Refractive Outcomes of Uneventful Cataract Surgery in Pseudoexfoliation Syndrome and Pseudoexfoliation Glaucoma.
To compare the refractive outcomes after cataract surgery between patients with and without pseudoexfoliation, and to evaluate the risk factors of refractive error. Retrospective review of 210 eyes with pseudoexfoliation (study group) and 510 normal eyes (control group) that underwent uneventful phacoemulsification with intraocular lens implantation. The study group included pseudoexfoliation syndrome and pseudoexfoliation glaucoma (PXG) subgroups. The main outcome measure was refractive error, defined as the difference between the target refraction and postoperative refraction in diopter (D). A refractive error >±1.0 D was identified as a large-magnitude refractive error. The frequency of the large-magnitude refractive error was compared between study and control groups, and also between each subgroup and normal eyes. The factors influencing refractive error were analyzed by logistic regression. There was a significantly higher frequency of a refractive error >± 1.0 D and hyperopic error >1.0 D in the study group than in the control group (p = 0.001 and p = 0.003, respectively). In the multivariate logistic regression analysis, PXG and poor preoperative visual acuity were related with a large-magnitude refractive error (p = 0.001 and p = 0.02, respectively) Refractive error >± 1.0 D and hyperopic error >1.0 D were noted more often in PXG eyes that had an intraocular pressure spike >25 mmHg at postoperative first 24 hours (p = 0.01 and p=0.03, respectively). The eyes with pseudoexfoliation were at a high risk for refractive error, especially in the presence of glaucoma. In PXG, the only significant risk factor for refractive error was observed to be the presence of an intraocular pressure spike.


The anti-tumor efficiency of pterostilbene is promoted with a combined treatment of Fas signaling or autophagy inhibitors in triple negative breast cancer cells.
High expression of vimentin, a canonical mesenchymal marker, is linked with poor prognosis in triple negative breast cancer (TNBC), implying that vimentin may be a potential biomarker in the application of TNBC therapy. Pterostilbene (PTE) has shown anti-invasion activity, and thus, we investigated whether PTE inhibited the epithelial-mesenchymal transition (EMT) in TNBC. Here, we show that PTE decreases the vimentin expression, but that the effect was transient. PTE stimulated Fas signaling, which drives EMT by the ERK1/2 and GSK3β/β-catenin pathways, supporting Fas signaling induction involved in EMT regulation. PTE also triggered autophagy in TNBC. The treatment of TNBC with 3-methyladenine an autophagy inhibitor, not only sustained PTE-inhibited EMT but also significantly promoted anti-proliferation, which indicates that autophagy plays a cyto-protective role and is associated with EMT. Taken together, these data showed that Fas signaling and autophagy accelerated the aggressiveness of TNBC. Inhibition of autophagy or Fas signaling may provide novel targets for TNBC therapy.


Passive element enriched photoacoustic computed tomography (PER PACT) for simultaneous imaging of acoustic propagation properties and light absorption.
We present a 'hybrid' imaging approach which can image both light absorption properties and acoustic transmission properties of an object in a two-dimensional slice using a computed tomography (CT) photoacoustic imager. The ultrasound transmission measurement method uses a strong optical absorber of small cross-section placed in the path of the light illuminating the sample. This absorber, which we call a passive element acts as a source of ultrasound. The interaction of ultrasound with the sample can be measured in transmission, using the same ultrasound detector used for photoacoustics. Such measurements are made at various angles around the sample in a CT approach. Images of the ultrasound propagation parameters, attenuation and speed of sound, can be reconstructed by inversion of a measurement model. We validate the method on specially designed phantoms and biological specimens. The obtained images are quantitative in terms of the shape, size, location, and acoustic properties of the examined heterogeneities.


iBCS: 3. A Biopharmaceutics Classification System for Orally Inhaled Drug Products.
In this article, we specify for the first time a quantitative biopharmaceutics classification system for orally inhaled drugs. To date, orally inhaled drug product developers have lacked a biopharmaceutics classification system like the one developed to navigate the development of immediate release of oral medicines. Guideposts for respiratory drug discovery chemists and inhalation product formulators have been elusive and difficult to identify due to the complexity of pulmonary physiology, the intricacies of drug deposition and disposition in the lungs, and the influence of the inhalation delivery device used to deliver the drug as a respirable aerosol. The development of an inhalation biopharmaceutics classification system (iBCS) was an initiative supported by the Product Quality Research Institute (PQRI). The goal of the PQRI iBCS working group was to generate a qualitative biopharmaceutics classification system that can be utilized by inhalation scientists as a "rule of thumb" to identify desirable molecular properties and recognize and manage CMC product development risks based on physicochemical properties of the drug and the deposited lung dose. Herein, we define the iBCS classes quantitatively according to the dose number and permeability. The proposed iBCS was evaluated for its ability to categorize marketed inhaled drugs using data from the literature. The appropriateness of the classification of each drug was assessed based on published development, clinical and nonclinical data, and mechanistic physiologically based biopharmaceutics modeling. The inhaled drug product development challenges for each iBCS classification are discussed and illustrated for different classes of marketed inhaled drugs. Finally, it is recognized that discriminatory laboratory methods to characterize regional lung deposition, dissolution, and permeability will be key to fully realizing the benefits of an iBCS to streamline and derisk inhaled drug development.


Prospective evaluation of the performance and interobserver variation in endoscopic ultrasound staging of rectal cancer.
Treatment and prognosis of patients with rectal adenocarcinoma (RAC) are dependent on accurate locoregional staging. The aim of this study was to measure the performance characteristics of rectal endoscopic ultrasound (EUS) compared with surgical pathology, and to assess the interobserver variation of rectal EUS in the staging of RAC. Patients referred for rectal EUS staging of a recently diagnosed RAC were prospectively enrolled between 2012 and 2016. Tandem EUS exams were performed by two independent endosonographers (ES1 and ES2) blinded to each other's findings. Ninety-five patients were enrolled. Seventy-five (79%) underwent curative intent tumor resection, including 30 without neoadjuvant therapy. In this latter group, the sensitivity, specificity, and accuracy of transrectal ultrasonography staging were 75, 83, and 82% for uT1; 50, 65, and 58% for uT2; 56, 81, and 73% for T3; 72, 44, and 63% for N0, and 38, 75, and 63% for N1, respectively. Experienced operators rendered a more accurate N stage and were less likely to overstage compared with less experienced ones (P=0.01 and 0.02, respectively). Overall, T staging agreement between endosonographers was substantial (κ=0.61) and N stage agreement was moderate (κ=0.45). Rectal EUS is more accurate in staging T1 and T3 tumors compared with T2 tumors. Interobserver agreement of rectal EUS in rectal cancer staging is generally good.


The synergistic effect of two formulated biofungicides in the biocontrol of root and bottom rot of lettuce.
The aim of this study was to evaluate the synergistic effect of two formulated biofungicides (Rhizoleen-T and Rhizoleen-B) in the suppression of root and bottom rot of lettuce caused by Rhizoctonia solani, as well as the consequent effect on the phytosanitarian status of the plants.The results proved that application of the biofungicides either singly or in combination increased the germination and survival of the lettuce up to 61.67% and 100%, respectively. The phytosanitarian status of the plants, which was indicated by morphological and physiological parameters, was improved as the result of the application of the biofungicides. The noteworthy valuable result was the increase in fresh weight by 52.5% of the control when the two biofungicides were applied as a mixture. Interestingly, the mixture of the two biofungicides brought about a significant increase in most parameters compared to either of them in single preparation. Proline and phenols significantly increased as a result of the application of the biofungicides compared to the control. This means that the treated plants were more resistant against the pathogens. The study concludes that application of the biofungicides protects the lettuce plants against root and bottom rot, and in addition they increase the strength of the defense system of the plants. It is recommended that the application of a biofungicide mixture is a good and effective strategy in the biocontrol of plant diseases.


High-speed two-photon polymerization 3D printing with a microchip laser at its fundamental wavelength.
High-resolution, high-speed 3D printing by two-photon polymerization (2PP) with a Nd:YVO4 Q-switched microchip laser at its fundamental wavelength of 1064 nm is demonstrated. Polymerization scan speeds of up to 20 mm/s and feature sizes of 250 nm are achieved using a high repetition rate Q-switched microchip laser with a semiconductor saturable absorber mirror (SESAM) and photoresist with a new photo-initiator bearing 6-dialkylaminobenzufuran as electron donor and indene-1,3-dione moiety as electron acceptor. The obtained results demonstrate the high potential of Q-switched microchip lasers for applications in 2PP 3D printing.


Corneal confocal microscopy in small and mixed fiber neuropathy-Comparison with skin biopsy and cold detection in a large prospective cohort.
The diagnosis of small fiber neuropathy (SFN) is supported by reduced intraepidermal nerve fiber density (IENFD). The noninvasive method corneal confocal microscopy (CCM) has the potential to be a practical alternative. We aimed to estimate the diagnostic accuracy of CCM compared with IENFD and cold detection thresholds (CDT) in SFN and mixed fiber neuropathy (MFN). CCM was performed in an unselected prospective cohort of patients with a clinical suspicion of polyneuropathy. Predefined criteria were used to classify SFN and MFN. Neuropathy scores, including the Utah early neuropathy scale (UENS), were used to describe severity. Patients with established other diagnoses were used for diagnostic specificity calculations. Data were taken from 680 patients, of which 244 had SFN or MFN. There was no significant difference in sensitivities [95%CI] of CCM (0.44 [0.38-0.51]), IEFND (0.43 [0.36-0.49]), and CDT (0.34 [0.29-0.41]). CCM specificity (0.75 [0.69-0.81]) was lower (p = .044) than for IENFD (0.99 [0.96-1.00]) but not than for CDT (0.81 [0.75-0.86]). The AUCs of the ROC curves of 0.63, 0.63 and 0.74 respectively, was lower for corneal nerve fiber density (p = .0012) and corneal nerve fiber length (p = .0015) compared with IENFD. While UENS correlated significantly with IENFD (p = .0016; R2 = .041) and CDT (p = .0002; R2 = .056), it did not correlate with CCM measures. The diagnostic utility of CCM in SNF and MFN is limited by the low specificity compared with skin biopsy. Further, CCM is less suitable than skin biopsy and CDT as a marker for neuropathy severity.


Management of cardiovascular risk factors in patients with metabolic syndrome.
Metabolic syndrome is defined as the combination of abdominal obesity, insulin resistance, atherogenic dyslipidemia, and prothrombotic and proinflammatory states. Due to the epidemic proportion of overweight and obesity worldwide and the development of useful clinical tools to identify these patients more easily, metabolic syndrome is increasingly recognized in adults and represents a clear risk factor for the development of both type 2 diabetes and cardiovascular disease. Management of patients with metabolic syndrome is a clinical challenge and requires a multifactorial, multidisciplinary approach. Changes in lifestyle are obviously the first therapeutic step and include both dietary modifications and increased daily exercise. Several questions remain to be elucidated with respect to pharmacological treatment. The blood pressure levels required to initiate antihypertensive treatment, the blood pressure goal to be achieved and the possibility of including a renin-angiotensin system blocker as a part of the pharmacological treatment are still under discussion. The management of atherogenic dyslipidemia is focused on LDL-cholesterol levels, although most patients with metabolic syndrome have normal LDL-cholesterol. There is lack or poor evidence on the need for specific drugs to reduce triglycerides, to increase HDL-cholesterol, to improve insulin sensitivity or to decrease abdominal obesity. There is an urgent need for consensus in the treatment of subjects with metabolic syndrome in order to prevent very high future rates of type 2 diabetes and cardiovascular disease.


Klebsiella pneumoniae Spinal Epidural Abscess treated conservatively: case report and review.
Spinal infections are rare but potentially life-threatening disorders. A high level of clinical suspicion is necessary for rapid diagnosis and treatment initiation. The treatment combines both antibiotics and surgical intervention in the vast majority of cases. The authors report the case of a 84-year old female patient with a three week history of persistent lumbar back pain radiating to both thighs following a lower respiratory tract infection. She had lumbar spine tenderness but no neurological compromise. Her inflammatory markers were elevated and lumbar spine magnetic resonance imaging revealed L4-L5 spondylodiscitis with spinal epidural abscess. Blood cultures isolated Klebsiella pneumoniae and, since she was neurologically stable, conservative treatment with two-week intravenous gentamicin and eight-week intravenous ceftriaxone was initiated with positive inpatient and outpatient evolution.


Combined Fascia Iliaca and Sciatic Nerve Block for Hip Surgery in the Presence of Severe Ankylosing Spondylitis: A Case-Based Literature Review.
Selecting an appropriate anesthetic technique for patients with ankylosing spondylitis undergoing hip surgery is challenging because of a potentially difficult airway, the risk of cardiovascular and respiratory complications, and the technical difficulty of performing central neuraxial blocks in patients with ankylosing spondylitis. Our objective was to report a case in which combination neural blockade was used successfully in an elderly patient with ankylosing spondylitis undergoing hip fracture surgery. In addition, a literature review of the anesthetic techniques reported for these patients was conducted. A 70-year-old man with severe ankylosing spondylitis and respiratory dysfunction was scheduled for a closed intertrochanteric fracture reduction and internal fixation. Combined fascia iliaca block and parasacral sciatic nerve block were used successfully for the surgery. Postoperative analgesia was accomplished by continuous fascia iliaca block. According to the literature review, general anesthesia is the most commonly performed anesthetic technique for patients with ankylosing spondylitis undergoing hip surgeries. Special intubation techniques and cautious airway management were very important for these patients. Although both general anesthesia and central neuraxial blockade pose considerable risks to the patients, this case report suggests that combined fascia iliaca block and sciatic nerve block might be a promising option.


A link between vascular damage and cognitive deficits after whole-brain radiation therapy for cancer: A clue to other types of dementia?
Whole brain radiation therapy for the treatment of tumors can sometimes cause cognitive impairment. Memory deficits were noted in up to 50% of treated patients over a short period of several months. In addition, an increased rate of dementia in young patients has been noted over the longer term, i.e. years. A deficit in neurogenesis after irradiation has been postulated to be the main cause of cognitive decline in patients, but recent data on irradiation therapy for limited parts of the brain appear to indicate other possibilities. Irradiation can directly damage various types of cells other than neuronal stem cells. However, this paper will focus on injury to brain vasculature leading to cognitive decline since vessels represent a better therapeutic target for drug development than other cells in the brain because of the blood-brain barrier.


[Is there a psychological and physiological difference between DIEP- and free TRAM-flap? A retrospective patient survey].
The DIEP- (Deep Inferior Epigastric Perforator) flap and the free TRAM- (Transverser Rectus Abdominis Musculocutaneous) flap are common procedures for breast reconstruction. The aim of the study was to identify a difference in the psychological and physiological patient satisfaction between DIEP- and free TRAM-flap. To provide a homogenous group, with a stable result of the reconstruction, the collective for questioning was picked out of the years 2009 and 2010. All patients included underwent a breast reconstruction with a DIEP-flap or free TRAM-flap at our division. For evaluation we formed 2 groups: DIEP-flap group (DLG) and TRAM-flap group (TLG). After preparing the questionnaire a telephone survey was performed. For the null hypothesis we postulated that there is no difference between DLG and TLG in the patient satisfaction. We contacted 44 patients, 30 of them took part in our survey (15 from the DLG and 15 from the TLG). The mean BMI in the questionnaire group was 26.9 kg/m² and the mean age was 48.3 years. 2 questions (lifting heavy loads (p=0.005) and performing sit-up's (p=0.001)) show a significant difference between DLG and TLG, a benefit of the DLG could be seen. Both questions had the physiology of the rectus abdominis muscle as background. The complication rate for partial flap loss or partial necrosis was one third lower (p=0.299) in the TLG than compared to the DLG. Up to now, physicians think that the DIEP-flap seems to be the best possible procedure for breast reconstruction with belly flaps. However, numerous studies disprove the superiority in the donor site morbidity. In the literature, an advantage of the TRAM-flap is clearly visible by comparing the complication rates. Our oral interviewing also states that there is no -difference in the psychological and physiological satisfaction of the patients. We can recommend a precise patient selection if a DIEP-flap for breast reconstruction should be performed. In case of comorbidities the possibility of the safer free TRAM-flap should be considered. In the future, a comparative analysis between the DIEP-flap, free TRAM-flap and pedicled TRAM-flap should be performed, by keeping the patients satisfaction, the complication rate and the cost effectiveness in mind.


Cognition in epilepsy: current clinical issues of interest.
This review provides an update and summary of recent neuropsychological findings in epilepsy focusing on three major clinical topics among the many developments in the field. We will critically outline the current state with regard to cognition in new-onset epilepsies, social cognition in epilepsy, and the long-term outcome of epilepsy surgery and the cognitive outcomes of superselective surgical procedures. Current studies indicate that neuropsychological impairments are prevalent already at the onset of epilepsy and even before, social cognition (i.e., emotion recognition and theory of mind) is impaired in different epilepsy populations, the long-term outcome of epilepsy surgery is mostly characterized by a stable or even improved cognitive status, and superselective epilepsy surgeries are associated with a promising neuropsychological outcome. The high prevalence of cognitive deficits around epilepsy onset challenges the assumption that epilepsy is the major cause of cognitive problems and calls for early neuropsychological diagnostics. Social cognition seems to be a relevant domain that is not yet routinely considered in epilepsy. The cognitive long-term outcome of epilepsy surgery is mostly positive. Stereotactic thermocoagulation and gamma knife surgery appear to be cognitively safe procedures.


Native low-density lipoprotein induces endothelial nitric oxide synthase dysfunction: role of heat shock protein 90 and caveolin-1.
Although native LDL (n-LDL) is well recognized for inducing endothelial cell (EC) dysfunction, the mechanisms remain unclear. One hypothesis is n-LDL increases caveolin-1 (Cav-1), which decreases nitric oxide (*NO) production by binding endothelial nitric oxide synthase (eNOS) in an inactive state. Another is n-LDL increases superoxide anion (O(2)(*-)), which inactivates *NO. To test these hypotheses, EC were incubated with n-LDL and then analyzed for *NO, O(2)(*-), phospho-eNOS (S1179), eNOS, Cav-1, calmodulin (CaM), and heat shock protein 90 (hsp90). n-LDL increased NOx by more than 4-fold while having little effect on A23187-stimulated nitrite production. In contrast, n-LDL decreased cGMP under basal and A23187-stimulated conditions and increased O(2)(*-) by a mechanism that could be inhibited by L-nitroargininemethylester (L-NAME) and BAPTA/AM. n-LDL increased phospho-eNOS by 149%, eNOS by approximately 34%, and Cav-1 by 28%, and decreased the association of hsp90 with eNOS by 49%. n-LDL did not appear to alter eNOS distribution between membrane fractions (approximately 85%) and cytosol (approximately 15%). Only 3-6% of eNOS in membrane fractions was associated with Cav-1. These data support the hypothesis that n-LDL increases O(2)(*-), which scavenges *NO, and suggest that n-LDL uncouples eNOS activity by decreasing the association of hsp90 as an initial step in signaling eNOS to generate O(2)(*-).


Simple Approach: Heat Treatment to Improve the Electrochemical Performance of Commonly Used Anode Electrodes for Lithium-Ion Batteries.
The lithium-ion battery (LIB) industry has been in high demand for simple and effective methods to improve the electrochemical performance of LIBs. Here, we treated three different widely studied anode electrodes (i.e., Li4Ti5O12, TiO2, and graphite) under vacuum at 250 °C, and compared their electrochemical performance with and without a 250 °C treatment. Without changing the composition of the fabricated electrodes, all of the 250 °C treated electrodes exhibited enhanced specific capacities, and the lithium-ion diffusion was improved in different degrees. By comparing the results of scanning electron microscopy (SEM) and energy-dispersive spectroscopy of the pristine and 250 °C treated electrodes, the 250 °C treatment improved the distribution of a polyvinylidene difluoride (PVDF) binder in the electrodes, resulting in a higher porosity of the 250 °C treated electrodes. The results of X-ray photoelectron spectrometry and SEM of the cycled electrodes confirmed that a uniform distribution of the PVDF binder from the 250 °C treatment played a positive role in the formation of a solid electrolyte interphase layer, thereby delivering higher capacities and capacity retentions than those of electrodes without heat treatment. The simplicity of this modification method provides considerable potential for building high-performance LIBs at a larger scale.


Behavioural and emotional problems in moderately preterm children with low socioeconomic status: a population-based study.
Moderately preterm (MP) birth is associated with higher rates of behavioural and emotional problems. To determine the extent to which low socioeconomic status (SES) contributes to these higher rates, we assessed independent and joint effects of MP birth and low SES, overall and by gender. Dutch preventive child health care centres provided a population-based sample of 915 MP children (32-36 weeks gestation) and 543 term-born children, born in 2002/2003. In multivariable logistic regression analyses, we determined the risk of behavioural and emotional problems per standard deviation (SD) decrease in gestational age and SES, using standardized measures for both. We also assessed three SES categories, being low (1SD or more below mean of standardized SES), intermediate (mean ± 1SD), and high (greater than mean + 1SD). The Child Behavior Checklist for 1.5-5 years was used to assess behavioural (externalizing), emotional (internalizing), and total problems at age 4 years. MP children with low SES had significantly higher total problem scores than those with high SES (11.3 vs. 5.1%, respectively). Each SD decrease in SES was associated with a 42% higher odds of elevated total problem scores (OR 1.42, 95% CI 1.14-1.77). No joint effects were found, meaning that lower gestational age independently added to the risk of behaviour problems (OR 1.24, 95% CI 1.00-1.56). Effects of MP birth and low SES were more pronounced in girls. In conclusion, MP birth and low SES multiply the risk of behavioural and emotional problems. The combination of risk factors identifies children who could benefit greatly from early intervention.


Design concepts and early utilization of a new femoral interlocking nail.
Interlocking nails provide excellent stability and control of femoral fractures from the hip to the supracondylar regions, yielding excellent clinical results. Advances in femoral nail design have provided for increased variability in their applications, allowing surgeons to stabilize a wide variety of fractures through either antegrade or retrograde nail insertion methods. In the past, nails were manufactured to be implanted with a specified insertion technique, requiring the surgeon to become facile with multiple nail systems to care for the entire spectrum of femoral injuries. A new femoral intramedullary nail system is being introduced with the capability of stabilizing both right- and left-sided femoral fractures in all 3 modes of interlocking--that is, first-generation antegrade nailing, second-generation reconstruction nailing, and retrograde nailing. The design and rationale of this system are discussed, and clinical examples of use of this new device are provided.


Implantable Systems for Continuous Liquorpheresis and CSF Replacement.
Liquorpheresis (cerebrospinal fluid filtration) comprises a therapeutical approach that has been proposed to treat several neurological conditions where antibodies, inflammatory mediators, or abnormal peptides are the cause or play an important role in the pathogenesis of the disease. Continuous or intermittent cerebrospinal fluid (CSF) replacement may be an alternative approach not explored thus far. Here, we review previous experiences in the use of liquorpheresis in autoimmune and degenerative neurological diseases. Then we describe previous technical reports and provide some new innovations in order to design bidirectional CSF shunting systems that can be complemented either with a deposit of artificial CSF or with a filter of CSF, allowing CSF replacement or liquorpheresis respectively. Both options would lead to mechanical dilution of the patient's CSF.


[Use of a domestic hydrogel as an occlusive agent of varicose veins of the lower limbs].
The authors propose experimental grounds of the method of surgical correction of the pathological blood flow along varicose subcutaneous veins and the endovasal catheter obliteration of them. The method was used in operations on 70 patients with varicosities of the lower extremity veins at the I and II stages of the disease. No complications or recurrences were noted in the following 1-3 years of observation.


Differentiation of calcified regions and iron deposits in the ageing brain on conventional structural MR images.
In the human brain, minerals such as iron and calcium accumulate increasingly with age. They typically appear hypointense on T2*-weighted MRI sequences. This study aims to explore the differentiation and association between calcified regions and noncalcified iron deposits on clinical brain MRI in elderly, otherwise healthy subjects. Mineral deposits were segmented on co-registered T1- and T2*-weighted sequences from 100 1.5 Tesla MRI datasets of community-dwelling individuals in their 70s. To differentiate calcified regions from noncalcified iron deposits we developed a method based on their appearance on T1-weighted images, which was validated with a purpose-designed phantom. Joint T1- and T2*-weighted intensity histograms were constructed to measure the similarity between the calcified and noncalcified iron deposits using a Euclidean distance based metric. We found distinct distributions for calcified regions and noncalcified iron deposits in the cumulative joint T1- and T2*-weighted intensity histograms across all subjects (correlations ranging from 0.02 to 0.86; mean = 0.26 ± 0.16; t = 16.93; P < 0.001) consistent with differences in iron and calcium signal in the phantom. The mean volumes of affected tissue per subject for calcified and noncalcified deposits were 236.74 ± 309.70 mm(3) and 283.76 ± 581.51 mm(3); respectively. There was a positive association between the mineral depositions (β = 0.32, P < 0.005), consistent with existing literature reports. Calcified mineral deposits and noncalcified iron deposits can be distinguished from each other by signal intensity changes on conventional 1.5T T1-weighted MRI and are significantly associated in brains of elderly, otherwise healthy subjects.


Oral deferiprone for iron chelation in people with thalassaemia.
Thalassaemia major is a genetic disease characterised by a reduced ability to produce haemoglobin. Management of the resulting anaemia is through transfusions of red blood cells. Repeated transfusions result in excessive accumulation of iron in the body (iron overload), removal of which is achieved through iron chelation therapy. A commonly used iron chelator, deferiprone, has been found to be pharmacologically efficacious. However, important questions exist about the efficacy and safety of deferiprone compared to another iron chelator, desferrioxamine. To summarise data from trials on the clinical efficacy and safety of deferiprone and to compare the clinical efficacy and safety of deferiprone for thalassaemia with desferrioxamine. We searched the Group's Haemoglobinopathies Trials Register, MEDLINE, EMBASE, Biological Abstracts, ZETOC, Current Controlled Trials and bibliographies of relevant publications. We contacted the manufacturers of deferiprone and desferrioxamine. Most recent searches: June 2006. Randomised controlled trials comparing deferiprone with another iron chelator; or comparing two schedules of deferiprone, in people with transfusion-dependent thalassaemia. Two authors independently assessed trial quality and extracted data. Missing data were requested from the original investigators. Ten trials involving 398 people (range 10 to 144 people) were included. Nine trials compared deferiprone with desferrioxamine or a combination of deferiprone and desferrioxamine and one compared different schedules of deferiprone. There was little consistency between outcomes and little information to fully assess the methodological quality of most of the included trials. No trial reported long-term outcomes (mortality and end organ damage). There was no consistent effect on reduction of iron overload between all treatment comparisons, with the exception of urinary iron excretion in comparisons of deferiprone with desferrioxamine. An increase in iron excretion levels favoured deferiprone in one trial and desferrioxamine in three trials, even though measurement of urinary iron excretion underestimates total iron excretion by desferrioxamine.Adverse events were recorded in trials comparing deferiprone with desferrioxamine. There was evidence of adverse events in all treatment groups. Adverse events in one trial were significantly more likely with deferiprone than desferrioxamine, relative risk 2.24 (95% confidence interval 1.19 to 4.23). We found no reason to change current treatment recommendations, namely deferiprone is indicated for treating iron overload in people with thalassaemia major when desferrioxamine is contraindicated or inadequate. However, there is an urgent need for adequately-powered, high quality trials comparing the overall clinical efficacy and long-term outcome of deferiprone with desferrioxamine.


Modes of acquisition of Wolbachia: horizontal transfer, hybrid introgression, and codivergence in the Nasonia species complex.
Wolbachia are maternally inherited bacteria that infect a large number of insects and are responsible for different reproductive alterations of their hosts. One of the key features of Wolbachia biology is its ability to move within and between host species, which contributes to the impressive diversity and range of infected hosts. Using multiple Wolbachia genes, including five developed for Multi-Locus Sequence Typing (MLST), the diversity and modes of movement of Wolbachia within the wasp genus Nasonia were investigated. Eleven different Wolbachia were found in the four species of Nasonia, including five newly identified infections. Five infections were acquired by horizontal transmission from other insect taxa, three have been acquired by hybridization between two Nasonia species, which resulted in a mitochondrial-Wolbachia sweep from one species to the other, and at least three have codiverged during speciation of their hosts. The results show that a variety of transfer mechanisms of Wolbachia are possible even within a single host genus. Codivergence of Wolbachia and their hosts is uncommon and provides a rare opportunity to investigate long-term Wolbachia evolution within a host lineage. Using synonymous divergence among codiverging infections and host nuclear genes, we estimate Wolbachia mutation rates to be approximately one-third that of the nuclear genome.


The acceptability of voluntary HIV antibody testing in the United States: a decade of lessons learned.
As the benefits of early diagnosis of HIV increase, US adults are more likely to be offered HIV counseling and testing in settings where they may not seek testing. Rates and determinants of counseling and testing acceptance in these settings are poorly understood. We reviewed articles and abstracts published from 1985 to 1995 which addressed rates or determinants of counseling and testing acceptance in facilities that provide perinatal, family planning, gynecology, sexually transmitted disease (STD) and drug treatment services, hospitals, and prisons. Data reflected testing experience of more than 240,000 adults. Acceptance rates varied widely (3-100%), even within settings of the same type. Acceptance was generally higher (> 50%) among persons at high risk for acquiring or transmitting the infection (e.g., STD patients, pregnant women at high risk) than among low-risk persons. Factors associated with high acceptance rates included the client's perception of HIV risk, acknowledging risk behaviors; confidentiality protections; presenting counseling and testing as 'routine' rather than optional; and the provider's belief that counseling and testing will benefit the client. Factors associated with low acceptance rates included prior HIV testing, fears about coping with results, and explicit informed consent. To institute and evaluate counseling and testing programs for persons who do not specifically seek testing, multiple determinants of acceptance must be considered. Practices that protect confidentiality, endorse counseling directed to a client's unique circumstances, and highlight the medical and social benefits of testing are likely to promote acceptance. Acceptance of counseling and testing offered nonroutinely to the numerous Americans who have been previously tested or are at low risk is likely to be low.


[Predictive factors related to general well-being in adolescent students in Cartagena, Colombia].
Determining predictive factors related to well-being amongst adolescent students in Cartagena, Colombia. An analytical, cross-sectional study was designed using a random sample of adolescent students who were enrolled in public and private schools in Cartagena. The students filled out an individual, anonymous questionnaire to investigate selfesteem, the intensity of their religious feeling (attitude towards Christianity), their general well-being (depressive symptoms) and level of family functioning. A descriptive analysis of the variables was made; all qualitative and quantitative variables were then dichotomised. Odds ratios (OR) were estimated using 95 % confidence intervals (95 % CI). A group of 1,014 students successfully completed the survey. Mean age was 15.1 (SD=1.8); 54.5 % were girls. The variables significantly associated with well-being were high self-esteem (3.5 OR, 1.2-5.7 95 %CI), intense religiousness (2.2 OR, 1.3-3.4 95 %CI) and having a functional family (2.0 OR, 1.2-3.1 95 %CI). High self-esteem, intense religiousness and having a functional family were predictors of well-being among adolescent students in Cartagena, Colombia.


[Research in homeopathy: data, problems and prospects].
In the recent years the interest for the therapeutic use of exogenous and endogenous natural compounds, that are also employed at very low dosage, is growing up. In this context, an important role is played by homoeopathic medicine, which is involving increasing number of physicians and researchers, besides the common people. Here a critical approach to the problem of homoeopathy theory and research is attempted. The traditional concepts of the homoeopathy are challenged with the modern knowledge arising from basic and applied research. It is shown that at least a part of these concepts may find a good correspondence into the modern physiopathology. However, a number of problems, both of biological-biomedical and of practical nature remain unresolved. Moreover, any explanation of the effect of extremely diluted drugs is still hypothetical. In the second part of the work, laboratory investigations regarding the test of the homoeopathic drugs and of ultra-low doses of various substances in several experimental models are reviewed. Even if the evidence is far from to be conclusive, a number of studies showed that compounds, that are prepared and diluted according to the methods of the homoeopathic medicine, may exhibit specific stimulatory or inhibitory activities in selected experimental systems.


Carbocyclic 6-benzylthioinosine analogues as subversive substrates of Toxoplasma gondii adenosine kinase: biological activities and selective toxicities.
Toxoplasma gondii adenosine kinase (EC 126.96.36.199) is the major route of adenosine metabolism in this parasite. The enzyme is significantly more active than any other enzyme of the purine salvage in T. gondii and has been established as a potential chemotherapeutic target for the treatment of toxoplasmosis. Several 6-benzylthioinosines have already been identified as subversive substrates of the T. gondii but not human adenosine kinase. Therefore, these compounds are preferentially metabolized to their respective nucleotides and become selectively toxic against the parasites but not its host. In the present study, we report the testing of the metabolism of several carbocyclic 6-benzylthioinosines, as well as their efficacy as anti-toxoplasmic agents in cell culture. All the carbocyclic 6-benzylthioinosine analogues were metabolized to their 5'-monophosphate derivatives, albeit to different degrees. These results indicate that these compounds are not only ligands but also substrates of T. gondii adenosine kinase. All the carbocyclic 6-benzylthioinosine analogues showed a selective anti-toxoplasmic effect against wild type parasites, but not mutants lacking adenosine kinase. These results indicate that the oxygen atom of the sugar is not critical for substrate binding. The efficacy of these compounds varied with the position and nature of the substitution on their phenyl ring. Moreover, none of these analogues exhibited host toxicity. The best compounds were carbocyclic 6-(p-methylbenzylthio)inosine (IC(50)=11.9 microM), carbocyclic 6-(p-methoxybenzylthio)inosine (IC(50)=12.1 microM), and carbocyclic 6-(p-methoxycarbonylbenzylthio)inosine (IC(50)=12.8 microM). These compounds have about a 1.5-fold better efficacy relative to their corresponding 6-benzylthioinosine analogues (Rais et al., Biochem Pharmacol 2005;69:1409-19 [29]). The results further confirm that T. gondii adenosine kinase is an excellent target for chemotherapy and that carbocyclic 6-benzylthioinosines are potential anti-toxoplasmic agents.


[Estimates of velocity of the travelling wave in the high-range cochlea of the dolphin].
Auditory brainstem responses (ABR) to sound pulses of precisely defined spectrum band of 0.5 oct (from 11.2-16 to 90-128 kHz) were recorded in bottlenose dolphins Tursiops truncatus. At equal stimulus levels, ABR amplitude depended on the stimulus spectrum band: the higher the frequency, the higher the amplitude. ABR waveform little depended on the stimulus spectrum band, however ABR latency did depend: the higher the frequency, the shorter the latency. The latency difference between responses to the lowest-frequency (11.2-16 kHz) and the highest-frequency (90-129 kHz) stimuli was up to 0.3 ms. This latency difference was attributed to the time of the wave travelling along the basilar membrane. Therefore, the data were used to compute the travelling-wave velocity. The obtained estimates were: 38.2 oct/ms at the proximal (high-frequ- ency) end of the basilar membrane to 2.8 oct/ms at the distal (low-frequency) end. Comparison of the travelling-wave velocities in humans and dolphins shows that the travelling-wave velocity is linked to the characteristic frequency, not to the place in the cochlea.


Effect of ivermectin in heifers on mortality and egg production of Psoroptes ovis.
Ten stanchioned heifers, heavily infested with Psoroptes ovis (Hering), were each given a single subcutaneous injection of 200 micrograms of ivermectin/kg. Another 10 heavily infested heifers (stanchioned) were injected subcutaneously with the solvent system (vehicle) used to formulate the ivermectin. Treatment with the vehicle did not reduce mite populations or total egg counts. The 10 heifers treated with ivermectin had an immediate reduction in live mite and egg counts (an increase in the percentage of mortality of mites) and were completely free of psoroptic mites by 20 days after treatment. Ivermectin was equally effective against adult and immature psoroptic mites.


A survey of fasting during pregnancy.
Fasting during the month of Ramadan is compulsory in the Muslim faith. Although pregnant women may be exempted, many still choose to fast while others are more careful in practising it. This survey examines the practice of fasting among pregnant Muslim women in Singapore based on the prevalence in relation to factors such as parity, social and economic circumstances. It also analyses the factors that influence the decision to fast and the successful completion of the fast, and examines their knowledge, belief and attitudes on fasting during the holy month of Ramadan. This is a retrospective study of all Muslim women who were pregnant and received antenatal care in our hospital during the month of Ramadan from 17 November 2001 to 16 December 2001. A four-page questionnaire was mailed to all eligible subjects in March 2002. Of 202 eligible subjects, 125 responded via mail and 57 via the phone, yielding a response rate of 90 percent. Most women chose to fast during pregnancy, and they do so with adequate support from their spouses and family members. Most of them do not experience any adversities during fasting and even if they do, most were able to overcome them. Most women adopt a positive attitude towards fasting. However, there is a lack of basic religious knowledge among many pregnant women pertaining to the Muslim law of fasting during pregnancy. Doctors and health workers need to understand the religious obligations of a Muslim towards fasting during Ramadan. Only through this can a doctor adequately counsel Muslim patients and allow informed decision with regards to fasting. With respect to pregnant women, provisions are allowed for them not to observe fasting.


Characteristics of Contact Force and Muscle Activation During Choreographed Falls With 2 Common Landing Techniques in Contemporary Dance.
This study investigated the contact forces and muscle activation during 2 choreographed fall techniques in contemporary dancers and how these were affected by the fall technique. Ten collegiate-level dancers were instructed in 2 choreographed falls: (1) an anteriorly focused fall involving ankle plantar flexion, knee flexion, and hip flexion with dispersion of forces up the anterior surface of the shank (technique 1) and (2) a laterally focused fall involving inversion at the ankle with dispersion of forces up the lateral aspect of the shank (technique 2). The knee and hip contact forces were 26.3% smaller (technique 1: 1743 N vs technique 2: 1284 N) and 24.1% greater (technique 1: 1334 N vs technique 2: 1656 N), respectively, in technique 2 (P < .03). At the time of knee contact, percentage of maximal voluntary isometric contraction (%MVIC) was 45.8% greater for rectus femoris muscle (technique 1: 7.2% vs technique 2: 10.5%) and 96.9% greater for gluteus medius muscle (technique 1: 3.2% vs technique 2: 6.3%) (P < .01) in technique 2. The results provide insight into determining safer landing strategies to avoid knee injuries in individuals who experience a fall (ie, dancers, athletes, and older adults).


Risk factors for multimorbidity in adulthood: A systematic review.
Multimorbidity, the coexistence of multiple chronic diseases in an individual, is highly prevalent and challenging for healthcare systems. However, its risk factors remain poorly understood. To systematically review studies reporting multimorbidity risk factors. A PRISMA-compliant systematic review was conducted, searching electronic databases (MEDLINE, EMBASE, Web of Science, Scopus). Inclusion criteria were studies addressing multimorbidity transitions, trajectories, continuous disease counts, and specific patterns. Non-human studies and participants under 18 were excluded. Associations between risk factors and multimorbidity onset were reported. Of 20,806 identified studies, 68 were included, with participants aged 18-105 from 23 countries. Nine risk factor categories were identified, including demographic, socioeconomic, and behavioral factors. Older age, low education, obesity, hypertension, depression, low pysical function were generally positively associated with multimorbidity. Results for factors like smoking, alcohol consumption, and dietary patterns were inconsistent. Study quality was moderate, with 16.2% having low risk of bias. Several risk factors seem to be consistently associated with an increased risk of accumulating chronic diseases over time. However, heterogeneity in settings, exposure and outcome, and baseline health of participants hampers robust conclusions.


An inner centromere protein that stimulates the microtubule depolymerizing activity of a KinI kinesin.
Mitosis requires precise control of microtubule dynamics. The KinI kinesin MCAK, a microtubule depolymerase, is critical for this regulation. In a screen to discover previously uncharacterized microtubule-associated proteins, we identified ICIS, a protein that stimulates MCAK activity in vitro. Consistent with this biochemical property, blocking ICIS function in Xenopus extracts with antibodies caused excessive microtubule growth and inhibited spindle formation. Prior to anaphase, ICIS localized in an MCAK-dependent manner to inner centromeres, the chromosomal region located in between sister kinetochores. From Xenopus extracts, ICIS coimmunoprecipitated MCAK and the inner centromere proteins INCENP and Aurora B, which are thought to promote chromosome biorientation. By immunoelectron microscopy, we found that ICIS is present on the surface of inner centromeres, placing it in an ideal location to depolymerize microtubules associated laterally with inner centromeres. At inner centromeres, MCAK-ICIS may destabilize these microtubules and provide a mechanism that prevents kinetochore-microtubule attachment errors.


Alteration of thyroid hormone signaling triggers the diabetes-induced pathological growth, remodeling, and dedifferentiation of podocytes.
Thyroid hormone (TH) signaling is a universal regulator of metabolism, growth, and development. Here, we show that TH-TH receptor (TH-TR) axis alterations are critically involved in diabetic nephropathy-associated (DN-associated) podocyte pathology, and we identify TRα1 as a key regulator of the pathogenesis of DN. In ZSF1 diabetic rats, T3 levels progressively decreased during DN, and this was inversely correlated with metabolic and renal disease worsening. These phenomena were associated with the reexpression of the fetal isoform TRα1 in podocytes and parietal cells of both rats and patients with DN and with the increased glomerular expression of the TH-inactivating enzyme deiodinase 3 (DIO3). In diabetic rats, TRα1-positive cells also reexpressed several fetal mesenchymal and damage-related podocyte markers, while glomerular and podocyte hypertrophy was evident. In vitro, exposing human podocytes to diabetes milieu typical components markedly increased TRα1 and DIO3 expression and induced cytoskeleton rearrangements, adult podocyte marker downregulation and fetal kidney marker upregulation, the maladaptive cell cycle induction/arrest, and TRα1-ERK1/2-mediated hypertrophy. Strikingly, T3 treatment reduced TRα1 and DIO3 expression and completely reversed all these alterations. Our data show that diabetic stress induces the TH-TRα1 axis to adopt a fetal ligand/receptor relationship pattern that triggers the recapitulation of the fetal podocyte phenotype and subsequent pathological alterations.


Multifunctional receptor-targeted nanocomplexes for magnetic resonance imaging and transfection of tumours.
The efficient targeted delivery of nucleic acids in vivo provides some of the greatest challenges to the development of genetic therapies. We aim to develop nanocomplex formulations that achieve targeted transfection of neuroblastoma tumours that can be monitored simultaneously by MRI. Here, we have compared nanocomplexes comprising self-assembling mixtures of liposomes, plasmid DNA and one of three different peptide ligands derived from ApoE, neurotensin and tetanus toxin for targeted transfection in vitro and in vivo. Neurotensin-targeted nanocomplexes produced the highest levels of transfection and showed a 4.7-fold increase in transfected luciferase expression over non-targeted nanocomplexes in Neuro-2A cells. Transfection of subcutaneous Neuro-2A tumours in vivo with neurotensin-targeted nanocomplexes produced a 9.3-fold increase in gene expression over non-targeted controls. Confocal microscopy analysis elucidated the time course of DNA delivery with fluorescently labelled nanocomplex formulations in cells. It was confirmed that addition of a gadolinium lipid conjugate contrast agent allowed real time in vivo monitoring of nanocomplex localisation in tumours by MRI, which was maintained for at least 24 h. The peptide-targeted nanocomplexes developed here allow for the specific enhancement of targeted gene therapy both in vitro and in vivo, whilst allowing real time monitoring of delivery with MRI.


Binding of [3H]bradykinin in isolated nephron segments of the rabbit.
Binding of intrinsically labeled [3H]bradykinin was studied in isolated nephron segments of the rabbit. Highest binding was observed in the cortical collecting tubule (5.76 +/- 0.34 X 10(-18) mol/mm) and the outer medullary collecting tubule (5.24 +/- 0.25 X 10(-18) mol/mm, means +/- SE, n = 6). Small but significant binding was also seen in the glomerulus, proximal straight tubule, cortical thick ascending limb of Henle's loop, and distal convoluted tubule. Lysyl-bradykinin, methionyl-lysyl-bradykinin, and tyrosine-8-bradykinin (but not des-arginine-9-bradykinin, vasopressin, angiotensins I and II, or prostaglandins) competed with [3H]bradykinin. The site of highest kinin binding (collecting tubule) is downstream from the highest concentration of kallikrein (granular portion of distal convoluted tubule). The binding data indicate that the major sites of kinin action in the kidney are the cortical and medullary collecting tubules. One action of kinins could be the stimulation of prostaglandin synthesis in the collecting tubules, which are known to actively synthesize prostaglandins.


Sacubitril/valsartan attenuates myocardial inflammation, hypertrophy, and fibrosis in rats with heart failure with preserved ejection fraction.
Heart failure with preserved ejection fraction (HFpEF) represents a multifaceted syndrome related to complex pathologic mechanisms. Sacubitril/valsartan (Sac/val) has demonstrated therapeutic efficacy in HFpEF treatment. However, additional research is required to elucidate its pharmacological mechanisms. Accordingly, this study aimed to explore the potential therapeutic effects of Sac/val in HFpEF rats and the underlying molecular mechanisms. In this study, rats with HFpEF were induced by subjecting spontaneously hypertensive rats to a diet rich in fats, salts, and sugars, along with administering streptozotocin. Subsequently, they were administered Sac/val at a daily dosage of 18 mg/kg. Finally, cardiac structure and function were assessed using echocardiography; Hematoxylin and eosin staining and Masson's trichrome staining were employed to evaluate the pathological changes; Quantitative real-time polymerase chain reaction and Western blot analysis were conducted to determine the expression of pertinent mRNA and proteins. Sac/val treatment attenuated left ventricular (LV) remodeling and diastolic dysfunction in HFpEF rats, possibly related to its anti-inflammatory, anti-hypertrophic, and anti-fibrotic efficacy. Mechanistically, Sac/val might inhibit inflammation by down-regulating cell adhesion molecule (intercellular adhesion molecule-1 (ICAM-1) and vascular endothelial cell adhesion molecule-1 (VCAM-1)) expression. Additionally, it blocked the phosphorylation of glycogen synthase kinase 3β (GSK-3β) to prevent cardiomyocyte hypertrophy. Furthermore, it effectively suppressed myocardial fibrosis by inhibiting the transforming growth factor-beta1 (TGF-β1)/Smads pathway. Our findings suggest that Sac/val improved LV remodeling and diastolic dysfunction, potentially attributed to its anti-inflammatory, anti-hypertrophic, and anti-fibrotic effects. These results provide a sound theoretical rationale for the clinical application of Sac/val in patients with HFpEF.


Two mutations convert mammalian xanthine oxidoreductase to highly superoxide-productive xanthine oxidase.
Reactive oxygen species are generated by various systems, including NADPH oxidases, xanthine oxidoreductase (XOR) and mitochondrial respiratory enzymes, and contribute to many physiological and pathological phenomena. Mammalian xanthine dehydrogenase (XDH) can be converted to xanthine oxidase (XO), which produces both superoxide anion and hydrogen peroxide in a molar ratio of about 1:3, depending upon the conditions. Here, we present a mutant of rat XOR that displays mainly XO activity with a superoxide:hydrogen peroxide production ratio of about 6:1. In the mutant, tryptophan 335, which is a component of the amino acid cluster crucial for switching from the XDH to the XO conformation, was replaced with alanine, and phenylalanine 336, which modulates FAD's redox potential through stacking interactions with the flavin cofactor, was changed to leucine. When the mutant was expressed in Sf9 cells, it was obtained in the XO form, and dithiothreitol treatment only partially restored the pyridine nucleotide-binding capacity. The crystal structure of the dithiothreitol-treated mutant at 2.3 Angstroms resolution showed the enzyme's two subunits to be quite similar, but not identical: the cluster involved in conformation-switching was completely disrupted in one subunit, but remained partly associated in the other one. The chain trace of the active site loop in this mutant is very similar to that of the bovine XO form. These results are consistent with the idea that the XDH and XO forms of the mutant are in an equilibrium that greatly favours the XO form, but the equilibrium is partly shifted towards the XDH form upon incubation with dithiothreitol.


Fish oil decreases C-reactive protein/albumin ratio improving nutritional prognosis and plasma fatty acid profile in colorectal cancer patients.
Previous studies have shown that n-3 polyunsaturated fatty acids n-3 (n-3 PUFA) have several anticancer effects, especially attributed to their ability to modulate a variety of genomic and immune responses. In this context, this randomized, prospective, controlled clinical trial was conducted in order to check whether supplementation of 2 g/day of fish oil for 9 weeks alters the production of inflammatory markers, the plasma fatty acid profile and the nutritional status in patients with colorectal cancer (CRC). Eleven adults with CRC in chemotherapy were randomized into two groups: (a) supplemented (SG) daily with 2 g/day of encapsulated fish oil [providing 600 mg/day of eicosapentaenoic acid (EPA) + docosahexaenoic acid (DHA)] for 9 weeks (n = 6), and (b) control (CG) (n = 5). All outcomes were evaluated on the day before the first chemotherapy session and 9 weeks later. Plasma TNF-α, IL-1β, IL-10 and IL-17A, the pro/anti-inflammatory balance (ratio TNF-α/IL-10 and IL-1β/IL10) and serum albumin, showed no significant changes between times and study groups (p > 0.05). C-reactive protein (CRP) and the CRP/albumin ratio showed opposite behavior in groups, significantly reducing their values in SG (p < 0.05). Plasma proportions of EPA and DHA increased 1.8 and 1.4 times, respectively, while the ARA reduced approximately 0.6 times with the supplementation (9 weeks vs baseline, p < 0.05). Patients from SG gained 1.2 kg (median) while the CG lost -0.5 kg (median) during the 9 weeks of chemotherapy (p = 0.72). These results demonstrate that 2 g/day of fish oil for 9 weeks of chemotherapy improves CRP values, CRP/albumin status, plasma fatty acid profile and potentially prevents weight loss during treatment.


Cloning a cDNA for the pro-alpha 2 chain of human type I collagen.
Poly(A)-RNA enriched for type I procollagen sequences was isolated from normal human fibroblasts and used as template to synthesize double-stranded cDNA with avian myeloblastosis virus (AMV) reverse transcriptase. After the ends had been blunted with nuclease S1 and dGMP tails had been added with terminal deoxynucleotidyltransferase, the double-stranded cDNA was annealed with pBR322 DNA that had previously been cleaved with EcoRI, blunted with AMV reverse transcriptase, and dCMP-tailed with terminal deoxynucleotidyltransferase. The chimeric molecule was used to transform Escherichia coli strain HB101. Ninety-five recombinant clones were obtained and screened by dot hybridization analysis using 32P-labeled cDNA synthesized from the original poly(A)-RNA collagen-enriched population. Three positive clones were isolated and further characterized by blot hybridization techniques and by EcoRII digestion. One clone with an insert of 2.2 kilobases was shown to contain sequences encoding for the pro-alpha 2 chain of human type I procollagen. DNA sequence analysis of a 172-nucleotide fragment demonstrated that the cloned cDNA extends from amino acid position 450 of the alpha 2 chain to the middle of the COOH-terminal propeptide.


Evolution of intron splicing towards optimized gene expression is based on various Cis- and Trans-molecular mechanisms.
Splicing expands, reshapes, and regulates the transcriptome of eukaryotic organisms. Despite its importance, key questions remain unanswered, including the following: Can splicing evolve when organisms adapt to new challenges? How does evolution optimize inefficiency of introns' splicing and of the splicing machinery? To explore these questions, we evolved yeast cells that were engineered to contain an inefficiently spliced intron inside a gene whose protein product was under selection for an increased expression level. We identified a combination of mutations in Cis (within the gene of interest) and in Trans (in mRNA-maturation machinery). Surprisingly, the mutations in Cis resided outside of known intronic functional sites and improved the intron's splicing efficiency potentially by easing tight mRNA structures. One of these mutations hampered a protein's domain that was not under selection, demonstrating the evolutionary flexibility of multi-domain proteins as one domain functionality was improved at the expense of the other domain. The Trans adaptations resided in two proteins, Npl3 and Gbp2, that bind pre-mRNAs and are central to their maturation. Interestingly, these mutations either increased or decreased the affinity of these proteins to mRNA, presumably allowing faster spliceosome recruitment or increased time before degradation of the pre-mRNAs, respectively. Altogether, our work reveals various mechanistic pathways toward optimizations of intron splicing to ultimately adapt gene expression patterns to novel demands.


Selective nucleotide-release from dense-core granules in insulin-secreting cells.
Secretory granules of insulin-secreting cells are used to store and release peptide hormones as well as low-molecular-weight compounds such as nucleotides. Here we have compared the rate of exocytosis with the time courses of nucleotide and peptide release by a combination of capacitance measurements, electrophysiological detection of ATP release and single-granule imaging. We demonstrate that the release of nucleotides and peptides is delayed by approximately 0.1 and approximately 2 seconds with respect to membrane fusion, respectively. We further show that in up to 70% of the cases exocytosis does not result in significant release of the peptide cargo, likely because of a mechanism that leads to premature closure of the fusion pore. Release of nucleotides and protons occurred regardless of whether peptides were secreted or not. These observations suggest that insulin-secreting cells are able to use the same secretory vesicles to release small molecules either alone or together with the peptide hormone.


Endogenous glucocorticoids cause thymus atrophy but are protective during acute Trypanosoma cruzi infection.
The cytokine-mediated stimulation of the hypothalamus-pituitary-adrenal (HPA) axis is relevant for survival during bacterial endotoxemia and certain viral infections. However, only limited information is available regarding the effects of endogenous glucocorticoids on parasite diseases. We have studied this issue using, as a model, C57Bl/6 and Balb/c mice infected with Trypanosoma cruzi, the causal agent of Chagas' disease. These two mouse strains differ in the susceptibility to infection with the parasite. An intense stimulation of the HPA-axis was observed 3 weeks after infection in both strains, but glucocorticoid levels were already increased two- to threefold in the less susceptible Balb/c strain during the first week. Blockade of glucocorticoid receptors with the glucocorticoid antagonist RU486, starting on day 10 after infection, partially reversed the thymic atrophy and decreased the number of CD4(+)CD8(+) thymocytes without affecting parasitemia and the number of inflammatory foci in the heart. However, tumor necrosis factor-alpha blood levels were increased in infected mice of both strains treated with RU486. Furthermore, the blockade of glucocorticoid receptors accelerated death in C57Bl/6J mice and increased lethality to 100% in Balb/c mice. The results obtained represent the first evidence that an endocrine host response that is coupled to the immune process can strongly affect the course of a parasite infection.


Interactions of the antimicrobial peptide Ac-FRWWHR-NH(2) with model membrane systems and bacterial cells.
The acetylated and amidated hexapeptide FRWWHR (combi-2), previously identified by combinatorial chemistry methods, shows strong antimicrobial activity. The binding of the peptide to 1-palmitoyl-2-oleoyl-sn-glycero-3-[(phospho-rac-(1-glycerol)] (POPG) and 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) vesicles was studied using fluorescence spectroscopy and isothermal titration calorimetry (ITC). Differential scanning calorimetry (DSC) with dipalmitoylphosphatidylcholine (DPPC) and dipalmitoylphosphatidylglycerol (DPPG) multilamellar vesicles was performed to determine changes in the lipid phase behaviour upon binding the peptide. Two-dimensional proton nuclear magnetic resonance (NMR) spectroscopy, to solve the bound peptide structure, was performed in the presence of dodecylphosphatidylcholine (DPC) and sodium dodecyl sulphate (SDS) micelles. The fluorescence, ITC and DSC studies indicate that the peptide interacts preferentially with lipid vesicles containing negatively charged head groups. Conformational information determined using NMR indicate that the combi-2 peptide adopts a coiled amphipathic conformation when bound to SDS and DPC micelles. Leakage assays indicate that the peptide is not very efficient at causing leakage from calcein-filled large unilamellar vesicles comprised of POPG/POPC (1 : 1). The rapid passage of either the fluorescent-tagged peptides combi-2 or the previously studied peptide Ac-RRWWRF-NH(2) (combi-1) into Escherichia coli and Staphylococcus aureus suggests that instead of membrane disruption, the main bactericidal site of action of these peptides might be located inside bacteria.


Characterization of differential Toll-like receptor responses below the optical diffraction limit.
Many membrane receptors are recruited to specific cell surface domains to form nanoscale clusters upon ligand activation. This step appears to be necessary to initiate cell signaling, including pathways in innate immune system activation. However, virulent pathogens such as Yersinia pestis (the causative agent of plague) are known to evade innate immune detection, in contrast to similar microbes (such as Escherichia coli) that elicit a robust response. This disparity has been partly attributed to the structure of lipopolysaccharides (LPS) on the bacterial cell wall, which are recognized by the innate immune receptor TLR4. It is hypothesized that nanoscale differences exist between the spatial clustering of TLR4 upon binding of LPS derived from Y. pestis and E. coli. Although optical imaging can provide exquisite details of the spatial organization of biomolecules, there is a mismatch between the scale at which receptor clustering occurs (<300 nm) and the optical diffraction limit (>400 nm). The last decade has seen the emergence of super-resolution imaging methods that effectively break the optical diffraction barrier to yield truly nanoscale information in intact biological samples. This study reports the first visualizations of TLR4 distributions on intact cells at image resolutions of <30 nm using a novel, dual-color stochastic optical reconstruction microscopy (STORM) technique. This methodology permits distinction between receptors containing bound LPS from those without at the nanoscale. Importantly, it is also shown that LPS derived from immunostimulatory bacteria result in significantly higher LPS-TLR4 cluster sizes and a nearly twofold greater ligand/receptor colocalization as compared to immunoevading LPS.


We need more replication research - A case for test-retest reliability.
Following debates in psychology on the importance of replication research, we have also started to see pleas for a more prominent role for replication research in medical education. To enable replication research, it is of paramount importance to carefully study the reliability of the instruments we use. Cronbach's alpha has been the most widely used estimator of reliability in the field of medical education, notably as some kind of quality label of test or questionnaire scores based on multiple items or of the reliability of assessment across exam stations. However, as this narrative review outlines, Cronbach's alpha or alternative reliability statistics may complement but not replace psychometric methods such as factor analysis. Moreover, multiple-item measurements should be preferred above single-item measurements, and when using single-item measurements, coefficients as Cronbach's alpha should not be interpreted as indicators of the reliability of a single item when that item is administered after fundamentally different activities, such as learning tasks that differ in content. Finally, if we want to follow up on recent pleas for more replication research, we have to start studying the test-retest reliability of the instruments we use.


Understanding factors associated with readmission disparities among Delta region, Delta state, and other hospitals.
To understand the factors that potentially account for differences in 30-day readmission ratios for pneumonia, heart failure, and acute myocardial infarction (AMI) among hospitals in the Mississippi Delta region (Delta region), in Delta states excluding the hospitals in the Delta region (Delta state), and in the rest of the nation (other). A longitudinal study design from 2013 to 2016. The dependent variables were 30-day readmission ratios for AMI, heart failure, and pneumonia. The key independent variables were 2 hospital categories (Delta region and Delta state), year dummies for 2014-2016, and the interactions among hospital categories and year dummies. We conducted 2 analyses for each study condition by estimating models with and without controls for hospital and community characteristics. The coefficients for the interactions among year dummies and Delta region and Delta state hospitals were negative, indicating that Delta region and Delta state hospitals had higher reductions in readmissions than did other hospitals. After controlling for hospital and community characteristics, the disparities in readmissions for pneumonia and AMI in 2013 between Delta region and other hospitals were weakened (P >.05). Major teaching hospitals and percentage of black population were positively associated with readmissions for all study conditions (P values ranged from <.05 to <.001). Disparities in 30-day readmissions for the study conditions among Delta region, Delta state, and other hospitals were reduced under the Hospital Readmissions Reduction Program (HRRP). However, community factors that are not currently used for adjustment in HRRP were associated with readmission ratios. Revisions of HRRP should consider including community characteristics in risk adjustment models.


The politics and practice of initiating a public health postgraduate programme in three universities in sub-Saharan Africa: the challenges of alignment and coherence.
In-country postgraduate training programme in low and middle income countries are widely considered to strengthen institutional and national capacity. There exists dearth of research about how new training initiatives in public health training institutions come about. This paper examines a south-south collaborative initiative wherein three universities based in Ethiopia, Rwanda and Mozambique set out to develop a local based postgraduate programme on health workforce development/management through partnership with a university in South Africa. We used a qualitative case study design. We conducted semi-structured interviews with 36 key informants, who were purposively recruited based on their association or proximity to the programme, and their involvement in the development, review, approval and implementation of the programme. We gathered supplementary data through document reviews and observation. Thematic analysis was used and themes were generated inductively from the data and deductively from literature on capacity development. University A successfully initiated a postgraduate training programme in health workforce development/management. University B and C faced multiple challenges to embed the programme. It was evident that multiple actors underpin programme introduction across institutions, characterized by contestations over issues of programme feasibility, relevance, or need. A daunting challenge in this regard is establishing coherence between health ministries' expectation to roll out training programmes that meet national health priorities and ensure sustainability, and universities and academics' expectations for investment or financial incentive. Programme champions, located in the universities, can be key actors in building such coherence, if they are committed and received sustained support. The south-south initiative also suffers from lack of long term and adequate support. Against the background of very limited human capacity and competition for this capacity, initiating the postgraduate programme on health workforce development/management proved to be a political as much as a technical undertaking influenced by multiple actors vying for recognition or benefits, and influence over issues of programme feasibility, relevance or need. Critical in the success of the initiative was alignment and coherence among actors, health ministries and universities in particular, and how well programme champions are able to garner support for and ownership of programme locally. The paper argues that coherence and alignment are crucial to embed programmes, yet hard to achieve when capacity and resources are limited and contested.


[Present aspects of neuropsychosurgery nursing].
A brief review of the medical literature, on neuropsychosurgery and the specific aspects of nursing care are presented. Emphasis is given to the importance of an objective attitude towards the results of this type of surgery.


[Effects of ursolic acid in ameliorating insulin resistance in liver of KKAy mice via peroxisome proliferator-activated receptors α and γ].
To explore the effects and mechanism of ursolic acid in improving hepatic insulin resistance in KKAy mice with spontaneous type 2 diabetes. Thirty-five KKAy mice were divided into five groups according to the randomized block design, namely, control, rosiglitazone, fenofibrate, and high- and low-dose ursolic acid groups with seven mice in each group. C57BL/6J mice were used as the normal control group. At the end of the 4th week, free fatty acid (FFA), tumor necrosis factor-α (TNF-α) and adiponectin contents in serum were detected by enzyme-linked immunosorbent assay; the protein expressions of phosphoenolpyruvate carboxykinase (PEPCK), insulin receptor substrate-2 (IRS-2) and glucose transport factor-2 (GLUT-2) were detected by Western blot method; the mRNA expressions of PEPCK, IRS-2 and GLUT-2 were detected by real-time polymerase chain reaction; the expressions of peroxisome proliferator-activated receptor α (PPARα) and peroxisome proliferator-activated receptor γ (PPARγ) in liver tissue were detected by immunohistochemical method. After four weeks of intervention, the contents of FFA, TNF-α and adiponectin in serum of the high-dose ursolic acid group had changed, showing statistically significant difference compared to those of the control group (P<0.01); high dose of ursolic acid had depressant effect on the expressions of PEPCK protein and PEPCK mRNA (P<0.01); low dose of ursolic acid depressed the expression of PEPCK mRNA and induced phosphorylation of IRS-2 in the liver (P<0.05); both high and low dose of ursolic acid improved the expression of PPARα in the liver (P<0.01). The effects of ursolic acid in improving hepatic insulin resistance in KKAy mice with spontaneous type 2 diabetes may be closely related to affecting the contents of FFA, TNF-α and adiponectin, improving the expression of PPARα protein, regulating transcription of PEPCK protein and inducing phosphorylation of IRS-2.


Dedicated C-fiber vagal sensory afferent pathways to the paraventricular nucleus of the hypothalamus.
The nucleus of the solitary tract (NTS) receives viscerosensory information from the vagus nerve to regulate diverse homeostatic reflex functions. The NTS projects to a wide network of other brain regions, including the paraventricular nucleus of the hypothalamus (PVN). Here we examined the synaptic characteristics of primary afferent pathways to PVN-projecting NTS neurons in rat brainstem slices.Expression of the Transient Receptor Potential Vanilloid receptor (TRPV1+ ) distinguishes C-fiber afferents within the solitary tract (ST) from A-fibers (TRPV1-). We used resiniferatoxin (RTX), a TRPV1 agonist, to differentiate the two. The variability in the latency (jitter) of evoked excitatory postsynaptic currents (ST-EPSCs) distinguished monosynaptic from polysynaptic ST-EPSCs. Rhodamine injected into PVN was retrogradely transported to identify PVN-projecting NTS neurons within brainstem slices. Graded shocks to the ST elicited all-or-none EPSCs in rhodamine-positive NTS neurons with latencies that had either low jitter (<200 µs - monosynaptic), high jitter (>200 µs - polysynaptic inputs) or both. RTX blocked ST-evoked TRPV1 + EPSCs whether mono- or polysynaptic. Most PVN-projecting NTS neurons (17/21 neurons) had at least one input polysynaptically connected to the ST. Compared to unlabeled NTS neurons, PVN-projecting NTS neurons were more likely to receive indirect inputs and be higher order. Surprisingly, sEPSC rates for PVN-projecting neurons were double that of unlabeled NTS neurons. The ST synaptic responses for PVN-projecting NTS neurons were either all TRPV1+ or all TRPV1-, including neurons that received both direct and indirect inputs. Overall, PVN-projecting NTS neurons received direct and indirect vagal afferent information with strict segregation regarding TRPV1 expression.


Localized and sustained delivery of fibroblast growth factor-2 from a nanoparticle-hydrogel composite for treatment of spinal cord injury.
After traumatic spinal cord injury, grossly injured blood vessels leak blood and fluid into the parenchyma, leading to a large cystic cavity. Fibroblast growth factor-2 (FGF2) can reduce immediate vasoconstriction of vessels in the tissue surrounding the primary injury and promote angiogenesis. A localized delivery system would both achieve restricted delivery of FGF2 to the spinal cord and limit possible systemic effects such as mitogenesis. To enhance the endogenous angiogenic response after spinal cord injury, FGF2 was encapsulated in poly(lactide-co-glycolide) (PLGA) nanoparticles which were embedded in a biopolymer blend of hyaluronan and methylcellulose (HAMC) and then injected into the intrathecal space. Treatment began immediately after a 26 g clip compression spinal cord injury in rats and consisted of intrathecal delivery of FGF2 from the HAMC/PLGA/FGF2 composite. Control animals received intrathecal HAMC loaded with blank nanoparticles, intrathecal HAMC alone or intrathecal artificial cerebrospinal fluid alone. Sustained and localized delivery of FGF2 from composite HAMC/PLGA/FGF2 achieved higher blood vessel density in the dorsal horns 28 days post-injury, due to either greater angiogenesis near the epicenter of the injury or vasoprotection acutely after spinal cord injury. Importantly, delivery of FGF2 from composite HAMC/PLGA/FGF2 did not produce proliferative lesions that had been previously reported for FGF2 delivered locally using a minipump/catheter. These results suggest that localized and sustained delivery with composite HAMC/PLGA/FGF2 is an excellent system to deliver biomolecules directly to the spinal cord, thereby circumventing the blood spinal cord barrier and avoiding systemic side effects.


Aspartame, low-calorie sweeteners and disease: regulatory safety and epidemiological issues.
Aspartame is a synthetic sweetener that has been used safely in food for more than 30 years. Its safety has been evaluated by various regulatory agencies in accordance with procedures internationally recognized, and decisions have been revised and updated regularly. The present review summarizes the most relevant conclusions of epidemiological studies concerning the use of low-calorie sweeteners (mainly aspartame), published between January 1990 and November 2012. In the Nurses' Health study and the Health Professionals Followup study some excess risk of Hodgkin lymphoma and multiple myeloma was found in men but not in women; no association was found with leukemia. In the NIH-AARP Diet and Health Study, there was no association between aspartame and haematopoietic neoplasms. US case-control studies of brain and haematopoietic neoplasms also showed no association. The NIH-AARP Diet and Health Study and case-control studies from California showed no association with pancreatic cancer, and a case-control study from Denmark found no relation with breast cancer risk. Italian case-control studies conducted in 1991-2008 reported no consistent association for cancers of the upper aerodigestive tract, digestive tract, breast, endometrium, ovary, prostate, and kidney. Low calorie sweeteners were not consistently related to vascular events and preterm deliveries.


Urine sample used for congenital toxoplasmosis diagnosis by PCR.
The diagnosis of toxoplasmosis in congenitally infected infants can be difficult; serology is unreliable, and diagnosis must be based on the combination of symptomatology and direct demonstration of the parasite. Four infants suspected of having Toxoplasma gondii infection were studied by serological analysis, tissue culture, and PCR determination. T. gondii was isolated from the urine of one patient. The parasite was detected by PCR in the blood and cerebrospinal fluid of three infants and in the urine in all patients. Because nested PCR proved to be a sensitive, relatively rapid, and specific method and because it can be applied to a variety of different clinical samples, PCR can be a valuable technique for the identification of T. gondii infections in children. The present study indicates that PCR examination of urine, a fluid never before used for diagnosis in this age group, may be valuable in diagnosing cases of congenital toxoplasmosis.


Generation of a vasoactive substance in human plasma during coagulation. Evidence of thrombin-induced contraction of rabbit aorta and dog coronary artery.
A stimulant of vascular smooth muscle contraction was generated in fresh, citrated human plasma during activation of the clotting system. Plasma, exposed briefly to thromboplastin and Ca++, induced a contraction of isolated rabbit aorta and dog coronary arteries that was slow in development and persisted after washout. The contractile activity was not blocked by phenoxybenzamine, atropine, or angiotensin inhibitor, but was blocked when heparin or hirudin was incubated with the plasma. The contractile stimulant produced in the plasma was short-lived (less than 3 min) and paralleled the appearance of thrombin in plasma. Purified human alpha-thrombin also induced a sustained contraction in these blood vessels that was not inhibited by phenoxybenzamine, atropine, or angiotensin inhibitor, but was blocked by hirudin. Partial relaxation of the thrombin-treated blood vessel was achieved by the addition of heparin. These results suggest that this vasoactive component of thromboplastin-activated human plasma is alpha-thrombin. Because of its potent and persistent effects, thrombin-induced vasospasm may be an important mechanism in the etiology of ischemic heart disease.


Influence of amino acids on gastric emptying in young pigs.
The effects of amino acids on gastric emptying and secretion were studied in four young conscious pigs provided with a chronic gastric cannula. A basal test meal of 500 ml containing 10 g citrus pectin, 17.5 g sucrose, 100 mg phenol red alone or with glycine, L- or DL-tryptophan, DL-methionine or L-glutamic acid was poured into the stomach and recovered 20 min later. Glycine at concentrations of 26.7--106.8 mM/l did significantly affect gastric emptying, although at the highest concentration gastric emptying appeared to slow down. L-lysine (41.0 mM/l), DL-methionine (40.3 mM/l or L-tryptophan (29.4 mM/l did not significantly affect the rate of stomach emptying; L-tryptophan increased the amount of Cl- and H+ secreted as compared with the basal diet alone. The effects of addition of the essential amino acids, L-lysine and DL-methionine, were compared with those of the nonessential glycine and L-glutamic acid. There was no significant difference in the rate of gastric emptying or secretion between them. The L and DL isomers of lysine and trypotphan were not found to differ significantly in their effects on gastric emptying and secretion.


Treatment as prevention (TasP) and perceived sexual changes in behavior among HIV-positive persons: a French survey in infectious diseases departments in Paris.
We evaluated awareness of treatment as prevention (TasP) among adults people living with HIV (PLHIV) in five infectious disease departments in Paris, then how they perceived its impact on their sexual well-being. This cross-sectional multicenter survey was conducted in 2014 during scheduled clinical appointments using a self-administered questionnaire. We analyzed 520 questionnaires (42% women, 54% men of whom 57% were MSM [men who have sex with men]). 75% of women were born abroad, most commonly in sub-Saharan Africa, whereas 64% of men were French-born. The mean time since HIV diagnosis was 12.8 ± 7.8 years. Eighty-seven percent [84-90%]95% reported being aware of the impact of ART on HIV transmission, 94% MSM, 86% women, 83% heterosexual men. PLHIV reported that they gained awareness of TasP through medical doctors (86%). The fear of transmission was perceived as alleviated for 73% [69%;78%]95%, more often among MSM; the sexual life was reported to be improved for 28% [24%;33%]95%; and ART adherence to be improved for 45% [40%;50%]95%, more often among women. The awareness of TasP was relatively high, but it seems important to understand the features of male and female populations of PLHIV to adapt counseling during follow-up appointments, as women's answers differed in various regards.


Tackling the mortality from long-term exposure to outdoor air pollution in megacities: Lessons from the Greater Cairo case study.
The poor outdoor air quality in megacities of the developing world and its impact on health is a matter of concern for both the local populations and the decision-makers. The objective of this work is to quantify the mortality attributable to long-term exposure to PM2.5, NO2, and O3 in Greater Cairo (Egypt). We analyze the temporal and spatial variability of the three pollutants concentrations measured at 18 stations of the area. Then, we apply the method recommended by the WHO to estimate the excess mortality. In this assessment, three different shapes (log-linear, linear, and log-log) of the concentration-response functions (CRF) are used. With PM2.5 concentrations varying from 50 to more than 100µg/m3 in the different sectors of the megacity, the spatial variability of this pollutant is found to be one important cause of uncertainty on the excess mortality associated with it. Also important is the choice of the CRF. With the average (75µg/m3) PM2.5 concentration and the most favorable log-log shape of the CRF, 11% (CI, 9-14%) of the non-accidental mortality in the population older than 30 years can still be attributed to PM2.5, which corresponds to 12520 (CI, 10240-15930) yearly premature deaths. Should the Egyptian legal 70µg/m3 PM10 limit (corresponding to approximately 37.5µg/m3 for PM2.5) be met, this number would be reduced to 7970, meaning that 4550 premature deaths could be avoided each year. Except around some industrial or traffic hot spots, NO2 concentration is found to be below the 40µg/m3 air quality guideline of the WHO. However, the average concentration (34µg/m3) of this gas exceeds the stricter 10µg/m3 recommendation of the HRAPIE project and it is thus estimated that from 7850 to 10470 yearly deaths can be attributed to NO2. Finally, with the ozone concentration measured at one station only, it is found that, depending on the choice of the CRF, between 2.4% and 8.8% of the mortality due to respiratory diseases can be attributed to this gas. In Greater Cairo, PM2.5 and NO2 constitute major health risks. The best estimate is that in the population older than 30 years, 11% and 8% of the non-accidental mortality can be attributed to these two pollutants, respectively.


Effect of spatial charge inhomogeneity on 1/f noise behavior in graphene.
Scattering mechanisms in graphene are critical to understanding the limits of signal-to-noise ratios of unsuspended graphene devices. Here we present the four-probe low-frequency noise (1/f) characteristics in back-gated single layer graphene (SLG) and bilayer graphene (BLG) samples. Contrary to the expected noise increase with the resistance, the noise for SLG decreases near the Dirac point, possibly due to the effects of the spatial charge inhomogeneity. For BLG, a similar noise reduction near the Dirac point is observed, but with a different gate dependence of its noise behavior. Some possible reasons for the different noise behavior between SLG and BLG are discussed.


Reciprocal patterns of methylation of H3K36 and H3K27 on proximal vs. distal IgVH genes are modulated by IL-7 and Pax5.
The usage of >100 functional murine Ig heavy chain V(H) genes, when rearranged to D(H)J(H) genes, generates a diverse antibody repertoire. The V(H) locus encompasses 2.5 Mb, and rearrangement of V(H) genes in the D(H)-distal half of the locus are controlled very differently from the V(H) genes in the proximal end of the locus. The rearrangement of distal but not proximal V(H) genes is impaired in mice deficient in the cytokine IL-7 or its receptor, in the transcription factor Pax5, or in Ezh2, a histone methyltransferase for Lys-27 of histone H3 (H3K27). The relative role of IL-7, Pax5, and Ezh2 in regulating distal vs. proximal V(H) rearrangement is not clear. Here, we show by ChIP and ChIP-on-chip that the active histone modification H3K36me2 is most highly associated with distal V(H) segments and the repressive histone modification H3K27me3 is exclusively present on proximal V(H) segments. We observed an absence of H3K27me3 in fetal pro-B cells, which predominantly rearrange proximal V(H) genes. Absence of IL-7 signaling reduces H3K36me2, and overexpression of IL-7 increases H3K36me2. In contrast, the major effect of the absence of Pax5 is the reduction in H3K27me3. Our data indicate that the cytokine IL-7 and the transcription factor Pax5 influence the rearrangement of the two regions of the V(H) locus by differentially modulating two reciprocal histone modifications during B lymphocyte development.


Physical activity and survival in postmenopausal women with breast cancer: results from the women's health initiative.
Although studies have shown that physically active breast cancer survivors have lower all-cause mortality, the association between change in physical activity from before to after diagnosis and mortality is not clear. We examined associations among pre- and postdiagnosis physical activity, change in pre- to postdiagnosis physical activity, and all-cause and breast cancer-specific mortality in postmenopausal women. A longitudinal study of 4,643 women diagnosed with invasive breast cancer after entry into the Women's Health Initiative study of postmenopausal women. Physical activity from recreation and walking was determined at baseline (prediagnosis) and after diagnosis (assessed at the 3 or 6 years post-baseline visit). Women participating in 9 MET-h/wk or more (∼ 3 h/wk of fast walking) of physical activity before diagnosis had a lower all-cause mortality (HR = 0.61; 95% CI, 0.44-0.87; P = 0.01) compared with inactive women in multivariable adjusted analyses. Women participating in ≥ 9 or more MET-h/wk of physical activity after diagnosis had lower breast cancer mortality (HR = 0.61; 95% CI, 0.35-0.99; P = 0.049) and lower all-cause mortality (HR = 0.54; 95% CI, 0.38-0.79; P < 0.01). Women who increased or maintained physical activity of 9 or more MET-h/wk after diagnosis had lower all-cause mortality (HR = 0.67; 95% CI, 0.46-0.96) even if they were inactive before diagnosis. High levels of physical activity may improve survival in postmenopausal women with breast cancer, even among those reporting low physical activity prior to diagnosis. Women diagnosed with breast cancer should be encouraged to initiate and maintain a program of physical activity.


The Relationship Between Imbalance Symptom and Cardiac Pulsation Induced Mechanical Strain in the Brainstem and Cerebellum for Chiari Malformation Type I.
Chiari malformation Type I (CMI) is known to have an altered biomechanical environment for the brainstem and cerebellum; however, it is unclear whether these altered biomechanics play a role in the development of CMI symptoms. We hypothesized that CMI subjects have a higher cardiac-induced strain in specific neurological tracts pertaining to balance, and postural control. We measured displacement over the cardiac cycle using displacement encoding with stimulated echoes magnetic resonance imaging in the cerebellum, brainstem, and spinal cord in 37 CMI subjects and 25 controls. Based on these measurements, we computed strain, translation, and rotation in tracts related to balance. The global strain on all tracts was small (<1%) for CMI subject and controls. Strain was found to be nearly doubled in three tracts for CMI subjects compared to controls (p < 0.03). The maximum translation and rotation were ∼150 μm and ∼1 deg, respectively and 1.5-2 times greater in CMI compared to controls in four tracts (p < 0.005). There was no significant difference between strain, translation, and rotation on the analyzed tracts in CMI subjects with imbalance compared to those without imbalance. A moderate correlation was found between cerebellar tonsillar position and strain on three tracts. The lack of statistically significant difference between strain in CMI subjects with and without imbalance could imply that the magnitude of the observed cardiac-induced strain was too small to cause substantial damage to the tissue (<1%). Activities such as coughing, or Valsalva may produce a greater strain.


RPG1-B-derived resistance to AvrB-expressing Pseudomonas syringae requires RIN4-like proteins in soybean.
Soybean (Glycine max) RPG1-B (for resistance to Pseudomonas syringae pv glycinea) mediates species-specific resistance to P. syringae expressing the avirulence protein AvrB, similar to the nonorthologous RPM1 in Arabidopsis (Arabidopsis thaliana). RPM1-derived signaling is presumably induced upon AvrB-derived modification of the RPM1-interacting protein, RIN4 (for RPM1-interacting 4). We show that, similar to RPM1, RPG1-B does not directly interact with AvrB but associates with RIN4-like proteins from soybean. Unlike Arabidopsis, soybean contains at least four RIN4-like proteins (GmRIN4a to GmRIN4d). GmRIN4b, but not GmRIN4a, complements the Arabidopsis rin4 mutation. Both GmRIN4a and GmRIN4b bind AvrB, but only GmRIN4b binds RPG1-B. Silencing either GmRIN4a or GmRIN4b abrogates RPG1-B-derived resistance to P. syringae expressing AvrB. Binding studies show that GmRIN4b interacts with GmRIN4a as well as with two other AvrB/RPG1-B-interacting isoforms, GmRIN4c and GmRIN4d. The lack of functional redundancy among GmRIN4a and GmRIN4b and their abilities to interact with each other suggest that the two proteins might function as a heteromeric complex in mediating RPG1-B-derived resistance. Silencing GmRIN4a or GmRIN4b in rpg1-b plants enhances basal resistance to virulent strains of P. syringae and the oomycete Phytophthora sojae. Interestingly, GmRIN4a- or GmRIN4b-silenced rpg1-b plants respond differently to AvrB-expressing bacteria. Although both GmRIN4a and GmRIN4b function to monitor AvrB in the presence of RPG1-B, GmRIN4a, but not GmRIN4b, negatively regulates AvrB virulence activity in the absence of RPG1-B.


Fine structure and multicomponents of the electrically evoked otoacoustic emission in gerbil.
Like the acoustically evoked distortion product otoacoustic emissions (DPOAE), the amplitude spectrum of the extracochlear electrically evoked otoacoustic emission (EEOAE) also shows peaks and valleys, which are termed the fine structure (FS) of the EEOAE. The hypothesis that the FS of the EEOAE is generated by multiple wave interactions in the cochlea is investigated by examining the relationship between the FS and the multiple-delay components of the EEOAE. The bulla of the gerbil was exposed using a ventral surgical approach. One pole of a bipolar electrode was placed in the round window niche, and the other pole on the surface of the first cochlear turn. A microphone was used to measure electrically evoked sound pressure change in the ear canal. A recently developed multicomponent analysis method was used to detect the EEOAE multiple delays. It was found that the FS is the spectral representation of the multiple-delay components. The relative power of a prominent long delay component (LDC) shows a negative relationship to the electrical stimulus level. Both the FS and the LDC were abolished by intravenous furosemide. Reconstructed signals showed that mathematical removal of the EEOAE LDC also completely eliminated the FS. These data demonstrate that the FS and the EEOAE multicomponents are properties of normal cochlear mechanics in a healthy ear and that the FS is a manifestation of the multicomponents. The findings in this study strongly indicate that the FS of the EEOAE evoked by extracochlear electrical stimulation is generated by wave interaction in the cochlea. The similarity between the EEOAE FS and the DPOAE FS suggests that they may share the same mechanism.