nodes, and extraordinary hepatosplenomegaly occupying the whole abdominal and pelvic cavity. Comprehensive therapies including HLH 2004 protocol, supportive care, and antibiotics, especially antituberculous agents, were given to her to induce remission. After remission, the patient received fully HLA-matched UCBT. The transplantation course was uneventful, except for fluctuation of donor chimerism. The patient has been alive for 36 months without infection and neurologic manifestations and is under further follow-up. Our result provides another case that UCBT can be effective for treating patients with CHS and remission before HCT is important for good prognosis.


The Effects of Telepractice to Support Family Members in Modeling a Speech-Generating Device in the Home.
Purpose Family members are an integral support for children with complex communication needs (CCN). However, there is limited research exploring "whole family" intervention to support children with CCN, including evidence-based approaches such as aided language modeling and innovative delivery options such as telepractice. The purpose of this study was to explore whether the use of telepractice-based training and coaching is a valid means of delivering intervention to the whole family unit to implement aided language modeling. Method A 4-year-old child with CCN who uses a speech-generating device and her four family members participated in the study. A single-case multiple-probe design across the four dyads was used to determine the effect of the memory aid, namely, Prepare, Show, Wait, and Respond, via telepractice intervention to teach family members to provide aided language modeling with fidelity during natural routines. Results We found that telepractice-based training and coaching increased family members' high-fidelity models and rate of modeling. The target child also showed an increase in independent communication and rate of augmentative and alternative communication use. Social validity interviews indicated that the participants found the intervention to be socially valid. Conclusions Given the findings of this study, speech-language pathologists should encourage the involvement of the whole family in augmentative and alternative communication interventions. Future research should examine the impact of training and coaching all family members together in their natural environment, explore specific adaptations for participants, and investigate the effects of intervention delivered by speech-language pathologists who work directly with families and utilize family-centered practices.


Management of acute COPD exacerbations in France: A qualitative survey in a private practice setting.
The current prevalence of chronic obstructive pulmonary disease (COPD) in France is estimated to be 2.6 million and is predicted to increase to 2.8 million by 2025. Presently, there is a lack of data on COPD management within the private healthcare setting. The aim of this study was to investigate the management of COPD exacerbations by pulmonologists within private practices in France. A prospective, online, qualitative survey was distributed to private practice pulmonologists in France. The survey covered all aspects of COPD management from diagnosis and therapeutic management, to secondary prevention and organization of care. Survey responses were collected between 27 January 2018 and 18 June 2018 and all data were summarized descriptively. The survey had a response rate of 20.6%, with 116 out of 563 pulmonologists providing responses. Overall, 87.4% of respondents stated that the management of COPD represented over 15% of their total clinical activity. Most respondents indicated that they work closely with general practitioners and a large multidisciplinary team to manage patients with numerous comorbidities. Following a COPD exacerbation, the majority of respondents (78.4%) were in favor of using respiratory-connected devices (class 2a-connected medical device according to the French HAS classification and available on medical prescription) to assist with patient follow-up at home. COPD management forms part of the core clinical activity for pulmonologists within the private practice setting in France. Patients with COPD generally have multiple comorbidities and are managed by a multidisciplinary team in line with French guidelines. The use of respiratory-connected devices was highlighted as an important new strategy for improving patient care following a COPD exacerbation.


Impact of cordectomy as a treatment option for posttraumatic and non-posttraumatic syringomyelia with tethered cord syndrome and myelopathy.
Spinal cordectomy has recently become more important in the treatment of end-stage posttraumatic or postoperative syringomyelia and arachnopathy as a last resort to manage ascending neurological dysfunction, spasticity, and pain in paraplegic patients. The aim in this study was to confirm a clinical benefit in strict indications for cordectomy. Between February 2000 and September 2007, 15 spinal cordectomies were performed at the Department of Neurosurgery, Cantonal Hospital, St. Gallen. Indications for treatment were end-stage myelopathies caused by syringomyelia, tethered cord syndrome, and arachnopathy with progressive spasticity and pain or progressive upper-level neurological deficits related to the tethered cord syndrome. All patients had severe motor and sensory deficits with no residual voluntary function below the affected level. Fourteen of 15 patients showed stabilization or even an improvement in motor and sensory function. Four patients suffered from progressive spasticity and 3 from deterioration due to pain. There were no other adverse surgical events. Cordectomy can be a useful instrument to preserve functions of the upper extremities and to improve spasticity and pain in patients with severe myelopathy and tethered cord, syringomyelia, or arachnopathy of various etiologies.


Exogenous proline effects on water relations and ions contents in leaves and roots of young olive.
The ability of exogenous compatible solutes, such as proline, to counteract salt inhibitory effects was investigated in 2-year-old olive trees (Olea europaea L. cv. Chemlali) subjected to different saline water irrigation levels supplied or not with exogenous proline. Leaf water relations [relative water content (RWC), water potential], photosynthetic activity, leaf chlorophyll content, and starch contents were measured in young and old leaves. Salt ions (Na(+), K(+), and Ca(2+)), proline and soluble sugars contents were determined in leaf and root tissues. Supplementary proline significantly mitigated the adverse effects of salinity via the improvement of photosynthetic activity (Pn), RWC, chlorophyll and carotenoid, and starch contents. Pn of young leaves in the presence of 25 mM proline was at 1.18 and 1.38 times higher than the values recorded under moderate (SS1) and high salinity (SS2) treatments, respectively. Further, the proline supply seems to have a more important relaxing effect on the photosynthetic chain in young than in old leaves of salt-stressed olive plants. The differential pattern of proline content between young and old leaves suggests that there would be a difference between these tissues in distinguishing between the proline taken from the growing media and that produced as a result of salinity stress. Besides, the large reduction in Na(+) accumulation in leaves and roots in the presence of proline could be due to its interference in osmotic adjustment process and/or its dilution by proline supply. Moreover, the lower accumulation of Na(+) in proline-treated plants, compared to their corresponding salinity treatment, displayed the improved effect of proline on the ability of roots to exclude the salt ions from the xylem sap flowing to the shoot, and thus better growth rates.


A Global Transcriptional Atlas of the Effect of Sleep Deprivation in the Mouse Frontal Cortex.
Sleep deprivation (SD) has negative effects on brain function. Sleep problems are prevalent in neurodevelopmental, neurodegenerative and psychiatric disorders. Thus, understanding the molecular consequences of SD is of fundamental importance in neuroscience. In this study, we present the first simultaneous bulk and single-nuclear (sn)RNA sequencing characterization of the effects of SD in the mouse frontal cortex. We show that SD predominantly affects glutamatergic neurons, specifically in layers 4 and 5, and produces isoform switching of thousands of transcripts. At both the global and cell-type specific level, SD has a large repressive effect on transcription, down-regulating thousands of genes and transcripts; underscoring the importance of accounting for the effects of sleep loss in transcriptome studies of brain function. As a resource we provide extensive characterizations of cell types, genes, transcripts and pathways affected by SD; as well as tutorials for data analysis.


Total scapulectomy for the treatment of chondrosarcoma in a cat.
A 10-year-old neutered male domestic shorthair cat was admitted for treatment of a mass affecting the right scapula. A firm soft tissue mass located over the craniolateral aspect of the right scapula was evident during palpation. The mass extended close to the shoulder joint but did not cause lameness of the affected limb. Examination of a biopsy specimen obtained from the mass indicated chondrosarcoma. Total scapulectomy was performed to allow wide excision of the tumor. Weight bearing on the operated limb was tolerated 12 hours after surgery. Six months after surgery, limb function was assessed and considered excellent. The owner reported that the cat had its typical amount of activity and was able to jump and play normally. No recurrence of the tumor was evident 6 months after surgery. On the basis of the functional outcome after surgery, total scapulectomy may be a viable limb-sparing technique for the treatment of local neoplasms in cats. Subtotal scapulectomy has been reported previously, with a good to excellent clinical outcome expected. Total scapulectomy associated with only a fair clinical outcome has been reported previously, which has led to the general recommendation that scapulectomy be performed with preservation of the shoulder joint. The information provided in this report revealed that total scapulectomy can be associated with an excellent outcome in a cat.


Navigating the bridge between wet and dry lab toxicology research to address current challenges with high-dimensional data.
Toxicology research has rapidly evolved, leveraging increasingly advanced technologies in high-throughput approaches to yield important information on toxicological mechanisms and health outcomes. Data produced through toxicology studies are consequently becoming larger, often producing high-dimensional data. These types of data hold promise for imparting new knowledge, yet inherently have complexities causing them to be a rate-limiting element for researchers, particularly those that are housed in "wet lab" settings (i.e., researchers that use liquids to analyze various chemicals and biomarkers as opposed to more computationally focused, "dry lab" researchers). These types of challenges represent topics of ongoing conversation amongst our team and researchers in the field. The aim of this perspective is to i) summarize hurdles in analyzing high-dimensional data in toxicology that require improved training and translation for wet lab researchers, ii) highlight example methods that have aided in translating data analysis techniques to wet lab researchers; and iii) describe challenges that remain to be effectively addressed, to date, in toxicology research. Specific aspects include methodologies that could be introduced to wet lab researchers, including data pre-processing, machine learning, and data reduction. Current challenges discussed include model interpretability, study biases, and data analysis training. Example efforts implemented to translate these data analysis techniques are also mentioned, including online data analysis resources and hands-on workshops. Questions are also posed to continue conversation in the toxicology community. Contents of this perspective represent timely issues broadly occurring in the fields of bioinformatics and toxicology that require ongoing dialogue between wet and dry lab researchers.


Suboptimal Compliance With National Comprehensive Cancer Network Melanoma Guidelines: Who Is at Risk?
National Comprehensive Cancer Network (NCCN) melanoma treatment guidelines are based on best available literature. We evaluated NCCN excision margin and sentinel lymph node biopsy (SLNB) guideline adherence to identify patient populations at risk for suboptimal care. Retrospective review of prospectively maintained database of all patients who underwent operation for invasive melanoma from January 2005 to 2015. In total, 865 patients underwent operation for 522 thin (60.3%), 268 intermediate-thickness (31.0%), and 75 thick (8.7%) melanomas. Tumor location was 349 extremity (40.4%), 348 trunk (40.2%), and 168 head/neck (19.4%). SLNB was performed in 422 patients (48.8%); 75 (17.8%) were positive, and 67 (15.9%) underwent therapeutic lymphadenectomy. A total of 154 lesions (17.8%) were ulcerated; 444 had mitotic rate ≥1 (51.3%). In total, 788 patients (91.1%) fulfilled both NCCN guidelines. Recommended surgical margins were achieved in 837 patients (96.8%) and SLNB was performed as appropriate in 806 patients (93.2%); 10 patients (1.2%) were deficient for both. Deficient margins and lack of SLNB were associated with increased invasion depth and head/neck location; deficient SLNB was associated with age 80 and above (P<0.0001). Overall recurrence was 7.1%: 15 local (1.7%), 23 regional (2.7%), and 23 distant (2.7%) failures. Local recurrence was associated with head/neck location (P=0.031); all recurrence types were associated with increased tumor thickness. NCCN excision and SLNB guidelines were almost always met. Patients at risk for not meeting criteria included the elderly and those with head/neck tumors. Failure to meet NCCN criteria was not associated with increased disease recurrence. Surgeons must carefully balance the risks of not pursuing NCCN guidelines with treatment goals.


Differential expression and effect of the porcine ANGPTL4 gene on intramuscular fat.
In a previous study, we investigated differences in gene expression in backfat between Meishan and Large White pigs and their F1 hybrids, Large White x Meishan, and Meishan x Large White pigs. One potential differentially expressed sequence tag from the mRNA differential display was a homolog of the human angiopoietin-like 4 (ANGPTL4) gene, which encodes a protein that is secreted by both liver and white adipose tissues and can inhibit lipoprotein lipase activity and stimulate white adipose tissue lipolysis. Here, ANGPTL4 mRNA was found to be upregulated in the backfat of Large White compared with that in the Meishan pigs and the F1 hybrids, Meishan x Large White and Large White x Meishan, whereas expression was lowest both in the longissimus dorsi and the heart, as shown by the tissue distribution profile. Only one mutation, a G/A transition located in the third intron, was found. The ANGPTL4 G/A polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) showed a significant effect on intramuscular fat (IMF), water moisture of the longissimus dorsi, meat marbling of the longissimus dorsi, and pH of the longissimus dorsi (P < 0.05). This site seemed to be significantly (P < 0.05) additive in its actions on IMF, water moisture, and pH, whereas it showed significant dominance in its action on meat marbling (P < 0.05). This locus can be potentially considered as a marker for IMF improvement.


Stringent analysis of gene function and protein-protein interactions using fluorescently tagged genes.
In Drosophila collections of green fluorescent protein (GFP) trap lines have been used to probe the endogenous expression patterns of trapped genes or the subcellular localization of their protein products. Here, we describe a method, based on nonoverlapping, highly specific, shRNA transgenes directed against GFP, that extends the utility of these collections to loss-of-function studies. Furthermore, we used a MiMIC transposon to generate GFP traps in Drosophila cell lines with distinct subcellular localization patterns, which will permit high-throughput screens using fluorescently tagged proteins. Finally, we show that fluorescent traps, paired with recombinant nanobodies and mass spectrometry, allow the study of endogenous protein complexes in Drosophila.


The use of locomotor activity as a behavioral screen for neuronal damage following transient forebrain ischemia in gerbils.
Five min bilateral carotid artery occlusion (BCO) in gerbils results in selective degeneration of neurons in the hippocampus, striatum and cortex, and an increase in spontaneous locomotor activity. These phenomena were examined to determine if an association could be made between the site or degree of neuronal degeneration and the increase in locomotor activity. The distance traveled by the BCO gerbils in a novel cage 1, 4, and 28 days after a 5 min occlusion was significantly greater than control. The extensive pyramidal cell damage in the CA1 region of the hippocampus in BCO gerbils was associated with the significant increase in locomotor activity. The increase in locomotor activity did not correlate with either the striatal or cortical damage present. The increase in gerbil locomotor activity following a 5 min BCO can be used as a predictor of CA1 damage, but not as a predictor of striatal or cortical damage.


Risk factors for ambulatory urinary tract infections caused by high-MIC fluoroquinolone-susceptible Escherichia coli in women: results from a large case-control study.
The prevalence of high-MIC fluoroquinolone-susceptible Escherichia coli (FQSEC) has been increasing. These isolates are one step closer to full fluoroquinolone (FQ) resistance and may lead to delayed response to FQ therapy. Our study aimed to investigate the epidemiology of high-MIC FQSEC in ambulatory urinary tract infections (UTIs). A case-control study was conducted at outpatient services within the University of Pennsylvania Health System, Philadelphia. All female subjects with non-recurrent UTI caused by FQSEC (levofloxacin MIC < 4 mg/L) were enrolled. Cases were subjects with high-MIC FQSEC UTI (levofloxacin MIC >0.12 but < 4 mg/L) and controls were subjects with low-MIC FQSEC UTI (levofloxacin MIC ≤0.12 mg/L). Data on microbiology results and baseline characteristics were extracted from electronic medical records. During the 3 year study period (May 2008-April 2011), 11 287 episodes of E. coli bacteriuria were identified. The prevalence of FQSEC, FQ-intermediate susceptible E. coli and FQ-resistant E. coli was 75.0%, 0.4% and 24.6%, respectively. A total of 2001 female subjects with FQSEC UTI were enrolled into our study (165 cases and 1836 controls). Independent risk factors for high-MIC FQ susceptibility included Asian race (OR = 2.92; 95% CI = 1.29-6.58; P = 0.02), underlying renal disease (OR = 2.18; 95% CI = 1.15-4.14; P = 0.02) and previous nitrofurantoin exposure (OR = 8.86; 95% CI = 1.95-40.29; P = 0.005). Asian race, underlying renal disease and previous exposure to nitrofurantoin were identified as independent risk factors for high-MIC FQSEC. There may be some factors that are more common in Asians, which may result in the selection of high-MIC FQSEC. Further studies are necessary to explore these findings.


[Interdisciplinary physio-reflexotherapy in the treatment of headache].
To treat the patients with a headache (HA) and with the signs of muscular-articular disorders in a cranio-cervical region a complex physioreflexotherapeutic approach was applied. It was directed to the relaxation of pericranial muscles, to the restoration of a physiologic mobility in a zone of cranio-cervical transition and to the action to the irritative zones of these regions. 60 patients with a headache of tension (HAT) and 48 ones with migraine (M) were treated. A therapy included laser and manual physioreflexotherapy and an education to the muscular autorelaxation technique. An estimation after 6 months of therapy gave good and excellent results in 61% of the patients with HAT and in 37% of the patients with M. A number of the days with HA, a duration and an intensity of the attacks decreased. A conclusion was made that the disorders of craniocervical structures may make worse a course of HA. In such cases there was indicated a described therapeutic approach.


Transurethral ultrasound applicators with dynamic multi-sector control for prostate thermal therapy: in vivo evaluation under MR guidance.
The purpose of this study was to explore the feasibility and performance of a multi-sectored tubular array transurethral ultrasound applicator for prostate thermal therapy, with potential to provide dynamic angular and length control of heating under MR guidance without mechanical movement of the applicator. Test configurations were fabricated, incorporating a linear array of two multi-sectored tubular transducers (7.8-8.4 MHz, 3 mm OD, 6 mm length), with three 120 degrees independent active sectors per tube. A flexible delivery catheter facilitated water cooling (100 ml min(-1)) within an expandable urethral balloon (35 mm long x 10 mm diameter). An integrated positioning hub allows for rotating and translating the transducer assembly within the urethral balloon for final targeting prior to therapy delivery. Rotational beam plots indicate approximately 90 degrees-100 degrees acoustic output patterns from each 120 degrees transducer sector, negligible coupling between sectors, and acoustic efficiencies between 41% and 53%. Experiments were performed within in vivo canine prostate (n = 3), with real-time MR temperature monitoring in either the axial or coronal planes to facilitate control of the heating profiles and provide thermal dosimetry for performance assessment. Gross inspection of serial sections of treated prostate, exposed to TTC (triphenyl tetrazolium chloride) tissue viability stain, allowed for direct assessment of the extent of thermal coagulation. These devices created large contiguous thermal lesions (defined by 52 degrees C maximum temperature, t43 = 240 min thermal dose contours, and TTC tissue sections) that extended radially from the applicator toward the border of the prostate (approximately15 mm) during a short power application (approximately 8-16 W per active sector, 8-15 min), with approximately 200 degrees or 360 degrees sector coagulation demonstrated depending upon the activation scheme. Analysis of transient temperature profiles indicated progression of lethal temperature and thermal dose contours initially centered on each sector that coalesced within approximately 5 min to produce uniform and contiguous zones of thermal destruction between sectors, with smooth outer boundaries and continued radial propagation in time. The dimension of the coagulation zone along the applicator was well-defined by positioning and active array length. Although not as precise as rotating planar and curvilinear devices currently under development for MR-guided procedures, advantages of these multi-sectored transurethral applicators include a flexible delivery catheter and that mechanical manipulation of the device using rotational motors is not required during therapy. This multi-sectored tubular array transurethral ultrasound technology has demonstrated potential for relatively fast and reasonably conformal targeting of prostate volumes suitable for the minimally invasive treatment of BPH and cancer under MR guidance, with further development warranted.


Impact of traffic states on freeway crash involvement rates.
Freeway traffic accidents are complicated events that are influenced by multiple factors including roadway geometry, drivers' behavior, traffic conditions and environmental factors. Among the various factors, crash occurrence on freeways is supposed to be strongly influenced by the traffic states representing driving situations that are changed by road geometry and cause the change of drivers' behavior. This paper proposes a methodology to investigate the relationship between traffic states and crash involvements on the freeway. First, we defined section-based traffic states: free flow (FF), back of queue (BQ), bottleneck front (BN) and congestion (CT) according to their distinctive patterns; and traffic states of each freeway section are determined based on actual measurements of traffic data from upstream and downstream ends of the section. Next, freeway crash data are integrated with the traffic states of a freeway section using upstream and downstream traffic measurements. As an illustrative study to show the applicability, we applied the proposed method on a 32-mile section of I-880 freeway. By integrating freeway crash occurrence and traffic data over a three-year period, we obtained the crash involvement rate for each traffic state. The results show that crash involvement rate in BN, BQ, and CT states are approximately 5 times higher than the one in FF. The proposed method shows promise to be used for various safety performance measurement including hot spot identification and prediction of the number of crash involvements on freeway sections.


What do people include when they self-rate their health? Differential associations according to health status in community-dwelling older adults.
Self-rated health (SRH) is widely regarded a valid and reliable indicator of health status. The validity of self-rated health has been demonstrated in many studies, for example by predicting mortality over and above medical and epidemiological data. However, the meaning of SRH can differ between individuals, especially in elderly individuals with considerable individual differences in their physical health states. It is thus important to determine whether predictors of self-rated health vary according to physical health status in order to interpret self-rated health data. In a representative survey study, 1174 individuals over 65 years of age rated their health and filled in questionnaires on subjective well-being, control beliefs, depressive symptoms, and functional health. Structural equation modeling with latent moderated structural equations was used to determine whether health status (number of illnesses) moderated the association of self-rated health with these predictors. Self-rated health was predicted by positive affect, depressive symptoms, control beliefs, and physical functioning. Moderated effects were found for positive affect and physical functioning, suggesting that there are stronger associations with positive affect in healthier individuals and stronger associations with physical functioning in less healthy individuals. This implies that SRH has differential associations depending on health status, which should be taken into account in interpreting any research with SRH as predictor or criterion.


Social interaction patterns, therapist responsiveness, and outcome in treatments for borderline personality disorder.
Inflexible social interaction patterns are defining features of borderline personality disorder (BPD). Specific beliefs about the self and others may be activated across interaction situations, often leading to instable relationships. It may be pivotal to address these difficulties in early treatment phases, through appropriate therapist responsiveness, which means an adaptation of therapist's activity to their client's behaviours using emerging information in the process (Stiles, 2009, Clinical Psychology: Science and Practice, 16, 86). In this process-outcome study, responsiveness is operationalized by the motive-oriented therapeutic relationship (Caspar, 2007, Handbook of psychotherapeutic case formulations, 2nd ed., 251-289, Guilford), based on the Plan analysis case formulation. The present study assesses the interplay between social interaction problems and therapist responsiveness, explaining symptoms at discharge and the therapeutic alliance. In total, N = 50 clients with BPD entered the study, and standard and responsive treatments were compared. Social interaction patterns were assessed by the newly developed Borderline Interaction Patterns Scale (BIPS), applied to recorded material of three sessions per therapy. Outcome was measured by general symptoms (OQ-45), borderline symptoms (BSL-23), interpersonal problems (IIP), and the therapeutic alliance (WAI). Results suggest that in standard treatment, social interaction patterns are neither related to outcome nor the therapeutic alliance. In responsive treatment, more activation of social interaction patterns predicted better outcome on IIP and lower therapist ratings of the alliance. The conclusions seem promising for specific effectiveness of responsive treatments in particular in the interpersonal problem area of BPD. Identifying social interaction patterns early in treatment may be a crucial pathway to change for BPD. Responsive therapy activating social interaction patterns may be crucial for better outcome. Future research should focus on mechanisms of change in early treatment phases for BPD. New scale for assessing social interaction patterns specific to borderline personality disorder.


Development of an assay for ozone-specific antioxidant capacity.
A method of determining the ozone-specific antioxidant capacity (OZAC) of lavage samples from the respiratory system was developed: Gaseous ozone (O(3)) was produced in cuvettes by irradiation with an ultraviolet lamp; aliquots of sample or of a saline control were then added and sufficient time was allowed for ozonation to reach completion; and an aliquot of indigo trisulfonate (ITS) was added to react with excess O(3). Because each molecule of O(3) rapidly bleaches one molecule of the deeply colored ITS, an OZAC value in concentration units was computed from the difference in light absorbance between the sample and the saline control multiplied by the extinction coefficient of ITS. Experiments in 0-40 micro M antioxidant solutions indicated that the OZAC values of uric acid and ascorbic acid were close to their actual concentrations and were independent of O(3) concentration. On the other hand, the OZAC of reduced glutathione and possibly human nasal lavage were nonlinearly related to antioxidant concentration and were directly related to O(3) concentration.


2010 Update of the international ASAS recommendations for the use of anti-TNF agents in patients with axial spondyloarthritis.
This paper presents the second update of the Assessment in SpondyloArthritis international Society (ASAS) consensus statement on the use of anti-tumour necrosis factor (anti-TNF) agents in patients with axial spondyloarthritis (SpA). A major change from the previous recommendations is that patients fulfilling the ASAS axial SpA criteria, which also include patients fulfilling the modified New York criteria for ankylosing spondylitis, can be treated with anti-TNF agents. This makes an earlier start in the disease process possible. A second major change is the mandatory pretreatment before anti-TNF agents can be started. All patients should have tried a minimum of two non-steroidal anti-inflammatory drugs for a minimum of 4 weeks in total. This is significantly shorter than the previous requirement of 3 months. As previously, patients with axial symptoms require no further pretreatment. Patients with symptomatic peripheral symptoms should normally have had an adequate therapeutic trial of a disease-modifying antirheumatic drug, preferably sulfasalazine. Sulfasalazine is no longer mandatory in this group of patients. Finally, efficacy should be evaluated after at least 12 weeks. The remaining recommendations stayed largely unchanged.


Post partum discharge against medical advice: who leaves and does it matter?
To examine risk factors and sequela for post partum discharge against medical advice. We conducted cross-sectional analyses of hospital discharge data linked to American Hospital Association data for women discharged following a live birth for California, Florida, and New York in the years 1998-2000. We examined rates, risk factors, hospital readmission rate and mortality (California only), associated with discharge against medical advice after controlling for patient and hospital characteristics. Post partum discharge against medical advice averaged 0.10%. Rates were lowest among women following uncomplicated cesarean and vaginal births (0.07%), intermediate following complicated vaginal birth (0.21%) and highest following complicated cesarean birth (0.29%). African American race, lower income, public health insurance, no health insurance, or greater comorbidity, particularly drug abuse or psychotic illness, discharge from a hospital in California or New York (compared to Florida), and location in medium or large metropolitan areas, were associated with significantly higher rates of discharge against advice. Asian or Hispanic race or ethnicity and delivery at an obstetrical specialized hospital were associated with lower risk. Patients discharged against medical advice in California were significantly more likely to be re-admitted within 30 days (adjusted odds ratio 2.7; 95% confidence interval [CI] 1.8-3.9), though none died during the period. Discharge against medical advice among post partum patients is uncommon, but occurs primarily among vulnerable women with psychosocial and medical risk factors. Thus, discharge against medical advice may help identify women who may benefit from additional maternal and/or child services.


Surgical management of the flatfoot.
The flatfoot in a child with sufficient deformity and symptoms to warrant surgery occurs infrequently. A prolonged trial of nonsurgical measures is always indicated. With the exception of the spastic paralytic foot, surgery involving alteration of the bony anatomy should be postponed until the child's foot matures. Restoration of the longitudinal arch at the midfoot naviculocuneiform articulation is a reliable solution to the symptomatic hypermobile flatfoot. The spastic paralytic foot requires tendo Achillis lengthening, medial imbrication, and Grice subtalar stabilization. The symptomatic, cartilaginous tarsal coalition will respond to resection. Treatment of the skewfoot must be individualized depending on the severity and location of symptoms, age of the patient, and joint mobility.


Hypocholesterolemic effect of soybean protein in rats and mice after peptic digestion.
Analyses of gastrointestinal contents of rats fed soybean protein isolate and casein showed that soybean protein was readily digested in the stomach but migrated slowly in the small intestine. The soluble fraction of the stomach contents of rats fed soybean protein was separated by gel-filtration on Sephadex G25 into large and small molecular fractions, the latter was not found in rats fed casein. The formation of low-molecular-weight peptides was pH dependent, and analogous peptides were produced by pepsin in vitro not only from soybean protein but also from casein. In rats the peptic digest of soybean protein was found to be as hypocholesterolemic as intact soybean protein. Meanwhile, the cholesterol-lowering action of the large molecular fraction of the peptic digest tended to be greater than that of the small molecular fraction in mice. These observations suggest a significant role of peptic digestion in the cholesterol-lowering action of soybean protein.


Contingency in the evolutionary emergence of reciprocal cooperation.
Reciprocity is characterized by individuals actively making it beneficial for others to cooperate by responding to them. This makes it a particularly powerful generator of mutual interest, because the benefits accrued by an individual can be redistributed to another. However, reciprocity is a composite biological function, entailing at least two subfunctions: (i) a behavioral ability to provide fitness benefits to others and (ii) a cognitive ability to evaluate the benefits received from others. For reciprocity to evolve, these two subfunctions must appear together, which raises an evolutionary problem of bootstrapping. In this article, I develop mathematical models to study the necessary conditions for the gradual emergence of reciprocity in spite of this bootstrapping problem. I show that the evolution of reciprocity is based on three conditions. First, there must be some variability in behavior. Second, cooperation must pre-evolve for reasons independent of reciprocity. Third, and most significantly, selection favors conditional cooperation only if the cooperation expressed by others is already conditional, that is, if some reciprocity is already present in the first place. In the discussion, I show that these three conditions help explain the specific features of the instances in which reciprocity does occur in the wild. For instance, it accounts for the role of spatial symmetry (as in ungulate allogrooming), the importance of synergistic benefits (as in nuptial gifts), the facilitating role of collective actions (as in many instances of human cooperation), and the potential role of kinship (as in primate grooming).


Characterization of a novel 99mTc-carbonyl complex as a functional probe of MDR1 P-glycoprotein transport activity.
Multidrug resistance (MDR) mediated by overexpression of MDR1 P-glycoprotein (Pgp) is one of the best characterized barriers to chemotherapy in cancer patients. Furthermore, the protective function of Pgp-mediated efflux of xenobiotics in various organs has a profound effect on the bioavailability of drugs in general. Thus, there is an expanding requirement to noninvasively interrogate Pgp transport activity in vivo. We herein report the Pgp recognition properties of a novel 99mTc(I)-tricarbonyl complex, [99mTc(CO)3(MIBI)3]+ (Tc-CO-MIBI). Tc-CO-MIBI showed 60-fold higher accumulation in drug-sensitive KB 3-1 cells compared to colchicine-selected drug-resistant KB 8-5 cells. In KB 8-5 cells, tracer enhancement was observed with the potent MDR modulator LY335979 (EC50 = 62 nM). Similar behavior was observed using drug-sensitive MCF-7 breast adenocarcinoma cells and MCF-7/MDR1 stable transfectants, confirming that Tc-CO-MIBI is specifically excluded by overexpression of MDR1 Pgp. By comparison, net accumulation in control H69 lung tumor cells was 9-fold higher than in MDR-associated protein (MRP1)-expressing H69AR cells, indicating only modest transport by MRP1. Biodistribution analysis following tail vein injection of Tc-CO-MIBI showed delayed liver clearance as well as enhanced brain uptake and retention in mdr1a/1b(-/-) gene deleted mice versus wild-type mice, directly demonstrating that Tc-CO-MIBI is a functional probe of Pgp transport activity in vivo.


The re-emergence of psychiatric neurosurgery: insights from a cross-national study of newspaper and magazine coverage.
Surgical approaches to treat psychiatric disorders have made a comeback. News media plays an essential role in exposing the public to trends in health care such as the re-emergence of therapeutic interventions in psychiatric neurosurgery that were set aside for decades, and in shaping attitudes and acceptance to them. We conducted an analysis of media articles covering all types of psychiatric neurosurgery published in Canada, USA, Germany, and Spain between the years 1960 and 2015. We applied both quantitative and qualitative methods to elucidate patterns of reporting for conditions, themes and tone, across geographic regions, time, and for type of intervention. Coverage of psychiatric neurosurgery has surged since 2001 and is largely consistent across the countries examined. It focuses on depression and deep brain stimulation, and is explicit about historical context. The tone of coverage becomes more positive for Canada, USA and Spain over time; the tone of coverage from Germany remains cautious. Identity and privacy are among the few ethical and philosophical issues raised, notably in the German press. The focused and optimistic attention to contemporary psychiatric neurosurgery in the media, but inattention to ethical issues, places an extra burden on functional neurosurgeons, psychiatrists, and other frontline health professionals to attend to queries from patients and policy makers about the full range of relevant emergent and emerging interventions and the mental health issues to which they may beneficially apply.


Role of ion channels in regulating Ca²⁺ homeostasis during the interplay between immune and cancer cells.
Ion channels are abundantly expressed in both excitable and non-excitable cells, thereby regulating the Ca(2+) influx and downstream signaling pathways of physiological processes. The immune system is specialized in the process of cancer cell recognition and elimination, and is regulated by different ion channels. In comparison with the immune cells, ion channels behave differently in cancer cells by making the tumor cells more hyperpolarized and influence cancer cell proliferation and metastasis. Therefore, ion channels comprise an important therapeutic target in anti-cancer treatment. In this review, we discuss the implication of ion channels in regulation of Ca(2+) homeostasis during the crosstalk between immune and cancer cell as well as their role in cancer progression.


The Enterococcus faecalis fsr two-component system controls biofilm development through production of gelatinase.
Bacterial growth as a biofilm on solid surfaces is strongly associated with the development of human infections. Biofilms on native heart valves (infective endocarditis) is a life-threatening disease as a consequence of bacterial resistance to antimicrobials in such a state. Enterococci have emerged as a cause of endocarditis and nosocomial infections despite being normal commensals of the gastrointestinal and female genital tracts. We examined the role of two-component signal transduction systems in biofilm formation by the Enterococcus faecalis V583 clinical isolate and identified the fsr regulatory locus as the sole two-component system affecting this unique mode of bacterial growth. Insertion mutations in the fsr operon affected biofilm formation on two distinct abiotic surfaces. Inactivation of the fsr-controlled gene gelE encoding the zinc-metalloprotease gelatinase was found to prevent biofilm formation, suggesting that this enzyme may present a unique target for therapeutic intervention in enterococcal endocarditis.


Volvulus due to a tumor of Meckel's diverticulum.
Small-bowel obstruction in an old woman was the result of a twisted Meckel's diverticulum containing a large neoplasm. As neoplasms comprise only 1.2-1.4% of the complications of the diverticulum, and generally bleed or cause intussusception, we believe that the condition described is not common.


Altered matrix production in the distal airways of individuals with asthma.
Although increasing evidence suggests involvement of the distal airway in all stages of asthma, it is not known whether structural changes (defined as airway remodelling) occur in the distal airways of subjects with mild asthma and those with atopy. The aim of this study was to compare control subjects and those with mild asthma in relation to fibroblast phenotypes and remodelling in central and distal airways. Distal and central fibroblasts from controls (n=12) and patients with mild asthma (n=11) were cultured and incubated for 24 h with 0.4% serum, or stimulated with transforming growth factor beta1 (TGFbeta1). [(35)S]Sulfate-labelled proteoglycans in culture medium were analysed by ion exchange chromatography and sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Proliferation was measured with crystal violet, and exhaled nitric oxide was measured by the fractional nitric oxide technique. Vesican production from distal fibroblasts was significantly elevated in patients with asthma compared with controls (p<0.001), and the percentage collagen-positive area in distal asthma tissue was also enhanced compared with controls (p<0.01). In addition, distal asthma fibroblasts had reduced proliferation capacity compared with those of controls (by 24%; p<0.01). Furthermore, the alveolar nitric oxide concentration was correlated to distal biglycan and perlecan production of subjects with asthma (r=-0.857, p<0.05 and r=-0.750, p<0.05 respectively) It is shown that centrally and distally derived fibroblasts differ in their proteoglycan production and proliferation between central and distal tissue, and in those with asthma compared with controls. It is also demonstrated that remodelling is present in distal lung of subjects with mild asthma. This may be of importance in airway remodelling and asthma progression.


Obstetric Outcomes in Non-Gynecologic Cancer Patients in Remission.
The aim of the present study was to evaluate the obstetric and perinatal outcomes in treated women who were diagnosed with non-gynecologic cancer and to compare these findings with pregnant women with no history of cancer. This retrospective study was conducted on 21 pregnant women with non-gynecologic cancer who were in remission (study group) and 63 pregnant women with no history of cancer (control group). The women were admitted to the high-risk pregnancy clinic of Zekai Tahir Burak Women's Health Training and Research Hospital with a diagnosis of pregnancy and cancer between January 2010 and January 2015. Obstetric outcomes and demographic characteristics of the patients were recorded. Age, gravida, parity, abortus, body mass index (BMI), gestational week, smoking, mode of delivery, gestational weight, and perinatal outcomes were examined for each woman. The most common cancer types were thyroid (28.5%) and breast cancers (23.8%), which constituted just over half of the non-gynecologic cancer cases during pregnancy. The time elapsed after the diagnosis was 3.8±2.2 (1-9) years. No statistically significant differences were found between the two groups with regard to age, obstetric history, BMI, gestational week, smoking, and obstetric and perinatal outcomes (p>0.05). Negative perinatal outcomes in non-gynecologic cancer patients in remission were found to be within acceptable levels.


Correlation between coronary artery calcium score and aortic diameter in a high-risk population of elderly male hypertensive patients.
Studies on the relationship between coronary artery calcium and aortic diameter are scarce. The aim of the current study was to evaluate the correlation between coronary artery calcium score (CACS) and maximal thoracic and abdominal aortic diameters in a population of elderly (>65 years) male hypertensive patients at high risk for coronary artery disease. From June 2012 to April 2013, we prospectively enrolled 393 male hypertensive patients older than 65 years of age who had no history of aortic aneurysm. Coronary artery calcium and maximal diameters of the ascending thoracic aorta (ATAmax), descending thoracic aorta (DTAmax), and abdominal aorta (AAmax) were measured using noncontrast computed tomography imaging. Aortic diameters are indexed to body surface area (BSA). Participants were divided into five groups according to CACS (0, 1-10, 10-100, 100-400, and >400). The mean ATAmax/BSA, DTAmax/BSA, and AAmax/BSA were 22.0±2.7, 16.3±1.9, and 13.0±2.9 mm, respectively. On multivariate analysis, ATAmax/BSA was associated independently with age, diabetes, and history of aortic valve replacement (all P<0.001). DTAmax/BSA was associated independently with age (P<0.001). However, there were no significant correlations between thoracic aorta diameter and CACS. In contrast, AAmax/BSA was associated independently with CACS as well as age and history of smoking (P=0.014, 0.003, and 0.019, respectively). Abdominal aortic aneurysm (>30 mm) was more prevalent in patients with a CACS of 400 or more compared with the others (14 vs. 3%, P<0.001). CACS was associated with increased abdominal aorta diameter, but not with thoracic aorta diameter. Therefore, screening for an abdominal aortic aneurysm is warranted in patients with a high risk of coronary artery disease and a high CACS. However, the necessity for thoracic aortic aneurysm screening is not clear in these patients.


The function of nuclear architecture: a genetic approach.
Eukaryotic genomes are distributed on linear chromosomes that are grouped together in the nucleus, an organelle separated from the cytoplasm by a characteristic double membrane studded with large proteinaceous pores. The chromatin within chromosomes has an as yet poorly characterized higher-order structure, but in addition to this, chromosomes and specific subchromosomal domains are nonrandomly positioned in nuclei. This review examines functional implications of the long-range organization of the genome in interphase nuclei. A rigorous test of the physiological importance of nuclear architecture is achieved by introducing mutations that compromise both structure and function. Focussing on such genetic approaches, we address general concepts of interphase nuclear order, the role of the nuclear envelope (NE) and lamins, and finally the importance of spatial organization for DNA replication and heritable gene expression.