ADAM12 expression predicts clinical outcome in estrogen receptor-positive breast cancer.
Our study was aimed to make sure whether ADAM12 could serve as a prognostic biomarker of estrogen receptor (ER) -positive breast cancer. 127 patients with ER-positive breast cancer were included in the present study. The level of ADAM12 was assayed through real-time quantitative PCR (RT-qPCR). Levels of ADAM12 in tumor tissues and adjacent normal tissues were compared with paired t-test. The association of ADAM12 expression with clinical characteristics was analyzed via χ(2) test. Kaplan-Meier survival curve was used to evaluate the role of ADAM12 expression in overall survival (OS) of patients. Cox-regression analysis was performed to judge if ADAM12 could serve as a prognostic marker in breast cancer. The level of ADAM12 was upregulated in tumor tissues of breast cancer compared to that of adjacent normal tissues (P < 0.05). The expression of ADAM12 was closely related to the Ki-67 and HER2 status (P < 0.05 for both). The results of Kaplan-Meier survival curve showed that patients with higher level of ADAM12 exhibited shorter survival time compared to that of low level of ADAM12 (P < 0.001). Cox regression analysis showed that ADAM12 might be a biomarker in predicting prognosis of patients with ER-positive breast cancer (HR = 7.116, 95% CI = 3.329-15.212). ADAM12 appears to be a prognostic marker in ER-positive breast cancer.


Smoking cessation support groups in Israel: a long-term follow-up.
Smoking is the most important preventable cause of chronic disease in the western world. Many smokers want to quit, but have difficulty overcoming the addictive effect of nicotine. To assess the quitting rate of smokers who participated in smoking cessation groups and to characterize predictors of success or failure over a 1-3 years follow-up period. We studied 89 participants in 7 groups. Questionnaires were completed at baseline and after a follow-up period of 1 to 3 years. Smoking cessation was determined by self-report and a carbon monoxide breath test. Of the 89 participants in the support groups 76 (85%) were located. An intention-to-treat analysis was done for these participants. At follow-up 25 (33%) were non-smokers. There was a 95% agreement rate between self-report of smoking status and CO breath analysis. There were no differences between quitters and non-quitters in education level, gender, age at initiation of smoking, previous quit attempts, extent of participation in group meetings, concern about gaining weight, Fagerstrom index, or the number of close friends or relatives who smoke. Belief in one's ability to quit, satisfaction with group meetings, and spouse support were significantly associated with success (P < 0.01). The quit rate was 33%. Self-report is a reliable method for assessing smoking status. Smokers' belief in their ability to quit must be reinforced. Spouse participation in some group meetings may be beneficial, as may the involvement of a dietician and an expert on exercise. Follow-up "booster" meetings may also help.


Inhibition of Erythrocyte Cell Membrane Scrambling by ASP3026.
The anaplastic lymphoma kinase (ALK) inhibitor ASP3026 is in clinical development for the treatment of ALK expressing non-small cell lung carcinoma (NSCLC). ASP3026 is in part effective by inducing apoptosis of tumor cells. Erythrocytes lack mitochondria and nuclei, key organelles in the execution of apoptosis, but are nevertheless able to enter suicidal death or eryptosis, which is characterized by cell membrane scrambling with phosphatidylserine translocation to the cell surface and by cell shrinkage. Eryptosis is triggered by cell stress, such as energy depletion, hyperosmotic shock, oxidative stress and excessive increase of cytosolic Ca2+ activity ([Ca2+]i). The present study explored, whether ASP3026 impacts on eryptosis. Human erythrocytes have been exposed to energy depletion (glucose withdrawal for 48 hours), oxidative stress (addition of 0.3 mM tert-butylhydroperoxide [tBOOH] for 50 min) or Ca2+ loading with Ca2+ ionophore ionomycin (1 µM for 60 min) in absence and presence of ASP3026 (1-4 µg/ml). Flow cytometry was employed to quantify phosphatidylserine exposure at the cell surface from annexin-V-binding, and cell volume from forward scatter. Treatment with ASP3026 alone did not significantly modify annexin-V-binding or forward scatter. Energy depletion, oxidative stress and ionomycin, all markedly and significantly increased the percentage of annexin-V-binding erythrocytes, and decreased the forward scatter. ASP3026 significantly blunted the effect of energy depletion and oxidative stress, but not of ionomycin on annexin-V-binding. ASP3026 did not significantly influence the effect of any maneuver on forward scatter. ASP3026 is a novel inhibitor of erythrocyte cell membrane scrambling following energy depletion and oxidative stress.


Results of carotid re-exploration for post-carotid endarterectomy thrombosis.
Evaluate the results of carotid re-exploration for post-carotid endarterectomy (CEA) thrombosis associated with major neurological deficit. Data obtained from ongoing vascular registry. Retrospective analysis of 2216 consecutive CEAs performed in a single surgical practice. New neurological deficits developed in 53 patients (2.4%) following CEA. Fourteen patients sustained intraoperative stroke. Of 33 patients with postoperative stroke, nine patients had mild neurological deficit. Of the remaining 24 patients with postoperative stroke, five experienced intracerebral hemorrhage, three had strokes unrelated to operated artery, and one had stroke following control of bleeding from CEA patch disruption. The remaining 15 patients developed a significant neurological deficit following CEA and underwent re-exploration for postoperative carotid thrombosis. Five patients had minimal neurological improvement, five patients showed moderate recovery, and the remaining five patients had near complete recovery.Conclusion. Prompt re-exploration for post CEA thrombosis associated with major stroke can result in satisfactory outcome in majority of patients.


Isolation of volatile oil from thyme (Thymbra spicata) by steam distillation.
The effects of steam flow rate (1.03 and 0.64 L/h), distillation time, and particle size (0.50, 1.00, 2.05 mm) of Thymbra spicata on essential oil yield and sequence of extraction of compounds were studied. A logarithmic model fitted well to experimental data. The composition of the essential oil obtained by steam distillation was investigated for whole leaves only since the grinding had an adverse effect on yield. The oil obtained was very rich with respect to its carvacrol content. For both steam flow rates, oxygenated monoterpenes were recovered the most rapidly. Using whole leaves (2.05 mm) and a higher steam flow rate (1.03 L/h) for 75 min of distillation was chosen as the optimum which gives the lowest amount of monoterpene hydrocarbons, the complete recovery of oxygenated compounds, and the highest yield in a shorter time. Yield was 1.57% at this optimum condition. The oil was composed of 53.1% oxygenated compounds, 25.7% monoterpene hydrocarbons, 4.4% sesquiterpenes, and 14.1% p-cymene.


Trend for hypospadias repair among surgeons in Saudi Arabia: Insights and recommendations.
Currently, there are many techniques available for repairing hypospadias in urogenital reconstructive surgery. The purpose of this survey is to determine the preferred age of hypospadias repair patients, as well as the preferred surgical techniques among Saudi urologic and pediatric surgeons. An E-mail questionnaire was sent to urologic and pediatric surgeons throughout Saudi Arabia. Forty-six participants from the Saudi regions returned completed questionnaires. Sixty-five percent of participants preferred age to do surgery on 6-18 months. While, 50% preferred meatal advancement and glanduloplasty techniques for coronal/glandular hypospadias, and 46% participate that tubularized incised plate (TIP). It was found that 86% of the participants admitted to using TIP procedure for subcoronal/distal penile hypospadias, whereas the majority of them (63%) used TIP for midpenile/proximal hypospadias with significant value P < 0.05. Ninety-eight percentage of surgeons stated that they prefer performing the chordee repair simultaneously. As a final note, 91% of participants have been omitted preoperative androgen in their protocols. We concluded from the surgeons' preferences regarding hypospadias repair in this study, that their preferences are highly successful rate and have few complications; however, we highly recommend using this study as a basis for future studies.


[The seated position in patent foramen ovale?].
Anesthetic management of patients presenting for posterior cranial fossa surgery in the seated position includes detection and treatment of venous air embolism. Atrial positioning of a central venous (cv) line may be verified by either X-ray or an atrial ECG tracing. We report a case where a chest X-ray film proved superior. A 26-year-old white female was scheduled for posterior cranial fossa exploration. A cv line was inserted via the left antecubital vein; the chest X-ray film documented correct positioning of the catheter tip within the atrium but an aberrant course of the superior vena cava. Echocardiography was performed in the induction room and indicated a patent foramen ovale. In view of the risk of paradoxical air embolism, surgery was postponed. Subsequent cardiologic and radiologic examinations revealed a patent foramen ovale and a persisting left superior vena cava draining into a dilated coronary sinus. Surgery was rescheduled and carried out uneventfully in the prone position. This case demonstrates: 1) an advantage of a thoracic-X-ray film compared to atrial ECG tracing as not only the catheter tip position, but also the course of the catheter can be identified; and 2) the usefulness of preoperative screening for a patent foramen ovale in patients scheduled for surgery in the seated position.


Retinal blood flow indices in patients infected with human immunodeficiency virus.
Abnormal blood flow dynamics are believed to contribute to the development of retinal microvascular disease in patients infected with human immunodeficiency virus (HIV). In this study, the scanning laser ophthalmoscope (SLO) was used, combined with fluorescein angiography, to measure retinal blood flow indices in HIV seropositive patients. Arteriovenous passage time (AVP) and perifoveal capillary blood flow velocity (CFV) were measured in 23 HIV infected patients and 23 control subjects with SLO fluorescein angiography. No significant difference in AVP was found between the two groups. However, CFV was significantly reduced in HIV infected patients (p = 0.013). Patients infected with HIV show abnormal haemodynamics at the level of the perifoveal capillaries.


[Is Sexual Identity Optional? A Study of The Genetics of Transsexuality].
Transsexualism in the ICD-10 (International Classification of Diseases, Tenth Revision), Gender Dysphoria in adolescents and adults in the DSM-5 (Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition), is characterized by a marked incongruence between one's experienced gender and biological sex. The etiology is complex, but some hypotheses suggest that Gender Dysphoria (GD) arises from discrepant cerebral and biological sexual differentiation. Increasing evidence supports the idea of genetic vulnerability. Henningsson et al, (2004) found significant differences when they examined estrogen receptor β (ERβ) in a male-to- female (MtF) population. They suggested that a long ERβ polymorphism is more common in MtFs. Hare et al, (2009) also examined an MtF population and found a significant association between the androgen receptor (AR) and GD. Our group analyzed the same polymorphisms and found an association between ERα, ERβ and AR in GD. Our results suggest a genetic basis of GD in MtF and FtM populations. Our data corroborate the implication of the two estrogen receptors, ERα and β, and the androgen receptor in the genetic basis of GD, and advise the importance of estrogens and androgens in cerebral masculinization. Our data also confirm that sexual identity is not optional, but is determined prenatally by the genes, although it has a very important hormonal component. Therefore, its substrate is cerebral, not ideological.


Respiratory health in pre-school and school age children following extremely preterm birth.
Increasing survival at extremely low gestational ages is associated with very high rates of bronchopulmonary dysplasia (BPD) but is rarely quantified. To identify respiratory morbidity and risk factors in the EPICure cohort over the first 6 years of life. 308 babies born at < or =25 weeks' gestation in 1995 were followed up at 30 months and 6 years of age. Respiratory outcome was evaluated using clinical assessment, parental questionnaire and peak expiratory flow (PEF) at 6 years. 74% of this population received supplemental oxygen at 36 weeks postmenstrual age and 36% were discharged with supplemental oxygen which continued for a median of 2.5 months (75th percentile: 8.5 months). 236 children were followed to 6 years. Respiratory symptoms and medication use were more prevalent at 30 months and 6 years in children with BPD compared to those without. Children without BPD (n = 56) were not significantly different from their classmates but had consistently higher prevalence of poor respiratory health. Symptoms, need for hospital admission and medication use declined between 30 months and 6 years. 200 index children completed three PEF measures; PEF was lower than in classmates (mean adjusted difference: 39 l/min (95% CI 30 to 47)) and was lowest in children discharged home with oxygen and in those with BPD. Gestational age, BPD and maternal smoking at home and in pregnancy were independent risk factors for symptoms, but BPD was the only independent associate of PEF. Extremely preterm children have a continuum of poor respiratory health over the first 6 years, which is exacerbated by smoking during pregnancy and in the home.


Rescue of noncultivatable human rotavirus by gene reassortment during mixed infection with ts mutants of a cultivatable bovine rotavirus.
Fastidious human rotaviruses that did not undergo productive infection in tissue culture were rescued by genetic reassortment during mixed infection with a temperature-sensitive (ts) mutant of a cultivatable bovine rotavirus. In this manner, the genes of the fastidious rotavirus that restricted growth in vitro were replaced by the corresponding genes from a tissue culture-adapted rotavirus. We recovered genetically reassorted viruses that grew to high titer and were neutralized specifically by hyperimmune guinea pig type 1 or type 2 human rotavirus antiserum. Preliminary RNA analysis of these clones disclosed that they were indeed viruses with reassorted genes.


Clinical characteristics and complications of skull base osteomyelitis: A 12-year study in a teaching hospital in South India.
Skull base osteomyelitis (SBO) is an uncommon disease with substantial morbidity and mortality. The aim of this study is to characterize clinical features, outcomes, and complications of SBO. We also looked at differences in clinical profile in otogenic and non-otogenic SBO. This is a single-center retrospective observational study. Patients aged more than 15 years of age with clinical and radiological diagnosis of SBO admitted in general medicine department in a teaching hospital in South India from March 2006 to February 2018 were recruited. A total of 41 patients with SBO were identified and included. Mean age was 56.9 ± 10.7 years. In all, 90% of patients (37/41) had diabetes mellitus and 29% (12/41) had recent head/neck surgery. Only 19% (8/41) needed ICU care, and mortality was 21% (9/41). Most common symptom was headache seen in 73% (30/41) of patients. Majority, 61% (25/41), had otogenic infections. Otogenic infections were associated with longer duration of diabetes mellitus (mean = 11.5 vs. 5 years, P = 0.01), higher creatinine levels (mean = 1.66 vs. 0.9 mg/dL, P = 0.014, odds ratio [OR] = 3.8), and higher incidence of cranial nerve palsy (92% vs. 56%; OR = 8.9) compared to non-otogenic SBO. Cranial nerve palsy (78%), meningitis (63%), and cerebral venous thrombosis (43%) were frequent complications of SBO in this study. The causative organisms for SBO in our cohort was bacterial in 60% (15/25) and fungal in 40% (10/25) of the patients. Surgical debridement for source control was done in 54% of patients (22/41) and was associated with survival at discharge (P = 0.001). Bacterial infections are the most common cause of SBO. Otogenic SBO is associated with longer duration of diabetes mellitus and higher incidence of cranial nerve palsy. Therapeutic surgical debridement plays an important role in treatment of SBO and is associated with improved survival.


A Preliminary Examination of the Interaction between Maternal Generalized Anxiety Disorder and Offspring Negative Affect in Relation to Maternal Worry about Offspring and Perceptions of Psychological Control.
Both maternal symptoms and adolescent offspring characteristics are associated with maladaptive parenting among families at risk for anxiety. One disorder that may be particularly associated with maladaptive parenting behaviors is generalized anxiety disorder (GAD). Previous work suggests that offspring negative affect (NA) is associated with different levels of maladaptive parenting behaviors among mothers with GAD. No work to date, however, has examined the association between offspring reported NA, maternal GAD, and maternal worry about offspring or maternal perceptions of psychological control (PC) among mothers of adolescents. Sixty-five mothers who were elevated in anxious arousal and their adolescent offspring between the ages of 12 and 16 years old (n = 65, 55% male, Mage = 13.89) reported on parenting (mother report), NA (offspring report), and GAD symptoms (assessed via structured clinical interview), and maternal anxiety sensitivity (AS) symptoms. Study results indicated that maternal GAD status interacted with offspring NA in relation to maternal reported use of PC and worry about offspring. Specifically, offspring NA was positively related to PC for mothers without GAD, but not for mothers with GAD. Further, for mothers with GAD, offspring NA was negatively related to worry about offspring, but this relation did not persist for mothers without GAD. Maternal AS was related to overall higher levels of worry about offspring and PC. Mothers with GAD report using higher levels of maladaptive parenting when offspring report lower levels of NA, and lower levels when offspring report high NA. This pattern was specific to maternal GAD (c.f. anxiety sensitivity).


Myocardial injury in a 41-year-old male treated with methylphenidate: a case report.
Elevated cardiac troponin levels are consistent with the diagnosis of an acute coronary syndrome, but may also represent adverse drug reactions. Psychostimulating drugs raise both blood pressure and heart rate, and case reports of sudden death, stroke, and myocardial infarction have led to regulatory and public concern about the cardiovascular safety of these drugs. We present a case where a 41-year-old Norwegian male with radiating chest pain, elevated troponins, and supraventricular tachycardia was hospitalized. Tentative diagnosis was acute coronary syndrome. Percutaneous coronary angiography, but not cardiac magnetic resonance imaging, was performed and medical antiplatelet treatment started. Because of an attention deficit/hyperactivity disorder the patient had recently increased his dose of methylphenidate, but still within the therapeutic dose range. Apart from venlafaxine, also in a therapeutic dose, the patient took no other drugs. An acute coronary syndrome was excluded during hospitalization, and a drug effect was suspected. When interpreting troponin results it is important to take into account the context of the patient's clinical presentation, including the possibility of adverse drug reactions. The adverse drug reaction could include a combination of vasospasm and/or increased oxygen demand due to tachycardia. This case should be borne in mind before a diagnosis of myocardial infarction is given, or a decision to perform invasive coronary angiography is made in patients that use methylphenidate or related substances. Cardiac magnetic resonance imaging could be of diagnostic value in such cases.


Cryptic Biosynthesis of the Berkeleypenostatins from Coculture of Extremophilic Penicillium sp.
Coculture fermentation of Penicillium fuscum and P. camembertii/clavigerum yielded berkeleypenostatins A-G (1-7) as well as the previously reported berkeleylactones A-H, the known macrolide A26771B, citrinin, and patulin. As was true with the berkeleylactones, there was no evidence of the berkeleypenostatins in either axenic culture. The structures were deduced from analyses of spectral data, and the absolute configuration of berkeleypenostatin A (1) was determined by single-crystal X-ray crystallography. Berkeleypenostatins A (1) and E (5) inhibited migration of human pancreatic carcinoma cells (HPAF-II). Both compounds were tested by the NCI Developmental Therapeutics Program. In the NCI 60 cell five-dose screen, berkeleypenostatin E (5) was the more active of the two, with 1-10 μM total growth inhibition (TGI) of all leukemia cell lines, as well as the majority of colon, CNS, melanoma, ovarian, prostate, renal, and breast cancer cell lines.


Vestibulo-ocular reflex gain values in the suppression head impulse test of healthy subjects.
To assess whether there are differences in vestibulo-ocular reflex (VOR) gain for suppression head impulse (SHIMP) and head impulse (HIMP) video head impulse test paradigms, and if so, what are their causes. Prospective multicenter observational double-blind nonrandomized clinical study was performed by collecting 80 healthy subjects from four reference hospitals. SHIMP data was postprocessed to eliminate impulses in which early SHIMP saccades were detected. Differences between HIMP and SHIMP VOR gain values were statistically evaluated. Head impulse maximum velocity, gender, age, direction of impulse, and hospital center were considered as possible influential factors. A small significant statistical difference between HIMP and SHIMP VOR gain values was found on repeated measures analysis of variance (-0.05 ± 0.006, P < 0.001). Optimized linear model showed a significant influence of age variable on the observed differences for HIMP and SHIMP gain values and did not find influence between gain values differences and maximum head impulse velocity. Both HIMP and SHIMP VOR gain values were significant lower (-0.09, P < 0.001) when the impulses were performed to the left side. We had observed a difference in SHIMP and HIMP gain values not adequately explained by known gain modification factors. The persistence of this slight but significant difference indicates that there are more factors causing lower SHIMP VOR gain values. This difference must to be considered in further studies as well as in the clinical SHIMP testing protocols. We hypothesized that VOR phasic response inhibition could be the underlying cause of this difference. 2b. Laryngoscope, 128:2383-2389, 2018.


Xanthine oxidase-induced lung injury inhibits removal of 5-hydroxytryptamine from the pulmonary circulation.
We were interested in determining the effect of lung injury initiated by superoxide anions and hydroxyl radicals on removal of 5-hydroxytryptamine (5-HT) and phenylethylamine by the isolated perfused lung. The rate of removal and percentage of removal of these bioamines was determined before and after lung injury initiated by perfusion of the lung with hypoxanthine (HX) and xanthine oxidase (XO) or xanthine oxidase alone for 10 or 30 minutes; free radicals are generated by such treatment. Because of variation in removal of bioamines among lungs of different animals, the effects of lung injury on bioamine removal were determined by calculating the percentage of inhibition of removal using data from the control and test period for each lung. Perfusion of the lung with HX/XO or XO for 10 or 30 minutes significantly inhibited 5-HT removal by 39.5% and 63.3%, respectively. In contrast, only perfusion of the lung for 30 minutes with HX/XO produced inhibition of phenylethylamine uptake (by 54.8%). As uptake of 5-HT is the rate-limiting step in 5-HT removal, these data demonstrate dose (time)-related depression of active 5-HT uptake by free radicals generated in vitro. The rate-limiting step of phenylethylamine uptake, metabolism by monoamine oxidase, is inhibited only by severe lung injury.


Actin assembly and endocytosis: from yeast to mammals.
Internalization of receptors, lipids, pathogens, and other cargo at the plasma membrane involves several different pathways and requires coordinated interactions between a variety of protein and lipid molecules. The actin cytoskeleton is an integral part of the cell cortex, and there is growing evidence that F-actin plays a direct role in these endocytic events. Genetic studies in yeast have firmly established a functional connection between actin and endocytosis. Identification of several proteins that may function at the interface between actin and the endocytic machinery has provided further evidence for this association in both yeast and mammalian cells. Several of these proteins are directly involved in regulating actin assembly and could thus harness forces produced during actin polymerization to facilitate specific steps in the endocytic process. Recent microscopy studies in mammalian cells provide powerful evidence that localized recruitment and polymerization of actin occurs at endocytic sites. In this review, we focus on progress made in elucidating the functions of the actin cytoskeleton in endocytosis.


The R7 RGS protein family: multi-subunit regulators of neuronal G protein signaling.
G protein-coupled receptor signaling pathways mediate the transmission of signals from the extracellular environment to the generation of cellular responses, a process that is critically important for neurons and neurotransmitter action. The ability to promptly respond to rapidly changing stimulation requires timely inactivation of G proteins, a process controlled by a family of specialized proteins known as regulators of G protein signaling (RGS). The R7 group of RGS proteins (R7 RGS) has received special attention due to their pivotal roles in the regulation of a range of crucial neuronal processes such as vision, motor control, reward behavior, and nociception in mammals. Four proteins in this group, RGS6, RGS7, RGS9, and RGS11, share a common molecular organization of three modules: (i) the catalytic RGS domain, (ii) a GGL domain that recruits G beta(5), an outlying member of the G protein beta subunit family, and (iii) a DEP/DHEX domain that mediates interactions with the membrane anchor proteins R7BP and R9AP. As heterotrimeric complexes, R7 RGS proteins not only associate with and regulate a number of G protein signaling pathway components, but have also been found to form complexes with proteins that are not traditionally associated with G protein signaling. This review summarizes our current understanding of the biology of the R7 RGS complexes including their structure/functional organization, protein-protein interactions, and physiological roles.


Advanced Stages and Increased Need for Adjuvant Treatments in Breast Cancer Patients: The Effect of the One-year COVID-19 Pandemic.
The COVID-19 lockdown includes restrictive measures and temporary health system reorganization. Resources were shifted to COVID-19 patients, screening programs were temporary suspended, and oncological care suffered slow-down. The aim of the study was to evaluate the impact of these measures on breast cancer patients. All breast cancer patients referred to our unit from February 21, 2019 to February 21, 2021 were enrolled. Type of treatments and surgery, TNM, tumor diameter, and predictive and prognostic factors were analyzed. Out of 445 patients with a breast cancer diagnosis, 182 (40.9%) were enrolled in the COVID-19 group (from February 21, 2010 to February 21, 2021). These patients were compared with 263 (59.1%) patients pre-COVID-19. Tumor diameters were bigger in the COVID-19 group. Type of surgery and N staging were statistically significantly different. Extreme advanced disease incidence was significantly different between the groups (2.7% COVID-19 group vs. 0 pre-COVID-19 group, p=0.011). Incidence of post-surgical radiation-therapy was higher in the COVID-19 group. Other variables analyzed were comparable without a statistically significant difference. COVID-19 led to increased tumor dimensions, advanced N-staging, and increased need for adjuvant treatments in breast cancer.


Disease gene-fishing in molecular interaction networks: a case study in colorectal cancer.
In the post-genome era, disease-relevant gene finding and prioritization have focused on genome-wide association studies and molecular interaction networks, due to their power in characterizing the functions of genes/proteins in genomics and network biology contexts. In this paper, we describe a simple yet generic computational framework based on protein interaction networks to perform and evaluate disease gene-hunting, using colorectal cancer as a case study. We applied statistical measurements including specificity, sensitivity and Positive Predictive Value (PPV) to evaluate the performance of disease gene ranking methods, which we broke down into seed gene selection, protein interaction data quality and coverage, and network-based gene-ranking strategies. We discovered that best results may be obtained by using curated gene sets as seeds, applying protein interaction data set with high data coverage and decent quality, and adopting variants of local degree methods.


FATTY ACID SIGNATURES DIFFERENTIATE MARINE MACROPHYTES AT ORDINAL AND FAMILY RANKS(1).
Primary productivity by plants and algae is the fundamental source of energy in virtually all food webs. Furthermore, photosynthetic organisms are the sole source for ω-3 and ω-6 essential fatty acids (EFA) to upper trophic levels. Because animals cannot synthesize EFA, these molecules may be useful as trophic markers for tracking sources of primary production through food webs if different primary producer groups have different EFA signatures. We tested the hypothesis that different marine macrophyte groups have distinct fatty acid (FA) signatures by conducting a phylogenetic survey of 40 marine macrophytes (seaweeds and seagrasses) representing 36 families, 21 orders, and four phyla in the San Juan Archipelago, WA, USA. We used multivariate statistics to show that FA composition differed significantly (P < 0.001) among phyla, orders, and families using 44 FA and a subset of seven EFA (P < 0.001). A second analysis of published EFA data of 123 additional macrophytes confirmed that this pattern was robust on a global scale (P < 0.001). This phylogenetic differentiation of macrophyte taxa shows a clear relationship between macrophyte phylogeny and FA content and strongly suggests that FA signature analyses can offer a viable approach to clarifying fundamental questions about the contribution of different basal resources to food webs. Moreover, these results imply that taxa with commercially valuable EFA signatures will likely share such characteristics with other closely related taxa that have not yet been evaluated for FA content.


Polymethylmethacrylate augmentation of the pedicle screw: the cement distribution in the vertebral body.
Many studies have proven that the polymethylmethacrylate (PMMA) augmentation of the pedicle screw can significantly increase stiffness and strength of spinal fixation. Some major complications have also been reported. However, there are no reports discussing cement distribution and its morphology in the osteoporotic vertebral body, which is critical in the analysis of the biomechanical strength of the pedicle screw and the risk of cement leakage after pedicle screw augmentation. In this study, we used computed tomography (CT) to evaluate the cement distribution in the osteoporotic vertebral body after PMMA augmentation of a pedicle screw and to analyze the factors leading to cement leakage. Two groups of patients were studied. Group A consisted 25 osteoporotic patients (mean age of 73 years) with spinal instrumentation who had a total of 145 pedicle screws and cement augmentation with biopsy needles. Group B consisted of 23 osteoporotic patients (mean age of 74.6 years) with spinal instrumentation who had a total of 125 cannulated pedicle screws with cement augmentation. All patients had CT evaluation of the cement distribution in the vertebral body after the surgery. The cement distribution in the vertebrae was divided into four zones in the axial CT view: anterior one-third, middle third, and posterior third of vertebral body, and the pedicle. The morphology of the cement distribution around the pedicle screw was defined as scattered type or concentrate type. The leakage pattern was divided to anterior-lateral, posterior-lateral, and canal leakage. The correlations among bone mineral density (BMD), the cement leakage rate, and cement distribution morphology were also analyzed. The results showed that most augmented pedicle screws had cement extension into three of the four zones of the vertebral body (66.3%), followed by two zones (20%), all four zones (11.5%), and only one zone (2.2%). Overall, 123 screws (84.8%) in Group A and 108 screws (86.4%) in Group B had cement concentrate type distribution. The cement leakage rate in Group A is 18.3% and 13.6% in Group B. Patients with a BMD <0.6 g/cm(2) had significantly higher rates of cement leakage and tended toward a scattered cement distribution. There was only one patient who had a symptomatic leakage (sciatica) in Group B. We concluded that the cement distribution after pedicle screw augmentation with biopsy needle or cannulated screw technique was mostly localized in three zones of the vertebral body, and patients with lower BMD had a higher risk of cement leakage and scattered cement distribution.


Human cancer evolution in the context of a human immune system in mice.
Immunotherapy is one of the most promising cancer treatment modalities, but the lack of appropriate preclinical in vivo models hampers the development of novel immunotherapeutic strategies. Here, we studied the ability of transplanted human cancer cells to form primary tumors and metastasize in humanized immune system (HIS) mice created by transfer of CD34+ human hematopoietic stem cells. All tested transplanted cancer cell lines developed primary tumors that progressed nearly synchronously. Spontaneous lung and liver metastases developed from both orthotopic and ectopic transplanted cancer cells, and the ability to spread inversely correlated with the extent of CD8+ infiltration in the primary tumor. Further analysis revealed that interactions between the cancer model and the tumor-infiltrating lymphocytes created tumor microenvironments (TMEs) resembling clinical cancers. Some models were largely immune cell-excluding, while others appeared to develop adaptive resistance to immune-mediated destruction by increased expression of programmed death ligand 1 (PDL1) and recruitment of human regulatory T cells. Our data suggest that HIS mice may provide a promising in vivo tumor model for evaluating immune modulatory anticancer therapies. Moreover, our study identified different tumor models resembling specific types of human TMEs, rendering each beneficial for addressing disease-specific issues.


The rotator cuff muscles are antagonists after reverse total shoulder arthroplasty.
There is disagreement regarding whether, when possible, the rotator cuff should be repaired in conjunction with reverse total shoulder arthroplasty (RTSA). Therefore, we investigated the effects of rotator cuff repair in RTSA models with varying magnitudes of humeral and glenosphere lateralization. Six fresh frozen cadaveric shoulders were tested on a validated in vitro muscle-driven motion simulator. Each specimen was implanted with a custom adjustable, load-sensing RTSA after creation of a simulated rotator cuff tear. The effects of 4 RTSA configurations (0 and 10 mm of humeral lateralization and glenosphere lateralization) on deltoid force and joint load during abduction with and without rotator cuff repair were assessed. Deltoid force was significantly affected by increasing humeral lateralization (-2.5% ± 1.7% body weight [BW], P = .016) and glenosphere lateralization (+7.7% ± 5.6% BW, P = .016). Rotator cuff repair interacted with humeral and glenosphere lateralization (P = .005), such that with no humeral lateralization, glenosphere lateralization increased deltoid force without cuff repair (8.1% ± 5.1% BW, P = .012). This effect was increased with cuff repair (12.8% ± 7.8% BW, P = .010), but the addition of humeral lateralization mitigated this effect. Rotator cuff repair increased joint load (+11.9% ± 5.1% BW, P = .002), as did glenosphere lateralization (+13.3% ± 3.7% BW, P < .001). These interacted, such that increasing glenosphere lateralization markedly increased the negative effects of cuff repair (9.4% ± 3.2% BW [P = .001] vs. 14.4% ± 7.4% BW [P = .005]). Rotator cuff repair, especially in conjunction with glenosphere lateralization, produces an antagonistic effect that increases deltoid and joint loading. The long-term effects of this remain unknown; however, combining these factors may prove undesirable. Humeral lateralization improves joint compression through deltoid wrapping and increases the deltoid's mechanical advantage, and therefore, could be used in place of rotator cuff repair, thus avoiding its complications.


The treatment of an unstable slipped capital femoral epiphysis by either intracapsular cuneiform osteotomy or pinning in situ: a comparative study.
We undertook a retrospective comparative study of all patients with an unstable slipped capital femoral epiphysis presenting to a single centre between 1998 and 2011. There were 45 patients (46 hips; mean age 12.6 years; 9 to 14); 16 hips underwent intracapsular cuneiform osteotomy and 30 underwent pinning in situ, with varying degrees of serendipitous reduction. No patient in the osteotomy group was lost to follow-up, which was undertaken at a mean of 28 months (11 to 48); four patients in the pinning in situ group were lost to follow-up, which occurred at a mean of 30 months (10 to 50). Avascular necrosis (AVN) occurred in four hips (25%) following osteotomy and in 11 (42%) following pinning in situ. AVN was not seen in five hips for which osteotomy was undertaken > 13 days after presentation. AVN occurred in four of ten (40%) hips undergoing emergency pinning in situ, compared with four of 15 (47%) undergoing non-emergency pinning. The rate of AVN was 67% (four of six) in those undergoing pinning on the second or third day after presentation. Pinning in situ following complete reduction led to AVN in four out of five cases (80%). In comparison, pinning in situ following incomplete reduction led to AVN in 7 of 21 cases (33%). The rate of development of AVN was significantly higher following pinning in situ with complete reduction than following intracapsular osteotomy (p = 0.048). Complete reduction was more frequent in those treated by emergency pinning and was strongly associated with AVN (p = 0.005). Non-emergency intracapsular osteotomy may have a protective effect on the epiphyseal vasculature and should be undertaken with a delay of at least two weeks. The place of emergency pinning in situ in these patients needs to be re-evaluated, possibly in favour of an emergency open procedure or delayed intracapsular osteotomy. Non-emergency pinning in situ should be undertaken after a delay of at least five days, with the greatest risk at two and three days after presentation. Intracapsular osteotomy should be undertaken after a delay of at least 14 days. In our experience, closed epiphyseal reduction is harmful. Cite this article: Bone Joint J 2015;97-B:412-19.


The clinical pattern of subclinical/silent celiac disease: an analysis on 1026 consecutive cases.
The demographic, clinical, and epidemiological features of subclinical/silent celiac disease in Italy were analyzed in a multicenter study carried out with the participation of 42 centers, in the years between 1990 and 1994. One thousand twenty-six subclinical/silent patients (644 children and 382 adults, 702 women and 324 men) were considered eligible for the study. The prevalence of the subclinical/silent form increased significantly during the study both in adults (p < 0.001) and in children (p < 0.005), but its prevalence was always lower (p < 0.001) in children than in adults. This increase appears more likely due to a greater diagnostic awareness and to a better use of screening than to a higher number of subclinical/silent cases. Whereas in 1990 a significantly higher proportion (p < 0.001) of subclinical/silent celiac patients was diagnosed in Northern Italy rather than in Southern-Insular Italy, both in adults (46.7% vs 17.2%) and in children (22.0% vs 9.0%), in 1994 such a difference was no longer conspicuous. Both in children and in adults, iron-deficiency anemia appeared to be the most frequent extraintestinal symptom, followed by short stature in children and cutaneous lesions of dermatitis herpetiformis in adults. In 25.9% of the cases another disease was present, with a significantly higher frequency (p < 0.05) in adults (30.1%) than in children (20.7%). Diabetes and atopy appeared to be the most frequently associated conditions both in children and in adults. This study has provided an analysis of the largest series of subclinical/silent celiac disease reported to date. In Italy, this form is most frequently recognized in adults, and prospective studies will clarify whether the lower frequency observed in children is a real or apparent phenomenon.


[Sanitary-microbiological studies of oysters and seawater by the coast of the northern Caucasus].
Sanitary-microbiological studies carried out in 1985-1989 in the area of experimental raising of oysters at the northern Caucasus coast of the Black Sea have detected the correlation between the microflora of oysters and the quantitative and qualitative composition of the microflora of marine water, seasonal dynamics of the number of sanitary-indicative, tentatively pathogenic and saprophytic microorganisms of water and the raised oysters.


Low-Mg(2+) treatment increases sensitivity of voltage-gated Na(+) channels to Ca(2+)/calmodulin-mediated modulation in cultured hippocampal neurons.
Culture of hippocampal neurons in low-Mg(2+) medium (low-Mg(2+) neurons) results in induction of continuous seizure activity. However, the underlying mechanism of the contribution of low Mg(2+) to hyperexcitability of neurons has not been clarified. Our data, obtained using the patch-clamp technique, show that voltage-gated Na(+) channel (VGSC) activity, which is associated with a persistent, noninactivating Na(+) current (INa,P), was modulated by calmodulin (CaM) in a concentration-dependent manner in normal and low-Mg(2+) neurons, but the channel activity was more sensitive to Ca(2+)/CaM regulation in low-Mg(2+) than normal neurons. The increased sensitivity of VGSCs in low-Mg(2+) neurons was partially retained when CaM12 and CaM34, CaM mutants with disabled binding sites in the N or C lobe, were used but was diminished when CaM1234, a CaM mutant in which all four Ca(2+) sites are disabled, was used, indicating that functional Ca(2+)-binding sites from either lobe of CaM are required for modulation of VGSCs in low-Mg(2+) neurons. Furthermore, the number of neurons exhibiting colocalization of CaM with the VGSC subtypes NaV1.1, NaV1.2, and NaV1.3 was significantly higher in low- Mg(2+) than normal neurons, as shown by immunofluorescence. Our main finding is that low-Mg(2+) treatment increases sensitivity of VGSCs to Ca(2+)/CaM-mediated regulation. Our data reveal that CaM, as a core regulating factor, connects the functional roles of the three main intracellular ions, Na(+), Ca(2+), and Mg(2+), by modulating VGSCs and provides a possible explanation for the seizure discharge observed in low-Mg(2+) neurons.


Crooked, coiled and crimpled are three Ly6-like proteins required for proper localization of septate junction components.
Cellular junction formation is an elaborate process that is dependent on the regulated synthesis, assembly and membrane targeting of constituting components. Here, we report on three Drosophila Ly6-like proteins essential for septate junction (SJ) formation. SJs provide a paracellular diffusion barrier and appear molecularly and structurally similar to vertebrate paranodal septate junctions. We show that Crooked (Crok), a small GPI-anchored Ly6-like protein, is required for septa formation and barrier functions. In embryos that lack Crok, SJ components are produced but fail to accumulate at the plasma membrane. Crok is detected in intracellular puncta and acts tissue-autonomously, which suggests that it resides in intracellular vesicles to assist the cell surface localization of SJ components. In addition, we demonstrate that two related Ly6 proteins, Coiled (Cold) and Crimpled (Crim), are required for SJ formation and function in a tissue-autonomous manner, and that Cold also localizes to intracellular vesicles. Specifically, Crok and Cold are required for correct membrane trafficking of Neurexin IV, a central SJ component. The non-redundant requirement for Crok, Cold, Crim and Boudin (Bou; another Ly6 protein that was recently shown to be involved in SJ formation) suggests that members of this conserved family of proteins cooperate in the assembly of SJ components, possibly by promoting core SJ complex formation in intracellular compartments associated with membrane trafficking.


Effects of cell banking manipulations on ex vivo amplification of umbilical cord blood.
The small volume of placental/umbilical cord blood (PUCB) collectable restricts the use of these stem cells to pediatric transplantation. To extend the use of PUCB to adult recipients, many laboratories are investigating the feasibility of ex vivo PUCB expansion. The present study analyses the effects that PUCB banking cell manipulations (cell sedimentation, cryopreservation and thawing, mononuclear and CD34+ cell isolation) have on the number, viability and ex vivo expansion potential of PUCB cells. The results presented indicate the necessity of an open discussion on whether procedures used for handling the cells in PUCB banks can be extrapolated or not as such to the clinical use of ex vivo expanded PUCB.


Intracranial hematomas: imaging by high-field MR.
Twenty intracranial hematomas between 1 day and over 1 year old were imaged using magnetic resonance at 1.5 T, with T1- and T2-weighted spin-echo pulse sequences. Characteristic intensity patterns were observed in the evolution of the hematomas, which could be staged as acute (less than 1 week old), subacute (greater than 1 week and less than 1 month old), or chronic (greater than 1 month old). Acute hematomas were characterized by central hypointensity on T2-weighted images (WIs). Subacute hematomas had peripheral hyperintensity on T1-WIs and then on T2-WIs. This hyperintensity proceeded to fill in the hematoma in the chronic stage. In subacute and chronic hematomas, there was hypointensity on T2-WIs in the immediately adjacent part of the brain. On T2-WIs of acute and subacute hematomas, the nearby white matter was characterized by hyperintensity, consistent with edema. A different mechanism is proposed for each of the three characteristic intensity patterns. Two of these mechanisms increase in proportion to the square of the magnetic field magnitude.


Effectiveness of table top water pitcher filters to remove arsenic from drinking water.
Arsenic contamination of drinking water is a serious threat to the health of hundreds of millions of people worldwide. In the United States ~3 million individuals drink well water that contains arsenic levels above the Environmental Protection Agency (EPA) maximum contaminant level (MCL) of 10μg/L. Several technologies are available to remove arsenic from well water including anion exchange, adsorptive media and reverse osmosis. In addition, bottled water is an alternative to drinking well water contaminated with arsenic. However, there are several drawbacks associated with these approaches including relatively high cost and, in the case of bottled water, the generation of plastic waste. In this study, we tested the ability of five tabletop water pitcher filters to remove arsenic from drinking water. We report that only one tabletop water pitcher filter tested, ZeroWater®, reduced the arsenic concentration, both As3+ and As5+, from 1000μg/L to < 3μg/L, well below the MCL. Moreover, the amount of total dissolved solids or competing ions did not affect the ability of the ZeroWater® filter to remove arsenic below the MCL. Thus, the ZeroWater® pitcher filter is a cost effective and short-term solution to remove arsenic from drinking water and its use reduces plastic waste associated with bottled water.


Clinical study and literature review of nasal irrigation.
Nasal disease, including chronic rhinosinusitis and allergic rhinitis, is a significant source of morbidity. Nasal irrigation has been used as an adjunctive treatment of sinonasal disease. However, despite an abundance of anecdotal reports, there has been little statistical evidence to support its efficacy. The objective of this study was to determine the efficacy of the use of pulsatile hypertonic saline nasal irrigation in the treatment of sinonasal disease. A prospective controlled clinical study. Two hundred eleven patients from the University of California, San Diego (San Diego, CA) Nasal Dysfunction Clinic with sinonasal disease (including allergic rhinitis, aging rhinitis, atrophic rhinitis, and postnasal drip) and 20 disease-free control subjects were enrolled. Patients irrigated their nasal cavities using hypertonic saline delivered by a Water Pik device using a commercially available nasal adapter twice daily for 3 to 6 weeks. Patients rated nasal disease-specific symptoms and completed a self-administered quality of well-being questionnaire before intervention and at follow-up. Patients who used nasal irrigation for the treatment of sinonasal disease experienced statistically significant improvements in 23 of the 30 nasal symptoms queried. Improvement was also measured in the global assessment of health status using the Quality of Well-Being scale. Nasal irrigation is effective in improving symptoms and the health status of patients with sinonasal disease.


[Impact of surgical aggression and postoperative septic problems on fibronectin levels].
The following study has been carried out in order to assess the repercussion of surgery on fibronectin (F) levels and its course, whether or not septic complications are presented. The F, albumin (ALB), prealbumin (PREALB), retinol binding protein (RBP) and alpha-1-glycoprotein (GLYCO) levels were controlled in 37 patients (29 undergoing scheduled digestive tract surgery and 8 undergoing heart surgery), through preoperative and postoperative tests every three days. A group of 40 healthy controls was taken as reference. Group I contained 19 patients free of septic complications, statistically significant changes were observed in PREALB and RBP levels but not in F, although a decrease was observed which return to normal by the third test. Group II contained 18 patients which were subdivided into: a) 12 patients suffering from brief septic complication without known focus of infection and, b) 6 patients suffering from more severe septic complication with known focus of infection. The IIA subgroup showed a significant decrease in all protein levels, returning to normal levels by the sixth or seventh day. Subgroup IIB showed lower F levels, which did not return to normal before the ninth day. CONCLUSION. Preoperative controls were similar in I and IIa, while IIB showed significantly lower values. Although F decreased in the first preoperative control, it was not statistically significant. Patients not suffering from complications showed F recuperation within the first week, which was not the case of septic patients. Due to the wide number of functions of F and of the factors that influence it, we believe it should not be interpreted on a single basis a nutritional parameters.


Superradiance and Subradiance due to Quantum Interference of Entangled Free Electrons.
When multiple quantum emitters radiate, their emission rate may be enhanced or suppressed due to collective interference in a process known as super- or subradiance. Such processes are well known to occur also in light emission from free electrons, known as coherent cathodoluminescence. Unlike atomic systems, free electrons have an unbounded energy spectrum, and, thus, all their emission mechanisms rely on electron recoil, in addition to the classical properties of the dielectric medium. To date, all experimental and theoretical studies of super- and subradiance from free electrons assumed only classical correlations between particles. However, dependence on quantum correlations, such as entanglement between free electrons, has not been studied. Recent advances in coherent shaping of free-electron wave functions motivate the investigation of such quantum regimes of super- and subradiance. In this Letter, we show how a pair of coincident path-entangled electrons can demonstrate either super- or subradiant light emission, depending on the two-particle wave function. By choosing different free-electron Bell states, the spectrum and emission pattern of the light can be reshaped, in a manner that cannot be accounted for by a classical mixed state. We show these results for light emission in any optical medium and discuss their generalization to many-body quantum states. Our findings suggest that light emission can be sensitive to the explicit quantum state of the emitting matter wave and possibly serve as a nondestructive measurement scheme for measuring the quantum state of many-body systems.


Antifertility activity of methanolic bark extract of Aegle marmelos (l.) in male wistar rats.
Aegle marmelos leaf, seed and fruit from earlier studies is known to affect male fertility in reversible manner. However they had delayed onset and recovery was found to be prolonged. The present study was undertaken with an aim to evaluate the effect of Aegle marmelos bark extract on rats as the extract is found to be a rich source of marmin and fagarine known for reducing male fertility. Three different concentration of methanolic bark extracts of Aegle marmelos (L.) were evaluated for male antifertility activity on albino wistar rats. Methanolic bark extract of Aegle marmelos at the dose of 200, 400, and 600 mg/Kg b.w was administered orally for 60 days. Treatments were stopped thereafter and animals were sacrificed after a recovery period of 30 days. Control animal were administered vehicle (0.5% CMC for 60 days). Lonidamine was used as standard drug to compare the effect of extract. Methanolic extract causes a dose & duration dependent infertility via reducing reproductive organ weight and serum testosterone levels. Sperm analysis results showed reduction in sperm density, motility, viability and sperm acrosomal integrity without interfering libido and vital organ body weight. Histopathological studies of testes revealed exfoliation of elongated spermatids, nuclear chromatin condensation, degeneration and prominent spaces detected within the germinal epithelium signifying testicular cytotoxicity and necrosis. Time dependent complete infertility was observed in all dose levels. Animals after the withdrawal from treatment, for 30 days showed restoration of the morphological as well as physiological parameters in extract treated rats. Methanolic extract showed lipid lowering activity compared to control, suggestive good candidature of this plant for further studies. Our studies suggested Aegle marmelos barks methanolic extract as strong candidate for male contraceptive via its ability to produce complete inhibition of pregnancy, rapid restoration of fertility after withdrawal from treatment and its lipid correcting ability proving further beneficial effects.


Differential glycosylation, virion incorporation, and sensitivity to neutralizing antibodies of human immunodeficiency virus type 1 envelope produced from infected primary T-lymphocyte and macrophage cultures.
Two primary cell targets for human immunodeficiency virus type 1 (HIV-1) infection in vivo are CD4+ T lymphocytes and monocyte-derived macrophages (MDM). HIV-1 encodes envelope glycoproteins which mediate virus entry into these cells. We have utilized infected and radiolabelled primary peripheral blood mononuclear cell (PBMC) and MDM cultures to examine the biochemical and antigenic properties of the HIV-1 envelope produced in these two cell types. The gp120 produced in MDM migrates as a broad, diffuse band in sodium dodecyl sulfate-polyacrylamide gel electrophoresis gels compared with that of the more homogeneous gp120 released from PBMCs. Glycosidase analyses indicated that the diffuse appearance of the MDM gp120 is due to the presence of asparagine-linked carbohydrates containing lactosaminoglycans, a modification not observed with the gp120 produced in PBMCs. Neutralization experiments, using isogeneic PBMC and MDM-derived macrophage-tropic HIV-1 isolates, indicate that 8- to 10-fold more neutralizing antibody, directed against the viral envelope, is required to block virus produced from MDM. These results demonstrate that HIV-1 released from infected PBMC and MDM cultures differs in its biochemical and antigenic properties.


The prescription design and key properties of nasal gel for CNS drug delivery: A review.
Central nervous system (CNS) diseases are among the major health problems. However, blood-brain barrier (BBB) makes traditional oral and intravenous delivery of CNS drugs inefficient. The unique direct connection between the nose and the brain makes nasal administration a great potential advantage in CNS drugs delivery. However, nasal mucociliary clearance (NMCC) limits the development of drug delivery systems. Appropriate nasal gel viscosity alleviates NMCC to a certain extent, gels based on gellan gum, chitosan, carbomer, cellulose and poloxamer have been widely reported. However, nasal gel formulation design and key properties for alleviating NMCC have not been clearly discussed. This article summarizes gel formulations of different polymers in existing nasal gel systems, and attempts to provide a basis for researchers to conduct in-depth research on the key characteristics of gel matrix against NMCC.


Current gut-directed therapies for irritable bowel syndrome.
Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder that can present with a wide array of symptoms that make treatment difficult. Current therapies are directed at relieving symptoms of abdominal pain or discomfort, bloating, constipation, and diarrhea. Pharmacologic agents used to treat IBS-associated pain include myorelaxants, peppermint oil, and peripherally acting opiates. Dicyclomine and hyoscyamine, the two myorelaxants available in the United States, have not been proven effective in reducing abdominal pain in patients with IBS. The efficacy of peppermint oil is debated, but methodological problems with existing studies preclude definitive judgment. Loperamide is ineffective for relief of abdominal pain. For IBS patients with excessive abdominal bloating, a small number of studies suggest that bacterial eradication with gut-directed antibiotics and bacterial reconstitution with nonpathogenic probiotics may reduce flatulence. For constipation-predominant (C-IBS) symptoms, current treatment options include fiber supplementation, polyethylene glycol, and tegaserod. Soluble fibers (ispaghula, calcium polycarbophil, psyllium) are more effective than insoluble fibers (wheat bran, corn fiber) in alleviating global symptoms and relieving constipation, although fiber in general has marginal benefit in treatment of overall IBS symptoms. Polyethylene glycol increases bowel frequency in chronic constipation, but its overall efficacy against IBS is unclear. Tegaserod, a 5-HT(4) agonist, demonstrates superiority over placebo in improving bowel frequency and stool consistency and alleviating abdominal pain and bloating in women with C-IBS. Overall global symptoms are modestly improved with tegaserod when compared with placebo. Additional agents under investigation for C-IBS include the ClC(2) chloride channel opener lubiprostone, mu-opioid receptor antagonist alvimopan, and 5-HT(4) agonist renzapride. For diarrhea-predominant (D-IBS) symptoms, available therapies include loperamide, alosetron, and clonidine. Alosetron, a 5-HT(3) antagonist, is superior to placebo for reducing bowel frequency, improving stool consistency, and relieving abdominal pain in women with D-IBS. However, alosetron is available under a restricted license because of concerns for ischemic colitis and severe constipation necessitating colectomy. Clonidine may be helpful in alleviating global symptoms for D-IBS patients.


Carbohydrate restricted diet in conjunction with metformin and liraglutide is an effective treatment in patients with deteriorated type 2 diabetes mellitus: Proof-of-concept study.
Type 2 diabetes mellitus is a chronic progressive disease. During the course of the disease intensive treatment is often necessary resulting in multiple interventions including administration of insulin. Although dietary intervention is highly recommended, the clinical results of the widely prescribed diets with low fat content and high carbohydrates are disappointing. In this proof-of-concept study, we tested the effect of dietary carbohydrate-restriction in conjunction with metformin and liraglutide on metabolic control in patients with type 2 diabetes. Forty patients with type 2 diabetes already being treated with two oral anti-diabetic drugs or insulin treatment and who showed deterioration of their glucose metabolism (i.e. HbA1c >7.5), were treated. A carbohydrate-restricted diet and a combination of metformin and liraglutide were instituted, after stopping either insulin or oral anti-diabetic drugs (excluding metformin). After enrollment, the study patients were scheduled for follow-up visits at one, two, three and six months. Primary outcome was glycemic control, measured by HbA1c at six months. Secondary outcomes were body weight, lipid-profile and treatment satisfaction. Thirty-five (88%) participants completed the study. Nearly all participating patients experienced a drop in HbA1c and body weight during the first three months, an effect which was maintained until the end of the study at six months. Seventy-one percent of the patients reached HbA1c values below 7.0%. The range of body weight at enrollment was extreme, reaching 165 kg as the highest initial value. The average weight loss after 6 months was 10%. Most patients were satisfied with this treatment. During the intervention no significant change of lipids was observed. Most patients who were on insulin could maintain the treatment without insulin with far better metabolic control. Carbohydrate restriction in conjunction with metformin and liraglutide is an effective treatment option for patients with advanced diabetes who are candidates for instituting insulin or who are in need of intensified insulin treatment. This proof-of-principle study showed a significant treatment effect on metabolic control.


[Surgical ablation of atrial fibrillation using radiofrequency].
To evaluate the effectiveness of intraoperative atrial fibrillation ablation using radiofrequency during mitral valve procedure. This report describes the early and midterms results. Between September 2003 and September 2005, 15 patients with mitral disease were operated. All patients were in chronic atrial fibrillation and with congestive symptoms despite full medication. The patients were analysed according to clinical criteria, electrical and echocardiographic findings. There were no hospital mortality or complications related to radiofrequency ablation. The mean follow-up period was 12.16 +/- 10.29 months. All patients left operating room in sinus rhythm, however, before hospital discharge, only nine (60%) were in regular cardiac rhythm. During follow-up, two patients presented atrial fibrillation recurrence and currently seven (46.7%) keep sinus rhythm. Despite low morbimortality related to the procedure, initial results in this report showed a less effectiveness of this technique when compared with other papers.


Prediction of higher mortality reduction for the UK Breast Screening Frequency Trial: a model-based approach on screening intervals.
The optimal interval between two consecutive mammograms is uncertain. The UK Frequency Trial did not show a significant difference in breast cancer mortality between screening every year (study group) and screening every 3 years (control group). In this study, the trial is simulated in order to gain insight into the results of the trial and to predict the effect of different screening intervals on breast cancer mortality. UK incidence, life tables and information from the trial were used in the microsimulation model MISCAN-Fadia to simulate the trial and predict the number of breast cancer deaths in each group. To be able to replicate the trial, a relatively low sensitivity had to be assumed. The model simulated a larger difference in tumour size distribution between the two groups than observed and a relative risk (RR) of 0.83 of dying from breast cancer in the study group compared with the control group. The predicted RR is lower than that reported from the trial (RR 0.93), but within its 95% confidence interval (0.63-1.37). The present study suggests that there is benefit of shortening the screening interval, although the benefit is probably not large enough to start annual screening.


Radiotherapy in Fibrodysplasia Ossificans Progressiva: A Case Report and Systematic Review of the Literature.
Fibrodysplasia ossificans progressiva (FOP) is an autosomal dominant disease, characterized by the formation of heterotopic ossification (HO) in muscles, ligaments, and tendons. Flare-ups, an inflammatory process that often precedes the formation of HO, can occur spontaneously, but trauma is also a common trigger. It is not known whether radiotherapy, especially in higher doses, might cause sufficient trauma or inflammation to trigger a flare-up and subsequent HO in FOP patients. We report the case of a patient undergoing radiotherapy for the treatment of a 1-cm-wide basal cell carcinoma (BCC) of the lower lip. In addition, we present a systematic review of the available literature. Our patient received 54 Gy in 18 fractions with orthovoltage therapy, resulting in a clinical complete response of the tumor. Six months after treatment, there were no signs of HO either clinically or on [18F]NaF PET/CT. The systematic review identified 11 publications describing either radiation treatment in FOP or radiation therapy as a cause of HO in non-FOP patients. Six case reports described the use of radiation in FOP patients for various reasons, including one with a high-dose treatment of a lip BCC using superficial X-ray therapy. The remaining five studies described the use of low-dose radiotherapy to prevent or treat either an FOP flare-up or HO formation. None of these cases showed worsening of disease that could be attributed to the use of radiation therapy. Radiation induced HO in non-FOP patients was rare and occurred in five studies. The largest of these studies suggested that HO was induced after treatment with high doses, resulting in more widespread evidence of tissue damage, potentially being the end result of this damage. In conclusion, available reports suggest no contraindication to radiotherapy in FOP patients; although the number of cases was small, systematic toxicity reports often were not available, and none of the reports described high-dose, high-energy radiation treatment at locations such as muscle and joint regions.


Identifying cancer-related microRNAs based on subpathways.
MicroRNAs (miRNAs) are a class of small endogenous non-coding genes that play important roles in post-transcriptional regulation as well as other important biological processes. Accumulating evidence indicated that miRNAs were extensively involved in the pathology of cancer. However, determining which miRNAs are related to a specific cancer is problematic because one miRNA may target multiple genes and one gene may be targeted by multiple miRNAs. The authors proposed a new approach, named miR_SubPath, to identify cancer-associated miRNAs by three steps. The targeted genes were determined based on differentially expressed genes in significant dysfunctional subpathways. Then the candidate miRNAs were determined according to miRNA-genes associations. Finally, these candidate miRNAs were ranked based on their relations with some seed miRNAs in a functional similarity network. Results on real-world datasets showed that the proposed miR_SubPath method was more robust and could identify more cancer-related miRNAs than a prior approach, miR_Path, miR_Clust and Zhang's method.


[Reactions of the adrenal cortex and thyroid gland of hypophysectomized rats to hypothermia].
Male Wistar rats were hypophysectomized 7 days (group 1) and 4-7 weeks (group II) before exposure to hypothermia (4 degrees C for 1 1/2 h). The hypophysectomized rats from group I were devoid of both the posterior lobe and the adenohypophysis, while the rats from group II had the posterior hypophysis but not the adenohypophysis regenerated. A decreased arginine-vasopressin (AVP) blood level in group I (32%) and a very high level of AVP in group II (311%, P less than 0.05) was determined by RIA. The exposure to hypothermia did not influence the AVP plasma level. The thyroid hypofunction was revealed morphometrically in both hypophysectomized groups. Nevertheless, cooling stimulated the thyroid glands in rats of both experimental groups, like it was in the control. Thus, there is no evidence that thyroid gland reaction to hypothermia is affected by AVP. Cooling caused an increase of corticosteroid blood and adrenal cortex content in nonoperated control rats as well as in group II, but not in group I of experimental animals. Hence, it may be assumed that when the adenohypophysis is ablated, a high AVP blood level is necessary to realize the adrenal cortex response to hypothermia.


Effects of photodynamic therapy on rapidly growing nontuberculous mycobacteria keratitis.
The authors investigated the antimicrobial effect of methylene blue (MB)-mediated photodynamic therapy (PDT) on Mycobacterium fortuitum keratitis. In the in vitro study, the mycobacterial suspension and colonies were treated with the following: no MB, no light (normal control); MB and no light (dye control); light and no MB (light control); MB and light (PDT). Morphologic characteristics were examined by transmission electron microscopy. The bactericidal effects of combined PDT and antibiotic therapy (ciprofloxacin, moxifloxacin, and amikacin) were determined using the broth microdilution technique. Twenty-one rabbits with Mycobacterium keratitis were randomly divided into three groups (no treatment, topical amikacin treatment, and PDT combined with amikacin treatment). The clinical features of keratitis were scored and graded before treatment and before euthanatization. The diseased corneas were trephined for quantitative bacteriologic analysis to determine the antibacterial efficacy of the treatment. In the in vitro tests, the bacterial count had a 2-log reduction immediately after PDT treatment at 100 J/cm(2) with 10(-3)% MB. After PDT at 100 J/cm(2) with 10(-2)% MB, almost no viable bacteria were detected. PDT had a synergistic antimicrobial effect in combination with antibiotics. The phototoxicity occurred in the cytoplasm first and then disrupted the mycobacterial cell walls by lysis. In the rabbit keratitis model, combined PDT resulted in significantly less bacterial burden (P < 0.01) than in the amikacin group. This study demonstrated the effectiveness of MB-mediated PDT against Mycobacterium fortuitum. PDT could be a potential alternative treatment for nontuberculous mycobacterial corneal infections.


Mutations in the regulatory domain of phenylalanine hydroxylase and response to tetrahydrobiopterin.
Tetrahydrobiopterin (BH4) is a co-factor that enhances the activity of other enzymes, and this co-factor level is found to be affected in phenylketonuria (PKU), an amino acid metabolism disorder. The present study was aimed at understanding the effect of BH4 on mutations in the regulatory domain of phenylalanine hydroxylase (PAH). Among 14 patients, 5 patients were classical PKU, 3 were atypical PKU, and 6 were mild PKU. All of these patients had at least one mutation in the regulatory domain. Patients were given 10 mg/kg BH4, and the response of blood phenylalanine (Phe) levels was monitored following treatment. The level of blood Phe decreased after BH4 treatment in all of the patients. These studies suggest that mutations in the regulatory domain also responded to BH4 even if the patient had classical PKU.


Novel murine homeo box gene on chromosome 1 expressed in specific hematopoietic lineages and during embryogenesis.
We describe here a new murine homeo box gene, denoted Hlx, which is expressed within specific hematopoietic lineages. The cDNA sequence indicates that Hlx differs markedly from known vertebrate homeo box genes, and linkage analysis of an interspecific murine backcross showed that it resides at a novel homeo box locus on the distal portion of mouse chromosome 1. The Hlx homeo domain is most similar to that of the Drosophila H2.0 gene, but outside this region the two polypeptides are related only within a few short segments, the most notable being a motif (denoted Hep) also partially conserved in the engrailed and invected homeo proteins and possibly related to an octapeptide in certain paired box proteins. The presence of an intron within the Hlx homeo box at the same position as in several divergent Drosophila genes (H2.0, labial, Distal-less, proboscipedia, Abdominal-B, NK-1) suggests an ancient evolutionary relationship between these genes. RNA analysis of 67 murine hematopoietic cell lines and normal hematopoietic cells revealed Hlx expression throughout the myeloid/macrophage lineage and at early stages of B lymphocyte development but not in T lymphocytes, erythroid cells, or mast cells. Hence, Hlx is a candidate regulator of hematopoietic lineage commitment and maturation. It probably also functions outside the hematopoietic system, however, because Hlx mRNA could be detected in diverse adult tissues and in embryos from as early as day 8 of development.


Atomoxetine for depression and other neuropsychiatric symptoms in Parkinson disease.
Depression and antidepressant use, especially selective serotonin reuptake inhibitors (SSRIs), are common in Parkinson disease (PD). The objective of this clinical trial was to assess the efficacy of atomoxetine, a selective norepinephrine reuptake inhibitor (SNRI), for the treatment of clinically significant depressive symptoms and common comorbid neuropsychiatric symptoms in PD. A total of 55 subjects with PD and an Inventory of Depressive Symptomatology-Clinician (IDS-C) score > or = 22 were randomized to 8 weeks of atomoxetine or placebo treatment (target dosage = 80 mg/day). Depression response (> 50% decrease in IDS-C score or Clinical Global Impression-Improvement [CGI-I] score of 1 or 2) was assessed using intention-to-treat modeling procedures. Secondary outcomes included global cognition, daytime sleepiness, anxiety, apathy, and motor function. There were no between-groups differences in a priori-defined response rates. Using a more liberal response criterion of > 40% decrease in IDS score from baseline, there was a trend (p = 0.08) favoring atomoxetine. Patients receiving atomoxetine experienced significantly greater improvement in global cognition (p = 0.003) and daytime sleepiness (p = 0.001), and atomoxetine was well-tolerated. Atomoxetine treatment was not efficacious for the treatment of clinically significant depressive symptoms in PD, but was associated with improvement in global cognitive performance and daytime sleepiness. Larger studies of SNRIs in PD for disorders of mood, cognition, and wakefulness are appropriate. This interventional study provides Class II evidence that atomoxetine (target dosage = 80 mg/day) is not efficacious in improving clinically significant depression in PD.


A novel hybrid kinase is essential for regulating the sigma(B)-mediated stress response of Bacillus cereus.
A common bacterial strategy for monitoring environmental challenges is to use two-component systems, which consist of a sensor histidine kinase (HK) and a response regulator (RR). In the food-borne pathogen Bacillus cereus, the alternative sigma factor sigma(B) is activated by the RR RsbY. Here we present strong indications that the PP2C-type phosphatase RsbY receives its input from the multi-sensor hybrid kinase BC1008 (renamed RsbK). Genome analyses revealed that, across bacilli, rsbY and rsbK are located in a conserved gene cluster. A B. cereus rsbK deletion strain was shown to be incapable of inducing sigma(B) upon stress conditions and was impaired in its heat adaptive response. Comparison of the wild-type and rsbK mutant transcriptomes upon heat shock revealed that RsbK was primarily involved in the activation of the sigma(B)-mediated stress response. Truncation of the RsbK RR receiver domain demonstrated the importance of this domain for sigma(B) induction upon stress. The domain architecture of RsbK suggests that in the B. cereus group and in other bacilli, environmental and intracellular stress signalling routes are combined into one single protein. This strategy is markedly different from the sigma(B) activation pathway in other low-GC Gram-positives.


Improving the Odds: Intercostal Metal Coils Mark Area to Resect in Rib Lesions.
Precise localization of a rib lesion for its resection remains a challenge because of multiple factors including nonpalpable pathology, unfavorable body habitus, inaccurate clinical examination, and unreliable rib count on physical examination, unfavorable lesion location within a rib (its posterior aspect), and resection of sclerotic lesions with grossly intact rib cortex. We describe a novel rib localization technique that eliminates potential mistakes and avoids resection of an inappropriate rib. Our method of rib localization includes placement of metallic coils by interventional radiologists under computed tomography guidance where two coils are deployed within the intercostal spaces, one superior and one inferior to the rib lesion. Intraoperative use of fluoroscopy results in precise localization of rib lesions even in cases where the pathology is not grossly apparent. We implemented this approach in 2014 and have since performed it in five patients for both lytic and sclerotic lesions. Placement of markers superficial to the intercostal spaces resulted in their displacement in one case. Successfully, we removed the correct ribs in each patient without technical difficulties or complications. Our series demonstrates a novel strategy for a highly accurate and relatively easy way to identify the exact portion of the rib for surgical resection. Intercostal space positioning of the coil markers superior and inferior to the lesion prevents their dislodgement during patient transport and positioning on the operating room table, which improves rib identification accuracy and reliability. When combined with intraoperative fluoroscopy, it will greatly eliminate resection of incorrect ribs.


Big Five traits predict stress and loneliness during the COVID-19 pandemic: Evidence for the role of neuroticism.
The rapid outbreak of the coronavirus disease (COVID-19) has affected citizens' daily lives in an unprecedented way. To curb the spread of the pandemic, governments have taken numerous measures such as social distancing and quarantine, which may be associated with psychological consequences, namely stress and loneliness globally. To understand differential associations of personality traits with psychological consequences of COVID-19, we utilize data from a sample of 99,217 individuals from 41 countries collected as part of the COVIDiSTRESS Global Survey. Data were analyzed using multigroup confirmatory factor analysis and multilevel regression models. Findings showed that while some of the associations were rather weak, Big Five personality traits were significantly associated with perceived stress and loneliness during the pandemic. Our study illustrates that neuroticism especially can be a vulnerability factor for stress and loneliness in times of crisis and can contribute to detection of at-risk individuals and optimization of psychological treatments during or after the COVID-19 pandemic.


Antioxidant potentials and ajmalicine accumulation in Catharanthus roseus after treatment with giberellic acid.
Changes in antioxidant potentials and indole alkaloid, ajmalicine, production were studied in Catharanthus roseus (L.) G. Don. plants under treatment with gibberellic acid (GA(3)). The GA(3) treatments were given in two ways, foliar spray and soil drenching methods on 30, 45, 60 and 75 days after planting (DAP). The plants were uprooted randomly on 90 DAP and separated into root, stem and leaves and used for analyses. The antioxidant potential was studied in terms of non-enzymatc antioxidant molecules like ascorbic acid (AA), alpha-tocopherol (alpha-toc) and reduced glutathione (GSH) and activities of antioxidant enzyme, viz., superoxide dismutase (SOD), ascorbate peroxidase (APX) and catalase (CAT). The alkaloid ajmalicine was extracted and estimated from roots of both control and treated plants. It was found that, GA(3) has a profound effect upon the antioxidant potentials and it caused a significant enhancement in the production of ajmalicine when compared to untreated control as well as foliar-sprayed plants. There was no significant enhancement in GSH and ajmalicine content under GA(3) foliar spray in C. roseus. These preliminary results suggest that, the application of GA(3) may be a useful tool to increase the antioxidant potential and alkaloid production in medicinal plants like C. roseus.


Radiotherapy in small-cell lung cancer.
Radiotherapy is a critical component of multi-modality treatment of LS-SCLC and has an emerging role in ES-SCLC. Many of the recent advances in the management of SCLC have come by refining the role of radiotherapy in this disease. A significant amount of research is currently focused on the targeting of specific signaling cascades implicated in SCLC pathogenesis (eg Hedgehog, c-MET, insulin-like growth factor receptor 1 [IGFR-1R], mammalian target of rapamycin [mTOR], vascular endothelial growth factor [VEGF], and p53 and Bcl-2 pathways) and on other novel approaches to therapy including treatment with a novel oncolytic virus with tropism for neuroendocrine cells and CD56-targeted drug delivery. Clinical investigations of many of these therapies are ongoing, and the results may become available over the next several years.


Detection of anti-arboviral immunoglobulin G by using a monoclonal antibody-based capture enzyme-linked immunosorbent assay.
Monoclonal antibody (MAb)-based capture enzyme-linked immunosorbent assays (ELISAs) for the detection of anti-arboviral immunoglobulin G (IgG ELISAs) were developed for a comprehensive array of medically important arboviruses from the Alphavirus, Flavivirus, and Bunyavirus genera. Tests were optimized and standardized so that maximum homology could be maintained among working parameters for the different viral agents, enabling a wide range of viruses to be easily tested for at one time. MAbs were screened for suitability as capture vehicles for antigens from the three genera. The final test configuration utilized group-reactive MAbs eastern equine encephalitis virus 1A4B-6, dengue 2 virus 4G2, and La Crosse encephalitis virus 10G5.4 to capture the specific inactivated viral antigens. Serum IgG was detected by using alkaline phosphatase-conjugated anti-human IgG (Fc portion). A dilution of 1:400 was chosen as the universal screening serum dilution, with endpoint titrations of serum samples testing positive eliminating occasional false-positive results. IgG ELISA results correlated with those of the standard plaque-reduction neutralization assays. As expected, some test cross-reactivity was encountered within the individual genera, and tests were interpreted within the context of these reactions. The tests were standardized for laboratory diagnosis of arboviral infections, with the intent that they be used in tandem with the corresponding IgM antibody-capture ELISAs.


Increased Lipogenesis Is Important for Hexavalent Chromium-Transformed Lung Cells and Xenograft Tumor Growth.
Hexavalent chromium, Cr(VI), is a known carcinogen and environmental health concern. It has been established that reactive oxygen species, genomic instability, and DNA damage repair deficiency are important contributors to the Cr(VI)-induced carcinogenesis mechanism. However, some hallmarks of cancer remain under-researched regarding the mechanism behind Cr(VI)-induced carcinogenesis. Increased lipogenesis is important to carcinogenesis and tumorigenesis in multiple types of cancers, yet the role increased lipogenesis has in Cr(VI) carcinogenesis is unclear. We report here that Cr(VI)-induced transformation of three human lung cell lines (BEAS-2B, BEP2D, and WTHBF-6) resulted in increased lipogenesis (palmitic acid levels), and Cr(VI)-transformed cells had an increased expression of key lipogenesis proteins (ATP citrate lyase [ACLY], acetyl-CoA carboxylase [ACC1], and fatty acid synthase [FASN]). We also determined that the Cr(VI)-transformed cells did not exhibit an increase in fatty acid oxidation or lipid droplets compared to their passage-matched control cells. Additionally, we observed increases in ACLY, ACC1, and FASN in lung tumor tissue compared with normal-adjacent lung tissue (in chromate workers that died of chromate-induced tumors). Next, using a known FASN inhibitor (C75), we treated Cr(VI)-transformed BEAS-2B with this inhibitor and measured cell growth, FASN protein expression, and growth in soft agar. We observed that FASN inhibition results in a decreased protein expression, decreased cell growth, and the inhibition of colony growth in soft agar. Next, using shRNA to knock down the FASN protein in Cr(VI)-transformed BEAS-2B cells, we saw a decrease in FASN protein expression and a loss of the xenograft tumor development of Cr(VI)-transformed BEAS-2B cells. These results demonstrate that FASN is important for Cr(VI)-transformed cell growth and cancer properties. In conclusion, these data show that Cr(VI)-transformation in vitro caused an increase in lipogenesis, and that this increase is vital for Cr(VI)-transformed cells.


Spike Protein and the Various Cell-Surface Carbohydrates: An Interaction Study.
The SARS-CoV-2 virus has been known to gain entry into the host cell through the spike protein that binds to the host ACE2 cell surface protein. However, the role of the putative sugar-binding sites in the spike protein has remained unclear. We provide a comprehensive in silico outlook into the infection initiation wherein the virus first recognizes the sialosides on the cell via its S1A domain of the spike protein as it surfs over the cell surface. This facilitates the subsequent interaction with the cellular glycosaminoglycans through the S1B domain of the spike protein as it binds to the ACE2 receptor. The unique coadaptation to recognize both the host protein and the cell-surface carbohydrate receptors provides an additional coupling mechanism for efficient viral attachment and infection.


Multivariate analysis of blood oxygen saturation recordings in obstructive sleep apnea diagnosis.
This study focuses on the analysis of blood oxygen saturation (SaO(2)) from nocturnal pulse oximetry (NPO) to help in the diagnosis of the obstructive sleep apnea (OSA) syndrome. A population of 148 patients suspected of suffering from OSA syndrome was studied. A wide set of 16 features was used to characterize changes in the SaO(2) profile during the night. Our feature set included common statistics in the time and frequency domains, conventional spectral characteristics from the power spectral density (PSD) function, and nonlinear features. We performed feature selection by means of a step-forward logistic regression (LR) approach with leave-one-out cross-validation. Second- and fourth-order statistical moments in the time domain (M2t and M4t), the relative power in the 0.014-0.033 Hz frequency band ( P(R)), and the Lempel-Ziv complexity (LZC) were automatically selected. 92.0% sensitivity, 85.4% specificity, and 89.7% accuracy were obtained. The optimum feature set significantly improved the diagnostic ability of each feature individually. Furthermore, our results outperformed classic oximetric indexes commonly used by physicians. We conclude that simultaneous analysis in the time and frequency domains by means of statistical moments, spectral and nonlinear features could provide complementary information from NPO to improve OSA diagnosis.


The Predicted Proteomic Network Associated with the Antiarthritic Action of Qingfu Guanjieshu in Collagen-II-Induced Arthritis in Rats.
Qingfu Guanjieshu (QFGJS) is an herbal preparation for treating rheumatoid arthritis (RA). Previous studies revealed that QFGJS significantly inhibited experimental arthritis and acute inflammation, accompanied by reduction of proinflammatory cytokines and elevation of anti-inflammatory cytokines. This study aims to identify the targeted proteins and predict the proteomic network associated with the drug action of QFGJS by using 2D gel and MALDI-TOF-MS/MS techniques. Thirty female Wistar rats were evenly grouped as normal and vehicle- and QFGJS-treated CIA rats. The antiarthritic effect of QFGJS was examined with a 19-day treatment course, and the knee synovial tissues of animals from each group were obtained for 2D gel and MALDI-TOF-MS/MS analysis. Results showed that QFGJS significantly ameliorated collagen II-induced arthritis when administrated at 2.8 g/kg body weight for 19 days. 2D gel image analysis revealed 89 differentially expressed proteins in the synovial tissues among the normal and vehicle- and QFGJS-treated CIA rats from over 1000 proteins of which 63 proteins were identified by MALDI-TOF-MS/MS analysis, and 32 proteins were included for classification of functions using Gene Ontology (GO) method. Finally, 14 proteins were analyzed using bioinformatics, and a predicted proteomic network related to the anti-arthritic effect of QFGJS was established, and Pgk1 plays a central role.


Ultrasound and intestinal lesions in Schistosoma mansoni infection: A case-control pilot study outside endemic areas.
Infection with Schistosoma mansoni is a major cause of morbidity and mortality in endemic areas, and is increasingly diagnosed in migrants and travellers outside transmission areas. Markers for the assessment of morbidity and impact of control programs in endemic areas and for the clinical management of patients in the clinical setting are scant, especially for intestinal involvement. Ultrasonography is well established to evaluate hepatosplenic pathology; on the contrary, ultrasound evaluation of intestinal schistosomiasis is virtually unexplored. In this pilot study, we aimed to describe and evaluate the accuracy of unenhanced intestinal ultrasound for morbidity due to intestinal S. mansoni infection. We performed a blind case-control study of unenhanced intestinal ultrasound on 107 adults accessing the outpatient clinic of our Centre for Tropical Diseases between January-July 2018 as part of a screening for tropical diseases in migrants and travellers returning from endemic areas. Other clinical and laboratory data were obtained routine examination reports. We could not find any overtly pathological thickness of the gut wall in the sigma, proximal ascending colon, and terminal ileum, in patients with S. mansoni infection (n = 17), S. haematobium infection (n = 7), positive anti-Schistosoma serology (n = 31), and uninfected individuals (n = 52), with no difference among groups as assessed by ANOVA. No polyps or other intestinal abnormalities were visualized. There was no significant change in gut wall thickness one month after treatment with praziquantel in patients with S. mansoni infection (n = 11). Our preliminary results suggest that intestinal ultrasound might not be a sensitive tool for detecting minor intestinal morbidity due to schistosomiasis. Further studies in a hospital setting comparing colonoscopy and ultrasonography may be envisaged; in endemic areas, further studies are needed to describe and assess the usefulness of intestinal ultrasound in patients stratified by infection intensity and compared with markers such as calprotectin and fecal occult blood.


Soi3p/Rav1p functions at the early endosome to regulate endocytic trafficking to the vacuole and localization of trans-Golgi network transmembrane proteins.
SOI3 was identified by a mutation, soi3-1, that suppressed a mutant trans-Golgi network (TGN) localization signal in the Kex2p cytosolic tail. SOI3, identical to RAV1, encodes a protein important for regulated assembly of vacuolar ATPase. Here, we show that Soi3/Rav1p is required for transport between the early endosome and the late endosome/prevacuolar compartment (PVC). By electron microscopy, soi3-1 mutants massively accumulated structures that resembled early endosomes. soi3Delta mutants exhibited a kinetic delay in transfer of the endocytic tracer dye FM4-64, from the 14 degrees C endocytic intermediate to the vacuole. The soi3Delta mutation delayed vacuolar degradation but not internalization of the a-factor receptor Ste3p. By density gradient fractionation, Soi3/Rav1p associated as a peripheral protein with membranes of a density characteristic of early endosomes. The soi3 null mutation markedly reduced the rate of Kex2p transport from the TGN to the PVC but had no effect on vacuolar protein sorting or cycling of Vps10p. These results suggest that assembly of vacuolar ATPase at the early endosome is required for transport of both Ste3p and Kex2p from the early endosome to the PVC and support a model in which cycling through the early endosome is part of the normal itinerary of Kex2p and other TGN-resident proteins.


Crossing the Cervicothoracic Junction in Posterior Cervical Decompression and Fusion: A Cohort Analysis.
The cervicothoracic junction (CTJ) has often been identified as an area of biomechanical vulnerability; however, few studies have examined the relative merits of extending fusions across this area. In this study, we sought to investigate the tradeoffs involved in fusing across the CTJ in cases of elective posterior cervical laminectomy and fusion. We conducted a single-institution retrospective cohort study of patients undergoing elective, multilevel, posterior cervical decompression and fusion for degenerative cervical stenosis. Data were collected on baseline clinical and radiographic variables as well any subsequent complications or reoperations. Outcomes measures were compared between those who received fusion stopping at C7 with those who received fusion crossing the CTJ, with multivariate logistic regression used to adjust for any known confounders. Patients whose fusion crossed the CTJ were found to have more levels fused (mean: 5.8 vs. 3.5 levels, P < 0.0001), longer surgical times (mean: 216 vs. 149 minutes, P < 0.0001), and higher estimated blood losses (mean: 475 vs. 116 mL, P < 0.0001) despite no significant differences in number of levels decompressed (mean: 4.2 vs. 4.3 levels, P = 0.63). The groups did not differ in overall reoperation rate (10.8% vs. 9.4%, P = 1.00), but crossing the CTJ was associated with a higher rate of wound dehiscence (7.8% vs. 0%, P = 0.03). This difference persisted in multivariate analysis (P < 0.001). Crossing the CTJ was associated with increased surgical time, estimated blood loss, and the rates of wound dehiscence. These tradeoffs should be considered in planning posterior cervical decompression and fusion procedures.


Anomalous Nernst and Righi-Leduc Effects in Mn_{3}Sn: Berry Curvature and Entropy Flow.
We present a study of electric, thermal and thermoelectric response in noncollinear antiferromagnet Mn_{3}Sn, which hosts a large anomalous Hall effect (AHE). Berry curvature generates off-diagonal thermal (Righi-Leduc) and thermoelectric (Nernst) signals, which are detectable at room temperature and invertible with a small magnetic field. The thermal and electrical Hall conductivities respect the Wiedemann-Franz law, implying that the transverse currents induced by the Berry curvature are carried by Fermi surface quasiparticles. In contrast to conventional ferromagnets, the anomalous Lorenz number remains close to the Sommerfeld number over the whole temperature range of study, excluding any contribution by inelastic scattering and pointing to the Berry curvature as the unique source of AHE. The anomalous off-diagonal thermo-electric and Hall conductivities are strongly temperature dependent and their ratio is close to k_{B}/e.