[Beliefs of undergraduate nursing students on aging].
The objective of this study was to identify the conceptions of undergraduate Nursing students on aging. A qualitative research was carried at the Cidade de São Paulo University (Unicid); 49 students were requested to write a text whose theme was "what does being old mean?". The texts were submitted to a content analysis, in which three thematic units were identified: Representations of the old being; How respondents perceive old the elder in society and within the family; and the Need to change public opinion regarding aging. The results showed that conceptions of the students on aging are tied to negative images and showed the need for changes in the society and in the family.


Gender and lung cancer.
Although lung cancer is the leading cause of cancer death among men and women in the United States, female smokers appear to be at increased risk. After controlling for the number of cigarettes smoked, female sex imparts a significant, independent risk for most histologic types of lung cancer. Cigarette smoking, genetics, and endocrine factors may interact to contribute to the disparity in lung cancer risk between the sexes. Estrogens have direct and indirect actions in the lung, and estrogen has been implicated in lung carcinogenesis in female smokers. This review of the literature will focus on endocrine factors and tobacco carcinogens as risk factors for lung cancer in women.


The in vitro efficacy of neutral electrolysed water and povidone-iodine against CRS-associated biofilms.
Despite best medical and surgical practice, some cases of chronic rhinosinusitis (CRS) can remain recalcitrant. Bacterial biofilms have been associated with the recalcitrance of sinonasal inflammation. Biofilms are highly resistant to commonly prescribed antibiotics. Accordingly, more effective antimicrobial treatment options are needed to treat refractory CRS. The aim of this study was to determine the in vitro efficacy of neutral electrolysed water (NEW) and povidone-iodine (PVI) against CRS-associated Staphylococcus aureus biofilms. Mature S. aureus biofilms were grown in a Centre for Disease Control (CDC) biofilm reactor. The antimicrobial activity of NEW, PVI and doxycycline was determined for both planktonic and biofilm cultures of a clinical S. aureus isolate using minimum inhibitory concentration (MIC), minimum bactericidal concentration (MBC) and minimum biofilm eradication concentration (MBEC) assays. MICs and MBCs were determined for all antimicrobials. MBC values were similar to MICs for both antiseptics, but doxycycline MBCs were significantly higher than the associated MICs. Biofilms were highly resistant to NEW and doxycycline. The MBEC for doxycycline was between 500 and 1000 Â#181;g/mL. NEW was ineffective against biofilms and no MBEC could be determined. In contrast, a concentration of 10% of the commercial PVI solution (10 mg/mL PVI) led to effective eradication of mature biofilms. In this study, only PVI showed promising antibiofilm activity at physiological concentrations. The in vivo efficacy of PVI warrants further investigation of its potential as a treatment for recalcitrant CRS.


Minimally Invasive Treatment of Class 4 Invasive Cervical Resorption with Internal Approach: A Case Series.
Invasive cervical resorption (ICR) is a type of external resorption that can involve the coronal, middle, and apical parts of the root in its advanced stages. The diagnosis and treatment of ICR depend on the extent of the resorption into the dentin. The treatment of advanced ICR is challenging, and these teeth have poor prognoses. This article describes 4 cases of class 4 ICR diagnosed by using cone-beam computed tomography and treated with a minimally invasive internal approach with sodium hypochlorite irrigation and calcium hydroxide dressing. All cases were followed for at least 3 years.


N- to C-sulfonyl photoisomerisation of dihydropyridinones: a synthetic and mechanistic study.
The scope and limitations of a photoinitiated N- to C-sulfonyl migration process within a range of dihydropyridinones is assessed. This sulfonyl transfer proceeds without erosion of either diastereo- or enantiocontrol, and is general across a range of N-sulfonyl substituents (SO2R; R = Ph, 4-MeC6H4, 4-MeOC6H4, 4-NO2C6H4, Me, Et) as well as C(3)-(aryl, heteroaryl, alkyl and alkenyl) and C(4)-(aryl and ester) substitution. Crossover reactions indicate an intermolecular step is operative within the formal migration process, although no crossover from C-sulfonyl products was observed. EPR studies indicate the intermediacy of a sulfonyl radical and a mechanism is proposed based upon these observations.


Mean and Variance of Phylogenetic Trees.
We describe the use of the Fréchet mean and variance in the Billera-Holmes-Vogtmann (BHV) treespace to summarize and explore the diversity of a set of phylogenetic trees. We show that the Fréchet mean is comparable to other summary methods, and, despite its stickiness property, is more likely to be binary than the majority-rule consensus tree. We show that the Fréchet variance is faster and more precise than commonly used variance measures. The Fréchet mean and variance are more theoretically justified, and more robust, than previous estimates of this type and can be estimated reasonably efficiently, providing a foundation for building more advanced statistical methods and leading to applications such as mean hypothesis testing and outlier detection.


The natural history of prostatic cancer.
There are inner and outer gland groups in the human prostate. Benign nodular hyperplasia develops from the inner group of glands. Cancer develops from the outer gland group and consequently spreads beyond the prostate at an early stage in the disease. The biological malignancy of prostatic cancer varies from patient to patient and from part to part of the same tumor. Some tumors remain biologically inactive or latent so that there must be some naturally-occurring factor which controls tumor growth in these cases. Prostatic cancer patients may be divided into groups which differ in their response to endocrine treatment. These differences in response may be due to changes in the host or in the tumor cells. The temporary state of tumor retardation or latency follows endocrine treatment - generally anti-androgenic - in about 70 - 80% of all cases of prostatic cancer, but whatever form of treatment is used, about 75% of all cases die within 3 years. Even in tumors which show a marked response, endocrine treatment does not destroy all tumor cells. Hormone sensitivity therefore is not a property of the tumor as a whole but may vary from part to part of the same tumor. We need adequate well controlled clinical trials before we can decide which method of teatment is best but before we can do this satisfactorily we need methods to allow us to assess the stage and biological activity of individual tumors, before treatment begins.


Bioactivity of a 29-kilodalton insulin-like growth factor binding protein-3 fragment present in excess in chronic renal failure serum.
Children with chronic renal failure (CRF) have normal or high serum levels of GH, IGF-I, and IGF-II. Despite this, the serum of CRF patients has low IGF bioactivity, which may contribute to CRF growth failure. Recent studies suggest that excess IGF binding proteins (IGFBPs) in the approximately 35-kD fractions of CRF serum contribute to this low IGF bioactivity. This report characterizes a 29-kD form of IGFBP-3, IGFBP-3(29), which accumulates in the approximately 35-kD fractions of CRF serum and peritoneal dialysate. Deglycosylation and [125I]IGF ligand blot studies show that IGFBP-3(29) is a glycosylated IGFBP-3 fragment with low affinity for IGF peptides. Using an IGFBP-3 antibody column, IGFBP-3(29) was purified to homogeneity from the approximately 35-kD fractions of peritoneal dialysate from children with CRF. Compared with native IGFBP-3, pure IGFBP-3(29) has a 4-10-fold lower affinity for IGF-II and a 200-fold lower affinity for IGF-I. Consistent with the binding data, IGFBP-3(29) inhibited IGF-II-stimulated thymidine incorporation in chondrosarcoma cells, but was a less potent inhibitor than native IGFBP-3; also, native IGFBP-3 clearly inhibited IGF-I-stimulated thymidine incorporation in chondrosarcoma cells and potentiated IGF-I-stimulated aminoisobutyric acid uptake in bovine fibroblasts, but higher concentrations of IGFBP-3(29) had no effect on these IGF-I actions. Thus, the 29-kD IGFBP-3 form that accumulates in CRF serum and extravascular spaces is an IGFBP-3 fragment that may modulate IGF-II, but not IGF-I, effects on target tissues. Whether IGFBP-3(29) plays any role in the growth failure of children with CRF remains to be determined.


[Analysis of heterocyclic amines in food by liquid chromatography-tandem mass spectrometry].
A analytical method for simultaneous determination of 10 heterocyclic amines (HCAs) applicable to prepared foods on the market was studied. HCAs were extracted with acidic methanol, and then purified on a diatomaceous column and an ion-exchange column prior to LC-MS/MS. The method was validated within laboratory using three groups among the total diet samples (oils and fats, fish and shellfish, meat and eggs). The method showed good precision and trueness (as recovery) in duplicate analyses over 5 days, though there were some unsatisfactory results. Limits of detection (LOD) and quantification (LOQ) of the method were estimated from the deviation of the analytical results in samples spiked at a level of near 1 ng/g. In addition,13 groups of total diet samples, 27 items of retail food ready to eat and a few foods cooked in the laboratory were analyzed using this validated method. The results showed that the method is applicable to the foods tested in this study and provided information on the content of HCAs in some foods in Japan.


Ultraviolet Light Gel Manicures: Is There a Risk of Skin Cancer on the Hands and Nails of Young Adults?
BACKGROUND: There appears to be limited research on whether the ultraviolet radiation used in nail lamps for gel manicures is increasing the incidence of skin cancer on the hands and nails of young adults. OBJECTIVE: We sought to assess evidence in the literature regarding the incidence of skin cancer on the hands and nails of young adults who receive gel manicures cured by ultraviolet light. METHODS: An extensive systematic literature review was conducted, focusing on patients aged 40 years or younger with a history of gel manicures diagnosed with nonmelanoma or melanoma skin cancers on the dorsum of their hands and nails. The Surveillance, Epidemiology and End-results Program (SEER) (SEER 9 and SEER 21) was chosen to analyze trends in the incidence of melanoma from 2007 to 2016. The SEER*Stat Client-serve Mode software was used to retrieve the incidence rates of melanoma of the skin among individuals aged 0 to 39 years from 1975 to 2016. RESULTS: There have been no cases reported of patients younger than the age of 40 years with a history of chronic gel manicures diagnosed with nonmelanoma skin cancer or melanoma on the dorsum of the hands or nail matrices. SEER revealed little to no change in the incidence of melanoma among patients under the age of 65 years. CONCLUSION: The literature is controversial regarding whether ultraviolet radiation from chronic gel manicures increases the risk of skin cancer on the hands and nails. A comprehensive literature search and the SEER database revealed that gel manicures have little to no carcinogenic risk.


Urban waste disposal explains the distribution of Black Vultures (Coragyps atratus) in an Amazonian metropolis: management implications for birdstrikes and urban planning.
Collision rates between aircraft and birds have been rising worldwide. The increases in both air traffic and population sizes of large-bodied birds in cities lacking urban planning result in human-wildlife conflicts, economic loss and even lethal casualties. Black Vultures (Coragyps atratus) represent the most hazardous bird to Brazilian civil and military aviation on the basis of their flight behavior, body mass and consequently physical damage to aircraft following collisions. This study investigated how storage apparatus and type of organic residue discarded in public street markets modulate the spatial distribution and abundance of urban Black Vultures in the largest city in the Amazon (Manaus, Brazil). We estimated Black Vulture abundance in relation to the type of solid human waste (animal or plant), the type of waste storage containers and market sizes in terms of the number of vendor stalls at 20 public markets. We also visually quantified the abundance of Black Vultures in urban markets in relation to air traffic. Our results suggest that urban solid waste storage procedures currently used (or the lack thereof) are related to the occurrence and abundance of Black Vultures. Moreover, storage type and the proportion of animal protein (red meat and fish) within rubbish bins directly affects foraging aggregations in vultures. We recommend that policymakers should invest more efforts in building larger and more resistant closable waste containers to avoid organic solid waste exposure. We also identified five outdoor markets as urgent priorities to improve waste disposal. Finally, our waste management guidelines would not only reduce aviation collision risks but also benefit human health and well-being in most cities.


Regeneration through nerve isografts is independent of nerve geometry.
Investigators have theorized that tortuosity in nerve grafts may adversely affect nerve regeneration. This study investigated the effect of graft configuration and redundancy on regeneration across 2.5-cm rat sciatic nerve isografts. Thirty-two Lewis rats were randomized to four nerve grafting groups defined by gap distance and isograft conformation. In Group 1, grafts were interposed into a 2-cm gap, resulting in mild graft redundancy. In Groups 2 and 3, grafts were tacked in sinusoidal or omega-shaped configurations, respectively, to bridge a 0.5-cm gap. In Group 4, grafts were interposed after 1 cm of native sciatic nerve was resected, resulting in no graft redundancy and an interstump distance of 2.5 cm. At 6 weeks, nerve tissue was harvested; subsequent histomorphometric analysis revealed no significant differences in regeneration between groups. These data suggest that regeneration through isografts is independent of the graft geometry and redundancy.


The Dutch Pregnancy Drug Register: Suitable to Study Paternal Drug Exposures?
Paternal medication use around the time of conception is common, but information about its effects on pregnancy outcome and the health of the child is generally limited. The aim of this study is to examine the feasibility of studying paternal exposure in the Dutch Pregnancy Drug Register by using immunosuppressants as a proof of concept. In 113 of 15,959 pregnancies, long-term paternal immunosuppressant use was reported 3 months before conception. In total, 134 immunosuppressants were used. Pregnancy outcome was known for 54 cases and was in accordance with previous findings. Two spontaneous abortions, two premature births, six small for gestational age babies, and two major congenital malformations were reported. Time to pregnancy (TTP) was known for 9548 pregnancies, including 89 with paternal immunosuppressant use. TTP analysis did not show a difference in pregnancies with paternal immunosuppressant use compared to the control group. Moreover, the number of fertility treatments in the paternal immunosuppressant group was similar to the control group. In our opinion, it is feasible to use the Dutch Pregnancy Drug Register to study the effects of paternal exposure on pregnancy outcome. However, to study the potential effects on fertility, more information is needed, particularly since the beginning of pregnancy attempts.


[Supraventricular tachycardia of the fetus in the 3d trimester of pregnancy following persistent supraventricular extrasystole].
Persistent supraventricular extrasystoles are antepartally, intrapartally and postpartally the most frequent form of arrhythmias, and do not cause fetal congestive heart failure (hydrops fetalis). The premature beats often disappear spontaneously prenatally, but in most cases within the first two weeks of life. The extremely rare observation of the occurrence of a supraventricular tachycardia in the 37th week of gestation in a fetus with persistent supraventricular extrasystoles from the 20th week of gestation onward and with a postnatally diagnosed Wolff-Parkinson-White syndrome is described. Because of the importance of this complication of supraventricular extrasystoles (a supraventricular tachycardia of the fetus can cause a cardiac failure with hydrops fetalis and eventually intrauterine death), it is important that all fetuses with supraventricular extrasystoles be closely monitored by frequent observation of the fetal heart rate using ultrasound (M-mode-echocardiography), cardiotocography and auscultation. Postpartally a cardiologic examination of these newborn infants is necessary, particularly in order to exclude the presence of a preexcitation.


Kinematic improvement following Botulinum Toxin-A injection in upper-limb spasticity due to stroke.
Background Focal spasticity is a significant motor disorder following stroke, and Botulinum Toxin Type-A (BoNT-A) is a useful treatment for this. The authors evaluated kinematic modifications induced by spasticity, and whether or not there is any improvement following injection of BoNT-A. Methods Eight patients with stroke with upper-limb spasticity, showing a flexor pattern, were evaluated using kinematics before and after focal treatment with BoNT-A. A group of sex- and age-matched normal volunteers acted as a control group. Results Repeated-measures ANOVA showed that patients with stroke performed more slowly than the control group. Following treatment with BoNT-A, there was a significant improvement in kinematics in patients with stroke, while in the control group, performance remained unchanged. Conclusions Focal treatment of spasticity with BoNT-A leads to an adaptive change in the upper limb of patients with spastic stroke.


Nitric oxide synthetic pathway in patients with microvascular angina and its relations with oxidative stress.
A decreased nitric oxide (NO) bioavailability and an increased oxidative stress play a pivotal role in different cardiovascular pathologies. As red blood cells (RBCs) participate in NO formation in the bloodstream, the aim of this study was to outline the metabolic profile of L-arginine (Arg)/NO pathway and of oxidative stress status in RBCs and in plasma of patients with microvascular angina (MVA), investigating similarities and differences with respect to coronary artery disease (CAD) patients or healthy controls (Ctrl). Analytes involved in Arg/NO pathway and the ratio of oxidized and reduced forms of glutathione were measured by LC-MS/MS. The arginase and the NO synthase (NOS) expression were evaluated by immunofluorescence staining. RBCs from MVA patients show increased levels of NO synthesis inhibitors, parallel to that found in plasma, and a reduction of NO synthase expression. When summary scores were computed, both patient groups were associated with a positive oxidative score and a negative NO score, with the CAD group located in a more extreme position with respect to Ctrl. This finding points out to an impairment of the capacity of RBCs to produce NO in a pathological condition characterized mostly by alterations at the microvascular bed with no significant coronary stenosis.


Alcohol intoxication and alcoholism in acute male medical admissions.
In order to assess alcohol related morbidity in male hospital patients we studied all acute male admissions over a period of three months. 9.3% of patients were found to have detectable alcohol on admission (level greater than 4 mmol/l). A total of 28.3% of admissions were judged to be alcoholic by questionnaire (Michigan Alcohol Screening Test). These results suggest that acute intoxication in male hospital admissions is not as common as previously recorded. The prevalence of alcoholism, however, was disturbingly high and has significant implications for in-patient management.


Tuberculous otitis media: a case presentation and review of the literature.
A 42-year-old farmer being treated for pulmonary tuberculosis was referred to our clinic after developing otorrhoea and hearing loss in his right ear. Examination revealed a large subtotal perforation in the right ear in addition to a purulent discharge with right facial nerve palsy. Audiometry indicated a 35 dB conductive hearing loss at 0.5, 1 and 2 kHz with air-bone gaps of 12, 15 and 10 dB, respectively. A middle ear biopsy was performed under direct visualisation, with a middle ear lavage which was positive for allergic fungal sinusitis (AFS). The final diagnosis was tuberculous otitis media (TOM). Clinical symptoms and signs should be reviewed in every case of chronic otitis media keeping the possibility of tuberculosis in mind. Otorrhoea in a patient with known or suspected active pulmonary tuberculosis should be assumed to be TOM until proven otherwise.


Pharmacogenetic reactivation of the original engram evokes an extinguished fear memory.
Fear memory extinction has several characteristic behavioral features, such as spontaneous recovery, renewal, and reinstatement, suggesting that extinction training does not erase the original association between the conditioned stimulus (CS) and the unconditioned stimulus (US). However, it is unclear whether reactivation of the original physical record of memory (i.e., memory trace) is sufficient to produce conditioned fear response after extinction. Here, we performed pharmacogenetic neuronal activation using transgenic mice expressing hM3Dq DREADD (designer receptor exclusively activated by designer drug) under the control of the activity-dependent c-fos gene promoter. Neuronal ensembles activated during fear-conditioned learning were tagged with hM3Dq and subsequently reactivated after extinction training. The mice exhibited significant freezing, even when the fear memory was no longer triggered by external CS, indicating that the artificial reactivation of a specific neuronal ensemble was sufficient to evoke the extinguished fear response. This freezing was not observed in non-fear-conditioned mice expressing hM3dq in the same brain areas. These results directly demonstrated that at least part of the original fear memory trace remains after extinction, and such residual plasticity might reflect the persistent memory.


Is there a high-risk subtype of depression in patients with coronary heart disease?
Depression is a risk factor for cardiac morbidity and mortality in patients with coronary heart disease, especially in those with a recent history of acute coronary syndrome. To improve risk stratification and treatment planning, it would be useful to identify the characteristics or subtypes of depression that are associated with the highest risk of cardiac events. This paper reviews the evidence concerning several putative depression subtypes and symptom patterns that may be associated with a high risk of morbidity and mortality in cardiac patients, including single-episode major depressive disorder, depression that emerges after a cardiac event, somatic symptoms of depression, and treatment-resistant depression.


Transvaginal Sacrospinous Ligament Fixation for Pelvic Organ Prolapse Stage III and Stage IV Uterovaginal and Vault Prolapse.
The result of transvaginal sacrospinous ligament fixation technique, as part of the vaginal repair procedure for massive uterovaginal (Pelvic Organ Prolapse stage III and stage IV and vault prolapse) is evaluated. A total of 32 women were included in the present case series. Marked uterovaginal prolapse was present in 28 women and four had vault prolapse following hysterectomy. Patients with vault prolapse and marked uterovaginal prolapse underwent sacrospinous colpopexy. The mean follow-up period was 2.5 years. Out of the 28 patients with previous marked uterovaginal prolapse, only one had small cystocele 3 years after the surgery. This patient was asymptomatic and did not require repeat surgery. One woman had post-operative urinary tract infection and two had buttock discomfort, one had ischiorectal abscess and two had cuff cellulitis. All complications were dealt with successfully. No other major intra- and post-operative complications occurred. Transvaginal sacrospinous colpopexy can be performed together with vaginal hysterectomy, with marked uterovaginal prolapse and vault prolapse.


Clinical analysis of microbiologically proven fungal keratitis according to prior topical steroid use: a retrospective study in South Korea.
To compare the clinical characteristics and treatment outcomes of microbiologically proven fungal keratitis between users and non-users of prior topical steroids (PS and NPS, respectively). Eighty-three cases with microbiologically proven fungal keratitis between January 2000 and December 2016 were reviewed retrospectively. Diagnosis of fungal keratitis was made through potassium hydroxide smear, culture, PCR, or biopsy. Baseline epidemiology, predisposing factors, clinical characteristics, microbiological profiles, and treatment outcomes were evaluated and compared between the PS and NPS groups. Treatment failure was defined as any case with complications or requiring surgery. The risk factors for treatment failure were evaluated using multivariate logistic regression in the overall cohort. A total of 30 cases with PS group and 53 cases with NPS group were included. Of these, sixteen fungal isolates were identified in the PS group and 14 isolates in the NPS group. Candida was the most common organism in both groups (6 cases, respectively), while Aspergillus (4 cases) was found only in the PS group (p = 0.103). No significant differences were observed in the mean age, sex, occupational distribution, epithelial defect size, hypopyon, and presenting best-corrected visual acuity (BCVA) between the two groups. Differences were observed between the PS and NPS groups in terms of previous ocular surface disease (OSD) (43.3% vs. 22.6%, p = 0.048) and deep infiltration (53.3% vs. 32.1%, p = 0.057). Regarding treatment outcomes, final BCVA < 0.1 (60% vs. 44.2%, p = 0.133), the use of voriconazole (topical 10% vs. 0%, p = 0.044; systemic 23.3% vs. 1.9%, p = 0.003), surgical intervention (43.3% vs. 20.8%, p = 0.029), and treatment failure (46.7% vs. 22.6%, p = 0.023) were more common in the PS group than in the NPS group. The significant risk factors for treatment failure were hypopyon (odds ratio [OR] 6.01, p = 0.005) and deep infiltration (OR 4.38, p = 0.013). Previous OSD and deep infiltration were more common in the PS group compared to the NPS group. The PS group also experienced worse disease progression and treatment outcomes. These results highlight the need for paying attention to the use of steroids in clinical practice.


Individual variation and intraclass correlation in arachidonic acid and eicosapentaenoic acid in chicken muscle.
Chicken meat with reduced concentration of arachidonic acid (AA) and reduced ratio between omega-6 and omega-3 fatty acids has potential health benefits because a reduction in AA intake dampens prostanoid signaling, and the proportion between omega-6 and omega-3 fatty acids is too high in our diet. Analyses for fatty acid determination are expensive, and finding the optimal number of analyses to give reliable results is a challenge. The objective of the present study was i) to analyse the intraclass correlation of different fatty acids in five meat samples, of one gram each, within the same chicken thigh, and ii) to study individual variations in the concentrations of a range of fatty acids and the ratio between omega-6 and omega-3 fatty acid concentrations among fifteen chickens. Fifteen newly hatched broilers were fed a wheat-based diet containing 4% rapeseed oil and 1% linseed oil for three weeks. Five muscle samples from the mid location of the thigh of each chicken were analysed for fatty acid composition. The intraclass correlation (sample correlation within the same animal) was 0.85-0.98 for the ratios of total omega-6 to total omega-3 fatty acids and of AA to eicosapentaenoic acid (EPA). This indicates that when studying these fatty acid ratios, one sample of one gram per animal is sufficient. However, due to the high individual variation between chicken for these ratios, a relatively high number of animals (minimum 15) are required to obtain a sufficiently high power to reveal significant effects of experimental factors (e.g. feeding regimes). The present experiment resulted in meat with a favorable concentration ratio between omega-6 and omega-3 fatty acids. The AA concentration varied from 1.5 to 2.8 g/100 g total fatty acids in thigh muscle in the fifteen broilers, and the ratio between AA and EPA concentrations ranged from 2.3 to 3.9. These differences among the birds may be due to genetic variance that can be exploited by breeding for lower AA concentration and/or a more favorable AA/EPA ratio to produce meat with health benefits.


Protective Effect and Mechanism of Action of Rosmarinic Acid on Radiation-Induced Parotid Gland Injury in Rats.
The parotid glands are damaged by oxidative stress and a series of pathophysiological changes after irradiation. Rosmarinic acid (RA) is a natural antioxidant that provides a radioprotective effect against harmful damage from ionizing radiation. The present study aims to explore the protective effects of RA on radiation-induced parotid gland injury and its underlying mechanism. Sprague-Dawley rats were irradiated with 15 Gy X-ray and treated with different concentrations of RA (30, 60, and 120 mg/kg) or amifostine (AMI, 250 mg/kg). Saliva secretion function, oxidative stress, apoptosis, the inflammatory response, and fibrosis were determined by the measurement of the salivary flow rate, enzyme-linked immunosorbent assay, transferase-mediated DUTP Nick end labeling, Western blot, quantitative real time polymerase chain reaction, and hematoxylin and eosin staining. Here, we show that RA treatment significantly attenuated reactive oxygen species by a direct hindrance effect and the indirect activation of peroxisome proliferator-activated receptor gamma coactivator 1-alpha/nicotinamide adenine dinucleotide phosphate oxidase 4 signaling. Rosmarinic acid not only reduced apoptosis by inhibiting p53/jun N-terminal kinase activation but also reduced parotid gland tissue fibrosis by downregulating inflammatory factor levels. Compared to AMI, RA has the obvious advantages of late efficacy and convenient usage. Moreover, 60 mg/kg is the minimum effective dose of RA. Therefore, RA can potentially be applied as a therapeutic radioprotective agent to treat radiation-induced parotid gland injury in the future.


Signal-Space Projection Suppresses the tACS Artifact in EEG Recordings.
To probe the functional role of brain oscillations, transcranial alternating current stimulation (tACS) has proven to be a useful neuroscientific tool. Because of the excessive tACS-caused artifact at the stimulation frequency in electroencephalography (EEG) signals, tACS + EEG studies have been mostly limited to compare brain activity between recordings before and after concurrent tACS. Critically, attempts to suppress the artifact in the data cannot assure that the entire artifact is removed while brain activity is preserved. The current study aims to evaluate the feasibility of specific artifact correction techniques to clean tACS-contaminated EEG data. In the first experiment, we used a phantom head to have full control over the signal to be analyzed. Driving pre-recorded human brain-oscillation signals through a dipolar current source within the phantom, we simultaneously applied tACS and compared the performance of different artifact-correction techniques: sine subtraction, template subtraction, and signal-space projection (SSP). In the second experiment, we combined tACS and EEG on one human subject to demonstrate the best-performing data-correction approach in a proof of principle. The tACS artifact was highly attenuated by SSP in the phantom and the human EEG; thus, we were able to recover the amplitude and phase of the oscillatory activity. In the human experiment, event-related desynchronization could be restored after correcting the artifact. The best results were achieved with SSP, which outperformed sine subtraction and template subtraction. Our results demonstrate the feasibility of SSP by applying it to a phantom measurement with pre-recorded signal and one human tACS + EEG dataset. For a full validation of SSP, more data are needed.


Health promotion interventions for community-dwelling older people with mild or pre-frailty: a systematic review and meta-analysis.
Mild or pre-frailty is common and associated with increased risks of hospitalisation, functional decline, moves to long-term care, and death. Little is known about the effectiveness of health promotion in reducing these risks. This systematic review aimed to synthesise randomised controlled trials (RCTs) evaluating home and community-based health promotion interventions for older people with mild/pre-frailty. We searched 20 bibliographic databases and 3 trials registers (January 1990 - May 2016) using mild/pre-frailty and associated terms. We included randomised controlled and crossover trials of health promotion interventions for community-dwelling older people (65+ years) with mild/pre-frailty and excluded studies focussing on populations in hospital, long term care facilities or with a specific condition. Risk of bias was assessed by two reviewers using the Cochrane Risk of Bias tool. We pooled study results using standardised mean differences (SMD) where possible and used narrative synthesis where insufficient outcome data were available. We included 10 articles reporting on seven trials (total n = 506 participants) and included five trials in a meta-analysis. Studies were predominantly small, of limited quality and six studies tested group exercise alone. One study additionally investigated a nutrition and exercise intervention and one evaluated telemonitoring. Interventions of exercise in groups showed mixed effects on functioning (no effects on self-reported functioning SMD 0.19 (95% CI -0.57 to 0.95) n = 3 studies; positive effects on performance-based functioning SMD 0.37 (95% CI 0.07 to 0.68) n = 3 studies). No studies assessed moves to long-term care or hospitalisations. Currently the evidence base is of insufficient size, quality and breadth to recommend specific health promotion interventions for older people with mild or pre- frailty. High quality studies of rigorously developed interventions are needed. CRD42014010370 (Review 2).


A randomized trial of laparoscopic versus open Nissen fundoplication in children under two years of age.
The surgery of gastroesophageal reflux disease (GERD) is common in modern pediatric surgical practice. Any differences in perioperative and long-term clinical outcomes following laparoscopic (LN) or open Nissen (ON) fundoplication have not been comprehensively described in young children. This randomized, prospective study examines outcomes following LN versus ON in children<2 years of age. Four surgeons at a single institution enrolled patients under 2 years of age that required surgical management of GERD, who were then randomized to LN or ON between 2005 and 2012. A universal surgical dressing was employed for blinding. Analgesia and enteral feeding pathways were standardized. The primary outcome was postoperative length of stay. Perioperative outcomes and long-term follow up were collected as secondary outcomes and used to compare groups. Of 39 enrolled patients, 21 were randomized to ON and 18 to LN. Length of postoperative hospital stay, time of advancement to full enteral feeds, and analgesic requirements were not significantly different between treatment cohorts. The LN group experienced longer median operating times (173 vs 91 min, P<0.001) and higher surgical charges ($4450 vs $2722, P=0.002). The incidence of post-discharge complications did not differ significantly between the groups at last follow-up (median 42 months). This randomized trial comparing postoperative outcomes following LN vs ON did not detect statistically significant differences in short- or long-term clinical outcomes between these approaches. LN was associated with longer surgical time and higher operating room costs. The benefits, risks, and costs of laparoscopy should be carefully considered in clinical pediatric surgical practice.


Magnolol depresses urotensin-II-induced cell proliferation in rat cardiac fibroblasts.
1. Accumulating evidence suggests that oxidative stress plays a key role in the development of cardiac fibrosis. Urotensin-II (U-II) has been reported to play an important role in cardiac remodelling and fibrosis. Recently, we demonstrated the involvement of reactive oxygen species (ROS) production in U-II-induced cardiac fibroblast proliferation. Magnolol is an anti-oxidant compound extracted from the cortices of Magnolia officinalis. Thus, it is feasible that magnolol may attenuate cardiac fibroblast proliferation by inhibiting ROS production. Therefore, the aims of the present study were to determine whether magnolol alters U-II-induced cell proliferation and to identify the putative underlying signalling pathways in rat cardiac fibroblasts. 2. Cultured rat cardiac fibroblasts were pretreated with magnolol (1, 3 and 10 micromol/L) for 30 min, followed by exposure to U-II (30 nmol/L) for 24 h, after which cell proliferation and endothelin-1 (ET-1) protein secretion was examined. The effects of magnolol on U-II-induced ROS formation and extracellular signal-regulated kinase (ERK) phosphorylation were examined to elucidate the intracellular mechanisms by which magnolol affects cell proliferation and ET-1 expression. 3. Urotensin-II (30 nmol/L) stimulated cell proliferation, ET-1 protein secretion and ERK phosphorylation, all of which were inhibited by magnolol (10 micromol/L). Pretreatment of cardiac fibroblasts with N-acetylcysteine (5 mmol/L) for 30 min prior to exposure to U-II resulted in inhibition of U-II increased ROS formation. Similar effects were observed with 10 micromol/L magnolol. 4. In conclusion, the results suggest that magnolol inhibits cardiac fibroblast proliferation by interfering with ROS generation. Thus, the present study provides important new insights into the molecular pathways involved, which may contribute to our understanding of the effects of magnolol on the cardiovascular system.


Morbidity associated with prolonged use of polyvinyl feeding tubes.
In two newborn infants, morbidity was associated with long-term use of polyvinyl chloride feeding tubes. In one case, a hard, sharp catheter was thought to be responsible for peritonitis. In other, the polyvinyl tube hardened into a coil that could only be extricated by introduction of an intraluminal guide wire and prolonged manipulation under fluoroscopic control. The rigidity acquired by these tubes is thought to present serious potential for morbidity and mortality. Methods and materials appropriate for short-term alimentation should no be presumed appropriate for long-term use, and alternatives should be considered.


Phylogeography of the pantropical sea urchin Tripneustes: contrasting patterns of population structure between oceans.
To understand how allopatric speciation proceeds, we need information on barriers to gene flow, their antiquity, and their efficacy. For marine organisms with planktonic larvae, much of this information can only be obtained through the determination of divergence between populations. We evaluated the importance of ocean barriers by studying the mitochondrial DNA phylogeography of Tripneustes, a pantropical genus of shallow water sea urchin. A region of cytochrome oxidase I (COI) was sequenced in 187 individuals from locations around the globe. The COI phylogeny agreed with a previously published phylogeny of bindin that barriers important to the evolution of Tripneustes are: (1) the cold water upwelling close to the tip of South Africa, (2) the Isthmus of Panama, (3) the long stretch of deep water separating the eastern from the western Atlantic, and (4) the freshwater plume of the Orinoco and the Amazon rivers between the Caribbean and the coast of Brazil. These barriers have previously been shown to be important in at least a subset of the shallow water marine organisms in which phylogeography has been studied. In contrast, the Eastern Pacific Barrier, 5000 km of deep water between the central and the eastern Pacific that has caused the deepest splits in other genera of sea urchins, is remarkably unimportant as a cause of genetic subdivision in Tripneustes. There is also no discernible subdivision between the Pacific and Indian Ocean populations of this genus. The most common COI haplotype is found in the eastern, central, and western Pacific as well as the Indian Ocean. Morphology, COI, and bindin data agree that T. depressus from the eastern Pacific and T. gratilla from the western Pacific are, in fact, the same species. The distribution of haplotype differences in the Indo-Pacific exhibits characteristics expected from a sea urchin genus with ephemeral local populations, but with high fecundity, dispersal, and growth: there is little phylogenetic structure, and mismatch distributions conform to models of recent population expansion on a nearly global scale. Yet, comparisons between local populations produce large and significant F(ST) values, indicating nonrandom haplotype distribution. This apparent local differentiation is only weakly reflected in regional divergence, and there is no evidence of isolation by distance in correlations between F(ST) values and either geographical or current distance. Thus, Tripneustes in the Indo-Pacific (but not in the Atlantic) seems to be one large metapopulation spanning two oceans and containing chaotic, nonequilibrium local variation, produced by the haphazard arrival of larvae or by unpredictable local extinction.


Linezolid-resistant Staphylococcus aureus strain 1128105, the first known clinical isolate possessing the cfr multidrug resistance gene.
The Cfr methyltransferase confers resistance to six classes of drugs which target the peptidyl transferase center of the 50S ribosomal subunit, including some oxazolidinones, such as linezolid (LZD). The mobile cfr gene was identified in European veterinary isolates from the late 1990s, although the earliest report of a clinical cfr-positive strain was the 2005 Colombian methicillin-resistant Staphylococcus aureus (MRSA) isolate CM05. Here, through retrospective analysis of LZD(r) clinical strains from a U.S. surveillance program, we identified a cfr-positive MRSA isolate, 1128105, from January 2005, predating CM05 by 5 months. Molecular typing of 1128105 revealed a unique pulsed-field gel electrophoresis (PFGE) profile most similar to that of USA100, spa type t002, and multilocus sequence type 5 (ST5). In addition to cfr, LZD resistance in 1128105 is partially attributed to the presence of a single copy of the 23S rRNA gene mutation T2500A. Transformation of the ∼37-kb conjugative p1128105 cfr-bearing plasmid from 1128105 into S. aureus ATCC 29213 background strains was successful in recapitulating the Cfr antibiogram, as well as resistance to aminoglycosides and trimethoprim. A 7-kb cfr-containing region of p1128105 possessed sequence nearly identical to that found in the Chinese veterinary Proteus vulgaris isolate PV-01 and in U.S. clinical S. aureus isolate 1900, although the presence of IS431-like sequences is unique to p1128105. The cfr gene environment in this early clinical cfr-positive isolate has now been identified in Gram-positive and Gram-negative strains of clinical and veterinary origin and has been associated with multiple mobile elements, highlighting the versatility of this multidrug resistance gene and its potential for further dissemination.


Inflammation in arterial diseases.
The pathophysiology of some inflammatory arterial diseases (such as vasculitis, atherogenesis and aneurysms) has been widely investigated in the last decades. Among different soluble molecules, proinflammatory cytokines (such as TNF-α, IL-1 and IL-6) were shown to trigger critical pathways regulating these arterial diseases. Together with these cytokines, chemokines were also associated with endothelial dysfunction and intima injury in arterial diseases. Recently, autoantibodies have been also described to pathophysiologically influence not only autoimmune vasculitis but also atherogenesis and more in general vascular inflammation. These soluble mediators actively trigger inflammatory functions of leukocytes and vascular cells. For instance, B and T lymphocytes, macrophages and neutrophils were shown to actively participate in inflammatory processes within the arterial wall in vasculitis, atherogenesis and aneurysms. The aim of this narrative review is to provide an overview of pathophysiology and treatments targeting arterial inflammation in these diseases.


Glucagon-stimulable adenylyl cyclase in rat liver. The impact of streptozotocin-induced diabetes mellitus.
Glucagon receptor levels, glucagon-stimulated and other forms of adenylyl cyclase activity, and regulatory component activity of adenylyl cyclase were determined in hepatic plasma membranes of rats administered streptozotocin without and with insulin to produce varying degrees of hyperglycemia. Receptor levels were assayed by direct binding of the specific probe [125I-Tyr10]-iodoglucagon; regulatory component activity was assayed by the capacity to reconstitute stimulatory regulation in deficient membranes from cyc- S49 murine lymphoma cells. In rats given 150 mg streptozotocin, glucagon stimulation of adenylyl cyclase as well as basal, sodium fluoride, 5' guanylylimidodiphosphate [GMP-P(NH)P] and Mn-dependent activities were reduced 50%, glucagon receptor levels but not affinity were reduced 67%, and regulatory component activity was decreased 50%. In addition, alpha 1-adrenergic receptors and 5'-nucleotidase were similarly reduced in diabetes. However, specific ouabain-inhibitable Na+, K+, ATPase activity was not altered by streptozotocin treatment. The streptozotocin-induced changes were noted within 24 h and became maximal by 120 h after its administration. All of these decreases were partially reversed by in vivo insulin treatment. DNA, cytochrome c oxidase, glucose-6-phosphatase, and N-acetyl-beta-glucosaminidase content in hepatic plasma membrane preparations were not substantially different in diabetic as compared with control animals. The data demonstrate that glucagon-mediated regulation of cyclic AMP formation is deranged in insulin deficiency owing to a combined decrease in receptors, derangement of the coupling mechanism intervening between receptor and adenylyl cyclase, and possibly, an altered basal effector system. Some of these changes appear to reflect a "desensitization-like" phenomenon which may or may not be attributable to the hyperglucagonemia of diabetes mellitus. There also appears to be a concurrent generalized decrease in several but not all plasma membrane receptor and enzymatic proteins. This may be the result of a number of processes among which is the accelerated proteolysis of uncontrolled diabetes.


Motivational intervention to enhance post-detoxification 12-Step group affiliation: a randomized controlled trial.
To compare a motivational intervention (MI) focused on increasing involvement in 12-Step groups (TSGs; e.g. Alcoholics Anonymous) versus brief advice (BA) to attend TSGs. Patients were assigned randomly to either the MI or BA condition, and followed-up at 6 months after discharge. One hundred and forty substance use disorder (SUD) patients undergoing in-patient detoxification (detox) in Norway. The primary outcome was TSG affiliation measured with the Alcoholics Anonymous Affiliation Scale (AAAS), which combines meeting attendance and TSG involvement. Substance use and problem severity were also measured. At 6 months after treatment, compared with the BA group, the MI group had higher TSG affiliation [0.91 point higher AAAS score; 95% confidence interval (CI) = 0.04 to 1.78; P = 0.041]. The MI group reported 3.5 fewer days of alcohol use (2.1 versus 5.6 days; 95% CI = -6.5 to -0.6; P = 0.020) and 4.0 fewer days of drug use (3.8 versus 7.8 days; 95% CI = -7.5 to -0.4; P = 0.028); however, abstinence rates and severity scores did not differ between conditions. Analyses controlling for duration of in-patient treatment did not alter the results. A motivational intervention in an in-patient detox ward was more successful than brief advice in terms of patient engagement in 12-Step groups and reduced substance use at 6 months after discharge. There is a potential benefit of adding a maintenance-focused element to standard detox.


MicroRNAs and ultraconserved genes as diagnostic markers and therapeutic targets in cancer and cardiovascular diseases.
MicroRNAs (miRNAs), approximately 19-25 nucleotides in length, are posttranscriptional regulators of protein expression that target and inhibit translation of messenger (m) RNAs. Recent research on miRNAs has produced a plethora of new material on the role of miRNAs in disease. Deregulation or ablation of miRNA expression has led to major pathologies including heart disease and cancer. Signatures of differential miRNA expression have been uncovered for nearly every disease. Recent research has focused on exploitation of the selectivity of these signatures as markers of disease and for therapeutic applications. The significance of additional mechanisms of abnormal posttranscriptional regulation, such as ultraconserved genes (UCGs), has recently been recognized. This review focuses on the identification of aberrant posttranscriptional regulators (miRNAs and UCGs) in cancer and cardiovascular disease and addresses the applications of this work towards diagnosis and therapy.


Hepatotoxicity of contemporary antiretroviral drugs.
To date, more than 30 antiretroviral drugs have been approved by the Food and Drug Administration for the treatment of HIV infection. As new drugs with better efficacy and safety profile become available for clinical practice, older drugs are either withdrawn from the market or become no longer actively prescribed. We review hepatotoxicity associated with contemporary antiretroviral drugs, with emphasis on data from the past 3 years. Although less robust data exists for side effects of contemporary antiretroviral medications recently approved for the management of HIV (i.e., doravirine, ibalizumab, fostemsavir, cabotegravir), the risks of substantial hepatotoxicity appears to be minimal with these agents. Although newer antiretroviral drugs are better tolerated than their earlier counterparts, they are not completely devoid of adverse drug reactions, including hepatotoxicity. Monitoring patients on antiretroviral therapy for treatment-emergent liver injury should continue to be part of routine clinical care.


Clinics in diagnostic imaging (68). Intradural extramedullary spinal paraganglioma.
Paragangliomas rarely present as spine tumours. The correct diagnosis is generally not suspected pre-operatively and initial imaging is often non-specific. A 36-year-old man with low back pain, and progressive leg numbness and weakness, was found to have an expansile intradural extramedullary spinal tumour on radiographs and magnetic resonance imaging. Surgery revealed a paraganglioma. The features of spinal paraganglioma and differential diagnosis of intradural extramedullary tumours are discussed.


Response to fibronectin of mouse primordial germ cells before, during and after migration.
The adhesive extracellular matrix glycoprotein fibronectin is thought to play a central role in cell migration during embryogenesis. In order to define this role, we have examined the response to fibronectin in cell culture of mouse primordial germ cells (PGCs) before, during and after their migration from the hindgut into their target tissue, the genital ridges. Using an explant culture system, we show that PGCs will emigrate from tissue fragments containing hindgut, and that fibronectin stimulates this migration. Adhesion assays show that the start of PGC migration is associated with a fall in adhesion to fibronectin. Double-labelling studies using in situ hybridization and histochemistry demonstrate that migrating PGCs do not contain detectable fibronectin mRNA, suggesting that they do not synthesize and secrete the fibronectin within their migratory substratum. Taken together, these findings are consistent with an important role for fibronectin in stimulating PGC migration. In addition, however, they suggest that the interaction between PGCs and fibronectin may be important in timing the start of migration, with the fall in adhesion allowing the PGCs to commence their migration towards the genital ridges.


Neuroprotective effects of the polyphenolic antioxidant agent, Curcumin, against homocysteine-induced cognitive impairment and oxidative stress in the rat.
Aging is the major risk factor for neurodegenerative diseases and oxidative stress is involved in the pathophysiology of these diseases. In this study, the possible antioxidant and neuroprotective properties of the polyphenolic antioxidant compound, Curcumin against homocysteine (Hcy) neurotoxicity was investigated. Curcumin (5 and 50mg/kg) was injected intraperitoneally once daily for a period of 10 days beginning 5 days prior to Hcy (0.2 micromol/microl) intrahippocampal injection in rats. Biochemical and behavioral studies, including passive avoidance learning and locomotor activity tests were studied 24h after the last Curcumin or its vehicle injection. We detected Malondialdehyde (MDA) and Super oxide anion (SOA) in rats' hippocampi. Results indicated that Hcy could induce lipid peroxidation and increase MDA and SOA levels in rats' hippocampi. Additionally, Hcy impaired memory retention in passive avoidance learning test. However, Curcumin treatment decreased MDA and SOA levels significantly as well as improved learning and memory in rats. Histopathological analysis also indicated that Hcy could decrease hippocampus cell count and Curcumin inhibited this toxic effect. These results suggest that Hcy may induce lipid peroxidation in rats' hippocampi and polyphenol treatment (Curcumin) improved learning and memory deficits by protecting the nervous system against Hcy toxicity.


Involvement of activated cytotoxic T lymphocytes and natural killer cells in Henoch-Schönlein purpura nephritis.
Immunoglobulin A vasculitis/Henoch-Schönlein purpura (IgAV/HSP) is a major cause of vasculitis in children. It is often accompanied by nephritis (HSPN) and could progress to chronic kidney disease. Galactose-deficient IgA1 was recently reported to be involved in the pathogenesis of HSPN, for which immunosuppressive drugs are considered key treatment. However, the involvement of immune cells in the development of HSPN remains unclear. We compared gene expressions of peripheral blood mononuclear cells (PBMCs) among healthy controls (n = 10), IgAV/HSP patients (n = 21) and HSPN patients (n = 8), which required nephritis development within 3 months of IgAV/HSP onset. Immunohistochemistry analysis and flow cytometry were performed to assess renal biopsy specimens and PBMCs, respectively. Serum CX3CL1 levels were measured by ELISA. GNLY and GZMB expressions increased in HSPN patients, consistent with increased number of glomerular granulysin- and/or granzyme B-positive cells demonstrated by immunohistochemistry analysis. Additionally, circulating cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells were activated with the up-regulated surface expressions of human leucocyte antigen DR (HLA-DR) and CX3CR1 in HSPN patients with severe proteinuria. Renal biopsies demonstrated increased number of CD8+ cells and/or CD56+ cells and up-regulated expression of glomerular CX3CL1, a specific ligand for CX3CR1, along with increased serum CX3CL1 level. Activated CTLs and NK cells play roles in the development of nephritis in IgAV/HSP patients and can be used as novel biomarkers for HSPN.


Genome-Wide Profiling of DNA Double-Strand Breaks by the BLESS and BLISS Methods.
DNA double-strand breaks (DSBs) are major DNA lesions that are constantly formed during physiological processes such as DNA replication, transcription, and recombination, or as a result of exogenous agents such as ionizing radiation, radiomimetic drugs, and genome editing nucleases. Unrepaired DSBs threaten genomic stability by leading to the formation of potentially oncogenic rearrangements such as translocations. In past few years, several methods based on next-generation sequencing (NGS) have been developed to study the genome-wide distribution of DSBs or their conversion to translocation events. We developed Breaks Labeling, Enrichment on Streptavidin, and Sequencing (BLESS), which was the first method for direct labeling of DSBs in situ followed by their genome-wide mapping at nucleotide resolution (Crosetto et al., Nat Methods 10:361-365, 2013). Recently, we have further expanded the quantitative nature, applicability, and scalability of BLESS by developing Breaks Labeling In Situ and Sequencing (BLISS) (Yan et al., Nat Commun 8:15058, 2017). Here, we first present an overview of existing methods for genome-wide localization of DSBs, and then focus on the BLESS and BLISS methods, discussing different assay design options depending on the sample type and application.


NFATc3 regulates trypsinogen activation, neutrophil recruitment, and tissue damage in acute pancreatitis in mice.
The signaling mechanisms that regulate trypsinogen activation and inflammation in acute pancreatitis (AP) are unclear. We explored the involvement of the calcium- and calcineurin-dependent transcription factor nuclear factor of activated T cells (NFAT) in development of AP in mice. We measured levels of myeloperoxidase and macrophage inflammatory protein 2 (CXCL2), trypsinogen activation, and tissue damage in the pancreas 24 hours after induction of AP by retrograde infusion of taurocholate into the pancreatic ducts of wild-type, NFAT luciferase reporter (NFAT-luc), and NFATc3-deficient mice. We isolated acinar cells and measured NFAT nuclear accumulation, trypsin activity, and expression of NFAT-regulated genes. Infusion of taurocholate increased the transcriptional activity of NFAT in the pancreas, aorta, lung, and spleen of NFAT-luc mice. Inhibition of NFAT with A-285222 blocked taurocholate-induced activation of NFAT in all organs. A-285222 also reduced taurocholate-induced increases in levels of amylase, myeloperoxidase, and CXCL2; activation of trypsinogen; necrosis of acinar cells; edema; leukocyte infiltration; and hemorrhage in the pancreas. NFATc3-deficient mice were protected from these effects of taurocholate. Similar results were obtained using an l-arginine-induced model of AP. Reverse-transcription polymerase chain reaction and confocal immunofluorescence analyses showed that NFATc3 is expressed by acinar cells. NFATc3 expression was activated by stimuli that increase intracellular calcium levels, and activation was prevented by the calcineurin blocker cyclosporin A or A-285222. Activation of trypsinogen by secretagogues in acinar cells was prevented by pharmacologic inhibition of NFAT signaling or lack of NFATc3. A-285222 also reduced expression of inflammatory cytokines such as CXCL2 in acinar cells. NFATc3 regulates trypsinogen activation, inflammation, and pancreatic tissue damage during development of AP in mice and might be a therapeutic target.


Radioactive seed localization is the preferred technique in nonpalpable breast cancer compared with wire-guided localization and radioguided occult lesion localization.
Three commonly used techniques for localization of nonpalpable breast cancer are radioactive seed localization (RSL), wire-guided localization (WGL) and radioguided occult lesion localization (ROLL). In this study, we analysed the surgical margins of these three techniques. Women diagnosed with nonpalpable breast cancer undergoing breast-conserving surgery with one of the above-mentioned techniques were retrospectively included. The primary outcome parameter was tumour-free margin rate. Secondary outcomes were re-excision rate, recurrence of disease and volume of removed tissue. In total, 272 women were included in whom RSL (n=69), WGL (n=76) or ROLL (n=137) was performed. RSL showed a higher tumour-free margin rate [64 (92.8%)] compared with WGL [51 (67.1%)] and ROLL [113 (82.5%)] (P=0.001). In our multivariable analysis, RSL showed a higher tumour-free margin rate as well compared with WGL (P=0.036) and ROLL (P=0.049). Also, fewer re-excisions were encountered using RSL [5 (7.2%)] compared with WGL [13 (17.1%)] and ROLL [15 (10.9%)] (P=0.171). In 11 patients (WGL n=2, ROLL n=9), recurrence of disease occurred, despite a radical excision. The mean resection volumes were comparable within the three groups. RSL results in a higher tumour-free margin rate in nonpalpable breast tumours compared with WGL and ROLL. Therefore, we prefer using RSL in nonpalpable breast tumours.


Modeling of Cerebral Oxygen Transport Based on In vivo Microscopic Imaging of Microvascular Network Structure, Blood Flow, and Oxygenation.
Oxygen is delivered to brain tissue by a dense network of microvessels, which actively control cerebral blood flow (CBF) through vasodilation and contraction in response to changing levels of neural activity. Understanding these network-level processes is immediately relevant for (1) interpretation of functional Magnetic Resonance Imaging (fMRI) signals, and (2) investigation of neurological diseases in which a deterioration of neurovascular and neuro-metabolic physiology contributes to motor and cognitive decline. Experimental data on the structure, flow and oxygen levels of microvascular networks are needed, together with theoretical methods to integrate this information and predict physiologically relevant properties that are not directly measurable. Recent progress in optical imaging technologies for high-resolution in vivo measurement of the cerebral microvascular architecture, blood flow, and oxygenation enables construction of detailed computational models of cerebral hemodynamics and oxygen transport based on realistic three-dimensional microvascular networks. In this article, we review state-of-the-art optical microscopy technologies for quantitative in vivo imaging of cerebral microvascular structure, blood flow and oxygenation, and theoretical methods that utilize such data to generate spatially resolved models for blood flow and oxygen transport. These "bottom-up" models are essential for the understanding of the processes governing brain oxygenation in normal and disease states and for eventual translation of the lessons learned from animal studies to humans.


Metabolic Recovery of the Failing Heart: Emerging Therapeutic Options.
Heart failure has mortality rates that parallel those of breast cancer. Current management strategies include neurohormonal blockade, rate control measures, natriuretic peptide preservation, implantation of mechanical assist devices, and heart transplantation. Despite these strategies, however, the failing myocardium remains energy depleted. New strategies to promote metabolic recovery are being developed to potentially augment current treatment guidelines. For example, an unexpected finding of our own studies showed that mechanical unloading with assist devices in advanced-stage heart failure restored metabolic flux. Unfortunately, at that point it is too late for myocardial recovery. Traditional metabolic therapies addressing hyperglycemia have had limited long-term outcome benefit. Now, new therapeutic options are emerging based on increased understanding of the molecular mechanisms underlying energy depletion. Metabolic cardiac imaging combined with laboratory diagnostics could guide the design of individual therapeutic strategies. To date, agents that show benefit in select individuals include mimetics that stimulate glucagon-like peptide-1, inhibitors of sodium-glucose cotransporter receptors, drugs that limit fatty acid oxidation, and hormonal therapy in select individuals. This review will summarize mechanisms and investigations related to these metabolic approaches to heart failure.


Control of the subthalamic innervation of the rat globus pallidus by D2/3 and D4 dopamine receptors.
The effects of activating dopaminergic D(2/3) and D(4) receptors during activation of the subthalamic projection to the globus pallidus (GP) were explored in rat brain slices using the whole cell patch-clamp technique. Byocitin labeling and both orthodromic and antidromic activation demonstrated the integrity of some subthalamopallidal connections in in vitro parasagittal brain slices. Excitatory postsynaptic currents (EPSCs) that could be blocked by CNQX and AP5 were evoked onto pallidal neurons by local field stimulation of the subthalamopallidal pathway in the presence of bicuculline. Bath application of dopamine and quinpirole, a dopaminergic D(2)-class receptor agonist, reduced evoked EPSCs by about 35%. This effect was only partially blocked by sulpiride, a D(2/3) receptor antagonist. The sulpiride-sensitive reduction of the subthalamopallidal EPSC was associated with an increase in the paired-pulse ratio (PPR) and a reduction in the frequency but not the mean amplitude of spontaneous EPSCs (sEPSCs), indicative of a presynaptic site of action, which was confirmed by variance-mean analysis. The sulpiride-resistant EPSC reduction was mimicked by PD 168,077 and blocked by L-745,870, selective D(4) receptor agonist and antagonist, respectively, suggesting the involvement of D(4) receptors. The reduction of EPSCs produced by PD 168,077 was not accompanied by changes in PPR or the frequency of sEPSCs; however, it was accompanied by a reduction in mean sEPSC amplitude, indicative of a postsynaptic site of action. These results show that dopamine modulates subthalamopallidal excitation by presynaptic D(2/3) and postsynaptic D(4) receptors. The importance of this modulation is discussed.


Long-term administration of ketamine induces erectile dysfunction by decreasing neuronal nitric oxide synthase on cavernous nerve and increasing corporal smooth muscle cell apoptosis in rats.
We investigated and evaluated the mechanisms of erectile dysfunction (ED) in a rat model of long-term ketamine administration. Adult male Sprague-Dawley rats (n = 32) were divided into four groups: namely the control group receiving intraperitoneal injection of saline, 1-month, 2-month and 3-month groups receiving daily intraperitoneal injection of ketamine (100 mg/kg/day) for 1, 2, and 3 month respectively. After treatment, animals underwent an erectile response protocol to assess intracavernosal pressure (ICP). Smooth muscle content was evaluated. Neuronal nitric oxide synthase (nNOS), inducible nitric oxide synthase (iNOS) and endothelial nitric oxide synthase (eNOS) expression were assessed using immunostaining assay. Ketamine-induced apoptosis was analyzed using TUNEL assay. Long-term ketamine administration caused significantly decreased erectile responses as measured by ICP. Smooth muscle content was significantly decreased in the ketamine-treated rats for 3 months. In the erectile tissue, ketamine administration significantly reduced nNOS expression and increased iNOS content compared with controls, whereas eNOS expression was not altered. Ketamine induced apoptosis in corpus cavernosum. The present study demonstrates that long-term ketamine administration led to erectile dysfunction in rat. The molecular mechanisms of ketamine-induced ED involved the increased apoptosis and up-regulated iNOS expression incorporating with loss of corporal smooth muscle content and reduced nNOS expression in cavernous nerve.


Reductively aminated D-xylose-albumin conjugate as the immunogen for generation of IgG and IgE antibodies specific to D-xylitol, a haptenic allergen.
Sugar alcohols are widely used as food additives and drug excipients. Xylitol, a five-carbon sugar alcohol, and a low-calorie alternative sweetener to sucrose (approx 40% fewer calories), has enjoyed an enviable record of safety, and allergic reactions to xylitol are very rare. A case of oral erosive eczema to xylitol has been reported recently [Hanakawa, Y., Hanakawa, Y., Tohyama, M., Yamasaki, K., Hashimoto, K. (2005) Xylitol as a causative agent of oral erosive eczema. Brit. J. Dermatol. 152, 821-822]. Xylitol does not contain any reactive groups; hence, it is nonimmunogenic. In order to explain the immunogenicity of xylitol, polyclonal antibodies to xylitol have been raised using the reductive aminated product of D-xylose conjugated to bovine serum albumin (BSA) as the immunogen. Rabbits immunized with xylitol-BSA conjugate (52 haptens/molecule) gave a good antibody response. Purification of antixylitol antibodies was carried out using hapten-affinity chromatography on xylitol-keyhole limpet hemocyanin-Sepharose CL-6B; the yield was approximately 40 microg/mL of rabbit immune serum. Purified xylitol-specific antibodies appeared to be homogeneous by native PAGE with a pI of approximately 7.2 by isoelectric focusing. Although the purified antibodies are specific for the xylitoyl moiety of xylitol-protein conjugates, they reacted equally well with the Schiff base conjugate of xylosyl-protein conjugates (68% cross-reactivity) indicating that carbons 2 to 5 of xylitol act as an epitope. Xylitol antibodies showed excellent specificity towards xylitol and <4.4% cross-reactivity with D-xylose and various sugar alcohols except ribitol and galactitol, which showed approximately 11% and 8% cross-reactivity, respectively. D-Xylitol-BSA conjugate was used to raise IgE antibodies in BALB/c mice by repeated intradermal administration. Passive cutaneous anaphylaxis using the immune sera confirmed the haptenic nature of xylitol.


Status and challenges for conservation of small mammal assemblages in South America.
South America spans about 44° latitude, covers almost 18 million km(2) , and is second only to Africa in continental mammal species richness. In spite of this richness, research on the status of this fauna and on the nature and magnitude of contemporary threats remains limited. Distilling threats to this diverse fauna at a continental scale is challenging, in part because of the limited availability of rigorous studies. Recognizing this constraint, we summarize key threats to small mammals in South America, emphasizing the roles of habitat loss and degradation, direct persecution, and the increasing threat of climate change. We focus on three regional 'case studies': the tropical Andes, Amazonia and adjacent lowland regions, and the southern temperate region. We close with a brief summary of recent findings at our long-term research site in north-central Chile as they pertain to projected threats to this fauna. Habitat alteration is a pervasive threat that has been magnified by market forces and globalization (e.g. extensive agricultural development in Amazonia), and threatens increasing numbers of populations and species. Climate change poses even greater threats, from changes in rainfall and runoff regimes and resulting changes in vegetative structure and composition to secondary influences on fire dynamics. It is likely that many changes have yet to be recognized, but existing threats suggest that the future may bring dramatic changes in the distribution of many mammal taxa, although it is not clear if key habitat elements (vegetation) will respond as rapidly as climatic factors, leading to substantial uncertainty. Climate change is likely to result in 'winners' and 'losers' but available information precludes detailed assessment of which species are likely to fall into which category. In the absence of long-term monitoring and applied research to characterize these threats more accurately, and to develop strategies to reduce their impacts, managers already are being faced with daunting challenges. As the line between 'pure' and 'applied' research blurs in the face of converging interests of scientists and society we hope that solutions to these critical issues will be incorporated in addressing anticipated conservation crises.


Patent ductus arteriosus, indomethacin and necrotizing enterocolitis in very low birth weight infants: a population-based study.
Patent ductus arteriosus is a risk factor for the development of necrotizing enterocolitis. The use of indomethacin to treat patent ductus arteriosus in preterm infants may either decrease the incidence of necrotizing enterocolitis by stabilizing or closing the ductus arteriosus or increase its incidence by a direct constricting effect on mesenteric blood vessels. The authors sought to evaluate the interrelationship between patent ductus arteriosus, treatment with indomethacin and the risk of necrotizing enterocolitis in very low birth weight infants. The Israel National database includes prospectively collected data on 99% of all very low birth weight infants in Israel. The study population comprised 6146 infants of 24-34 weeks' gestation born between 1995 and 2000. The effect of patent ductus arteriosus on necrotizing enterocolitis was assessed using multiple regression analysis. Necrotizing enterocolitis occurred in 5.5% (n = 343) of all infants, in 9.4% of infants with patent ductus arteriosus and in 8.9% of infants who received indomethacin. The occurrence of necrotizing enterocolitis was independently associated with the presence of patent ductus arteriosus among infants not treated with indomethacin (odds ratio, 1.85) and those who received indomethacin therapy (odds ratio, 1.53). Indomethacin therapy in absence of patent ductus arteriosus was not associated with an increased risk of necrotizing enterocolitis (odds ratio, 0.72). Patent ductus arteriosus is an independent risk factor for the development of necrotizing enterocolitis in very low birth weight infants. Therapy with indomethacin did not have a significant effect on the risk for necrotizing enterocolitis.


Failure of Isoflurane Cardiac Preconditioning in Obese Type 2 Diabetic Mice Involves Aberrant Regulation of MicroRNA-21, Endothelial Nitric-oxide Synthase, and Mitochondrial Complex I.
Diabetes impairs the cardioprotective effect of volatile anesthetics, yet the mechanisms are still murky. We examined the regulatory effect of isoflurane on microRNA-21, endothelial nitric-oxide synthase, and mitochondrial respiratory complex I in type 2 diabetic mice. Myocardial ischemia/reperfusion injury was produced in obese type 2 diabetic (db/db) and C57BL/6 control mice ex vivo in the presence or absence of isoflurane administered before ischemia. Cardiac microRNA-21 was quantified by real-time quantitative reverse transcriptional-polymerase chain reaction. The dimers and monomers of endothelial nitric-oxide synthase were measured by Western blot analysis. Mitochondrial nicotinamide adenine dinucleotide fluorescence was determined in Langendorff-perfused hearts. Body weight and fasting blood glucose were greater in db/db than C57BL/6 mice. Isoflurane decreased left ventricular end-diastolic pressure from 35 ± 8 mmHg in control to 23 ± 9 mmHg (P = 0.019, n = 8 mice/group, mean ± SD) and elevated ±dP/dt 2 h after post-ischemic reperfusion in C57BL/6 mice. These beneficial effects of isoflurane were lost in db/db mice. Isoflurane elevated microRNA-21 and the ratio of endothelial nitric-oxide synthase dimers/monomers and decreased mitochondrial nicotinamide adenine dinucleotide levels 5 min after ischemia in C57BL/6 but not db/db mice. MicroRNA-21 knockout blocked these favorable effects of isoflurane, whereas endothelial nitric-oxide synthase knockout had no effect on the expression of microRNA-21 but blocked the inhibitory effect of isoflurane preconditioning on nicotinamide adenine dinucleotide. Failure of isoflurane cardiac preconditioning in obese type 2 diabetic db/db mice is associated with aberrant regulation of microRNA-21, endothelial nitric-oxide synthase, and mitochondrial respiratory complex I.


Pulmonary tuberculosis due to Mycobacterium bovis in León.
In recent years, human infection due to Mycobacterium bovis has been considered almost eradicated in most industrialised countries. During the period 1998-2002, nine patients were diagnosed with pulmonary tuberculosis (TB) due to M. bovis in the Hospital Monte San Isidro, León, Spain. Their average age was 66 years. The response to therapy was good in seven cases, while two died, one from renal TB and the other from cancer of the pancreatic head.


Malignancies in Deceased Organ Donors: The Spanish Experience.
To better define the risk of malignancy transmission through organ transplantation, we review the Spanish experience on donor malignancies. We analyzed the outcomes of recipients of organs obtained from deceased donors diagnosed with a malignancy during 2013-2018. The risk of malignancy transmission was classified as proposed by the Council of Europe. Of 10 076 utilized deceased donors, 349 (3.5%) were diagnosed with a malignancy. Of those, 275 had a past (n = 168) or current (n = 107) history of malignancy known before the transplantation of organs into 651 recipients. Ten malignancies met high-risk criteria. No donor-transmitted cancer (DTC) was reported after a median follow-up of 24 (interquartile range [IQR]: 19-25) mo. The other 74 donors were diagnosed with a malignancy after transplantation. Within this group, 64 donors (22 with malignancies of high or unacceptable risk) whose organs were transplanted into 126 recipients did not result in a DTC after a median follow-up of 26 (IQR: 22-37) mo, though a prophylactic transplantectomy was performed in 5 patients. The remaining 10 donors transmitted an occult malignancy to 16 of 25 recipients, consisting of lung cancer (n = 9), duodenal adenocarcinoma (n = 2), renal cell carcinoma (n = 2), extrahepatic cholangiocarcinoma (n = 1), prostate cancer (n = 1), and undifferentiated cancer (n = 1). After a median follow-up of 14 (IQR: 11-24) mo following diagnosis, the evolution was fatal in 9 recipients. In total, of 802 recipients at risk, 16 (2%) developed a DTC, which corresponds to 6 cases per 10 000 organ transplants. Current standards may overestimate the risk of malignancy transmission. DTC is an infrequent but difficult to eliminate complication.


Increasing trust and vaccine uptake: Offering invitational rhetoric as an alternative to persuasion in pediatric visits with vaccine-hesitant parents (VHPs).
Healthcare professionals are increasingly concerned about vaccine hesitancy, an exigency the World Health Organization named one of the ten threats to global health, even before the COVID-19 pandemic. Traditional rhetorical strategies (e.g., persuasion) remain the default to help increase vaccine uptake, despite mounting evidence such techniques may not improve uptake and could alienate families. We offer invitational rhetoric-in which people honor opposing viewpoints rather than trying to change behavior-as an alternative to improve trust and childhood vaccine uptake. We conducted a six-month, mixed methods case study of a small, urban, pediatric healthcare practice in the western United States we believed used invitational methods in discussions with vaccine-hesitant parents (VHPs). We administered pre- and post-visit surveys to families; audio recorded and transcribed their two-month well child checks (WCCs); and facilitated individual interviews with the providers. We analyzed the data looking for patterns in how providers and families use and view traditional persuasion as compared to invitational rhetoric and the effect each has on vaccine uptake, trust, and provider wellbeing. One hundred five (n = 105) families and six healthcare providers participated, with 35 families planning to receive fewer than the CDC-recommended number of vaccinations prior to their WCC. After their visit, however, 37% of VHPs increased their vaccine uptake compared to their pre-visit plans; 80% of VHPs selected top box scores for trust of their providers; and 85% of VHPs who chose to increase their vaccine uptake also selected top box trust scores. Our findings indicate invitational rhetoric may play a meaningful role in increasing vaccine uptake; sustaining or even improving a family's trust in their provider; and positively impacting provider wellbeing. Further research is needed on the use of invitational rhetoric exclusively.


Quantum work and the thermodynamic cost of quantum measurements.
Quantum work is usually determined from two projective measurements of the energy at the beginning and at the end of a thermodynamic process. However, this paradigm cannot be considered thermodynamically consistent as it does not account for the thermodynamic cost of these measurements. To remedy this conceptual inconsistency we introduce a paradigm that relies only on the expected change of the average energy given the initial energy eigenbasis. In particular, we completely omit quantum measurements in the definition of quantum work, and hence quantum work is identified as a thermodynamic quantity of only the system. As main results we derive a modified quantum Jarzynski equality and a sharpened maximum work theorem in terms of the information free energy. A comparison of our results with the standard approach allows one to quantify the informational cost of projective measurements.


Palpable purpura and a visible sock line.
A 21-year-old woman came to the clinic, frightened by a painful purpuric rash on her lower extremities. The lesions appeared suddenly 3 days before, with no prior similar episodes. The pain, and some swelling that happened when she stood, had finally driven her to take some time off from her job and seek medical advice. She was diagnosed with a case of pharyngitis earlier that week; due to multiple drug allergies, she was prescribed a course of clindamycin. She had not experienced any nausea or vomiting, fever, abdominal cramping, or gross hematuria. On examination, the patient was friendly and good-humored, although she was concerned about her rash and visibly uncomfortable. She was walking with the aid of a borrowed cane, but her lesions were no longer tender to palpation. The rash consisted mainly of purpuric papules almost entirely limited to her legs, although some isolated lesions were on her back as well. The papules were concentrated around her distal lower extremities, with a clear line of lesions encircling her calves bilaterally where her knee-high socks had applied pressure for the last 2 days. Mild edema was noted, but the rest of her physical exam was normal. By dipstick, the patient had blood in her urine but no protein. What is the diagnosis? What is the treatment for this condition?


Feasibility of a screening program for at-risk children following accidental injury.
Screening is recommended as a simple method for identifying those who should be monitored for risk following trauma. Effective methods for implementing large-scale screening programs are yet to be established. This study tested the feasibility and utility of a screening program with hospitalized youth exposed to injury in 3 Australian hospitals. Eligible families (N = 1,134) were contacted and 546 children (48.0%) screened for risk of posttraumatic stress disorder (PTSD) at 1-2 weeks postinjury. There were 95 (17.4%) children whose screen result was at risk. A rescreening phase was introduced during the study, with 68 children completing the rescreen at 4-6 weeks postinjury, and 26 (38.2% of those rescreened) still at risk. Of those initially screened, 29 (5.3%) completed diagnostic assessments, 21 (3.8%) were diagnosed with partial or full PTSD, and 17 (3.1%) commenced treatment. Screening was successful at identifying and reaching children with PTSD, but the response rate was lower than expected, which limited the utility of the program. The addition of a rescreening phase demonstrated that not all at-risk children required intervention. These findings replicate previous studies that have shown natural remission in PTSD symptoms and highlight the potential for rescreening as part of a watchful waiting approach.


Preserved antibody levels and loss of memory B cells against pneumococcus and tetanus after splenectomy: tailoring better vaccination strategies.
Splenectomized patients are exposed to an increased risk of septicemia caused by encapsulated bacteria. Defense against infection is ensured by preformed serum antibodies produced by long-lived plasma cells and by memory B cells that secrete immunoglobulin in response to specific antigenic stimuli. Studying a group of asplenic individuals (57 adults and 21 children) without additional immunologic defects, we found that spleen removal does not alter serum anti-pneumococcal polysaccharide (PnPS) IgG concentration, but reduces the number of PnPS-specific memory B cells, of both IgM and IgG isotypes. The number of specific memory B cells was low in splenectomized adults and children that had received the PnPS vaccine either before or after splenectomy. Seven children were given the 13-valent pneumococcal conjugated vaccine after splenectomy. In this group, the number of PnPS-specific IgG memory B cells was similar to that of eusplenic children, suggesting that pneumococcal conjugated vaccine administered after splenectomy is able to restore the pool of anti-PnPS IgG memory B cells. Our data further elucidate the crucial role of the spleen in the immunological response to infections caused by encapsulated bacteria and suggest that glycoconjugated vaccines may be the most suitable choice to generate IgG-mediated protection in these patients.


Analysis of putative quadruplex-forming sequences in fungal genomes: novel antifungal targets?
Fungal infections cause >1 million deaths annually and the emergence of antifungal resistance has prompted the exploration for novel antifungal targets. Quadruplexes are four-stranded nucleic acid secondary structures, which can regulate processes such as transcription, translation, replication and recombination. They are also found in genes linked to virulence in microbes, and ligands that bind to quadruplexes can eliminate drug-resistant pathogens. Using a computational approach, we quantified putative quadruplex-forming sequences (PQS) in 1359 genomes across the fungal kingdom and explored their presence in genes related to virulence, drug resistance and biological processes associated with pathogenicity in Aspergillus fumigatus. Here we present the largest analysis of PQS in fungi and identify significant heterogeneity of these sequences throughout phyla, genera and species. PQS were genetically conserved in Aspergillus spp. and frequently pathogenic species appeared to contain fewer PQS than their lesser/non-pathogenic counterparts. GO-term analysis identified that PQS-containing genes were involved in processes linked with virulence such as zinc ion binding, the biosynthesis of secondary metabolites and regulation of transcription in A. fumigatus. Although the genome frequency of PQS was lower in A. fumigatus, PQS could be found enriched in genes involved in virulence, and genes upregulated during germination and hypoxia. Moreover, PQS were found in genes involved in drug resistance. Quadruplexes could have important roles within fungal biology and virulence, but their roles require further elucidation.


Neuropathology in Consecutive Forensic Consultation Cases with a History of Remote Traumatic Brain Injury.
Traumatic brain injury (TBI) is widely assumed to be causal in neurodegenerative disease, based on epidemiological surveys demonstrating an increased risk of Alzheimer disease (AD) following TBI, and on recent theories surrounding repetitive head movement. We tested this assumption by evaluating 30 consecutive forensic examinations in which neuropathology consultation was sought, and in which a history of remote TBI was uncovered during the course of the investigation. In this series, there was a high frequency of psychiatric co-morbidities (100%), remote contusion (90%), and seizures (63%). Extent of proteinopathy showed no differences with age-matched controls. A subset of the cases showed focal geographic tauopathy that correlated with older age at autopsy, but had no correlation with clinical signs, and was minimal in comparison with the encephalomalacia secondary to trauma. The results suggest that cerebral contusion and post-traumatic epilepsy may be over-represented in civilian TBI, while structural brain damage from trauma is the predominant cause of morbidity following TBI. We found no evidence that TBI initiates a progressive proteinopathy.


Modeling enculturated bias in entrainment to rhythmic patterns.
Long-term and culture-specific experience of music shapes rhythm perception, leading to enculturated expectations that make certain rhythms easier to track and more conducive to synchronized movement. However, the influence of enculturated bias on the moment-to-moment dynamics of rhythm tracking is not well understood. Recent modeling work has formulated entrainment to rhythms as a formal inference problem, where phase is continuously estimated based on precise event times and their correspondence to timing expectations: PIPPET (Phase Inference from Point Process Event Timing). Here we propose that the problem of optimally tracking a rhythm also requires an ongoing process of inferring which pattern of event timing expectations is most suitable to predict a stimulus rhythm. We formalize this insight as an extension of PIPPET called pPIPPET (PIPPET with pattern inference). The variational solution to this problem introduces terms representing the likelihood that a stimulus is based on a particular member of a set of event timing patterns, which we initialize according to culturally-learned prior expectations of a listener. We evaluate pPIPPET in three experiments. First, we demonstrate that pPIPPET can qualitatively reproduce enculturated bias observed in human tapping data for simple two-interval rhythms. Second, we simulate categorization of a continuous three-interval rhythm space by Western-trained musicians through derivation of a comprehensive set of priors for pPIPPET from metrical patterns in a sample of Western rhythms. Third, we simulate iterated reproduction of three-interval rhythms, and show that models configured with notated rhythms from different cultures exhibit both universal and enculturated biases as observed experimentally in listeners from those cultures. These results suggest the influence of enculturated timing expectations on human perceptual and motor entrainment can be understood as approximating optimal inference about the rhythmic stimulus, with respect to prototypical patterns in an empirical sample of rhythms that represent the music-cultural environment of the listener.


Tobacco TTG2 suppresses resistance to pathogens by sequestering NPR1 from the nucleus.
TRANSPARENT TESTA GLABRA (TTG) proteins that contain the WD40 protein interaction domain are implicated in many signalling pathways in plants. The salicylic acid (SA) signalling pathway regulates the resistance of plants to pathogens through defence responses involving pathogenesis-related (PR) gene transcription, activated by the NPR1 (nonexpresser of PR genes 1) protein, which contains WD40-binding domains. We report that tobacco (Nicotiana tabacum) NtTTG2 suppresses the resistance to viral and bacterial pathogens by repressing the nuclear localisation of NPR1 and SA/NPR1-regulated defence in plants. Prevention of NtTTG2 protein production by silencing of the NtTTG2 gene resulted in the enhancement of resistance and PR gene expression, but NtTTG2 overexpression or NtTTG2 protein overproduction caused the opposite effects. Concurrent NtTTG2 and NPR1 gene silencing or NtTTG2 silencing in the absence of SA accumulation compensated for the compromised defence as a result of the NPR1 single-gene silencing or the absence of SA. However, NtTTG2 did not interact with NPR1 but was able to modulate the subcellular localisation of the NPR1 protein. In the absence of NtTTG2 production NPR1 was found predominantly in the nucleus and the PR genes were expressed. By contrast, when NtTTG2 accumulated in transgenic plants, a large proportion of NPR1 was retained in the cytoplasm and the PR genes were not expressed. These results suggest that NtTTG2 represses SA/NPR1-regulated defence by sequestering NPR1 from the nucleus and the transcriptional activation of the defence-response genes.


Nocardia asteroides infection with dissemination to skin and joints.
A 56-year-old diabetic woman developed multiple cutaneous lesions and septic arthritis secondary to disseminated Nocardia asteroides pulmonary infection. The diagnosis was made rapidly by Gram's and acid-fast stains of pus, sputum, and synovial fluid and later confirmed by cultures. Sulfonamides are the drugs of choice for nocardiosis, and this patient had a complete response to two weeks of intravenous trimethoprim and sulfamethoxasole followed by three months of oral therapy.


Effects of C/Mn Ratios on the Sorption and Oxidative Degradation of Small Organic Molecules on Mn-Oxides.
Manganese (Mn) oxides have a high surface area and redox potential that facilitate sorption and/or oxidation of organic carbon (OC), but their role in regulating soil C storage is relatively unexplored. Small OC compounds with distinct structures were reacted with Mn(III/IV)-oxides to investigate the effects of OC/Mn molar ratios on Mn-OC interaction mechanisms. Dissolved and solid-phase OC and Mn were measured to quantify the OC sorption to and/or the redox reaction with Mn-oxides. Mineral transformation was evaluated using X-ray diffraction and X-ray absorption spectroscopy. Higher OC/Mn ratios resulted in higher sorption and/or redox transformation; however, interaction mechanisms differed at low or high OC/Mn ratios for some OC. Citrate, pyruvate, ascorbate, and catechol induced Mn-oxide dissolution. The average oxidation state of Mn in the solid phase did not change during the reaction with citrate, suggesting ligand-promoted mineral dissolution, but decreased significantly during reactions with the other compounds, suggesting reductive dissolution mechanisms. Phthalate primarily sorbed on Mn-oxides with no detectable formation of redox products. Mn-OC interactions led primarily to C loss through OC oxidation into inorganic C, except phthalate, which was predominantly immobilized in the solid phase. Together, these results provided detailed fundamental insights into reactions happening at organo-mineral interfaces in soils.


Long-term Outcomes of Mitomycin-C Trabeculectomy in Exfoliative Glaucoma Versus Primary Open-Angle Glaucoma.
To compare long-term surgical outcomes in exfoliative glaucoma (XFG) versus primary open-angle glaucoma (POAG) after primary trabeculectomy with mitomycin-C. This retrospective, case-control study included 32 eyes of XFG and 64 eyes of POAG matched by propensity score analysis. Surgical success was defined according to 3 different criteria: (1) intraocular pressure (IOP)<18 mm Hg and IOP reduction ≥20% without medication; (2) IOP<15 mm Hg and IOP reduction ≥25% without medication; and (3) IOP<18 mm Hg and IOP reduction ≥20% with or without medication. Cumulative probabilities of success were compared using Kaplan-Meier survival analysis, and risk factors of surgical failure were analyzed. Cumulative success rates were 84.4% at 1 year and 19.9% at 5 years for XFG, and 82.3% and 64.7%, respectively, for POAG by criterion A. Complete success rates were significantly lower for XFG than for POAG by criteria A and B. However, qualified success, as determined by criterion C, did not show a statistically significant difference. Postoperative hyphema was more frequent for XFG. The risk factors associated with surgical failure were a young age (<60 y; hazard ratio=2.58, P=0.047, criterion A) and exfoliation syndrome (hazard ratio=3.01, 2.96, P=0.006, 0.005, criteria A and B). Although trabeculectomy for XFG had success rates similar to POAG at 1 year, XFG showed poorer long-term IOP control from 2 years postoperatively. This study indicates that it is more difficult to achieve long-term low target IOP control in eyes with XFG than in eyes with POAG after trabeculectomy with mitomycin-C.


Cellobiohydrolase from Trichoderma reesei.
A 1,4-beta-D-glucan cellobiohydrolase (EC 126.96.36.199) was purified from the culture liquid of Trichoderma reesei by using biospecific sorption on amorphous cellulose and immunoaffinity chromatography. A single protein band in polyacrylamide-gel electrophoresis and one arc in immunoelectrophoresis corresponded to the enzyme activity. The Mr was 65 000. The pI was 4.2-3.6. The purified enzyme contained about 10% hexose. The enzyme differs from previously described cellobiohydrolases in being more effective in the hydrolysis of cellulose.


Calcineurin protein phosphatase activity in peripheral blood lymphocytes.
The protein phosphatase activity of peripheral blood T lymphocytes (PBLs) was examined to quantify the contribution of calcineurin and other members of the family of serine/threonine protein phosphatases. Using selective phosphatase inhibitors, the fractional phosphatase activities of calcineurin, protein phosphatases 1 (PP1), 2A (PP2A), and 2C (PP2C) were determined. Okadaic acid was used to inhibit the activity of both PP1 and PP2A while cyclosporin A/cyclophilin or trifluoperazine were used as a specific inhibitors of the calmodulin-dependent phosphatase calcineurin. Using a [32P]labeled 19-residue phosphopeptide substrate, RII peptide, it was found that PP1 and PP2A comprise the majority of the total phosphatase activity in PBLs with okadaic acid inhibiting 80% of the phosphatase activity. The remaining 20% of the phosphatase activity can be attributed primarily to calcineurin since it was Ca2+ dependent, sensitive to inhibition by the calmodulin antagonist trifluoperazine, and inhibited by the complex of cyclosporin A (CsA) and cyclophilin. These results indicate that PBL extracts contain little PP2C activity. In addition, PBLs treated with CsA had measurably lower calcineurin activity in cell lysates. The measurement of calcineurin activity may provide a useful means of assessing the extent of immunosuppression during drug therapy.