p53 protein oxidation in cultured cells in response to pyrrolidine dithiocarbamate: a novel method for relating the amount of p53 oxidation in vivo to the regulation of p53-responsive genes.
A novel method was developed to determine the oxidation status of proteins in cultured cells. Methoxy-polyethylene glycol-maleimide MW 2000 (MAL-PEG) was used to covalently tag p53 protein that was oxidized at cysteine residues in cultured cells. Treatment of MCF7 breast cancer cells with pyrrolidine dithiocarbamate (PDTC), a metal chelator, resulted in a minimum of 25% oxidation of p53. The oxidized p53 had an average of one cysteine residue oxidized per p53 protein molecule. The effect of PDTC treatment on downstream components of the p53 signal-transduction pathway was tested. PDTC treatment prevented actinomycin D-mediated up-regulation of two p53 effector gene products, murine double minute clone 2 oncoprotein and p21(WAF1/CIP1) (where WAF1 corresponds to wild-type p53-activated fragment 1 and CIP1 corresponds to cyclin-dependent kinase-interacting protein 1). Actinomycin D treatment led to accumulation of p53 protein in the nucleus. However, when cells were simultaneously treated with PDTC and actinomycin D, p53 accumulated in both the nucleus and the cytoplasm. The data indicate that an average of one cysteine residue per p53 protein molecule is highly sensitive to oxidation and that p53 can be efficiently oxidized by PDTC in cultured cells. PDTC-mediated oxidation of p53 correlates with altered p53 subcellular localization and reduced activation of p53 downstream effector genes. The novel method for detecting protein oxidation detailed in the present study may be used to determine the oxidation status of specific proteins in cells.


Anti-inflammatory effect of bee pollen ethanol extract from Cistus sp. of Spanish on carrageenan-induced rat hind paw edema.
Bee pollen, a honeybee product, is the feed for honeybees prepared themselves by pollens collecting from plants and has been consumed as a perfect food in Europe, because it is nutritionally well balanced. In this study, we aimed to investigate the anti-inflammatory effect of bee pollen from Cistus sp. of Spanish origin by a method of carrageenan-induced paw edema in rats, and to investigate the mechanism of anti-inflammatory action and also to elucidate components involved in bee pollen extracted with ethanol. The bee pollen bulk, its water extract and its ethanol extract were administered orally to rats. One hour later, paw edema was produced by injecting of 1% solution of carrageenan, and paw volume was measured before and after carrageenan injection up to 5 h. The ethanol extract and water extract were measured COX-1 and COX-2 inhibitory activities using COX inhibitor screening assay kit, and were compared for the inhibition of NO production in LPS-stimulated RAW 264.7 cells. The constituents of bee pollen were purified from the ethanol extract subjected to silica gel or LH-20 column chromatography. Each column chromatography fractions were further purified by repeated ODS or silica gel column chromatography. The bee pollen bulk mildly suppressed the carrageenan-induced paw edema and the water extract showed almost no inhibitory activity, but the ethanol extract showed relatively strong inhibition of paw edema. The ethanol extract inhibited the NO production and COX-2 but not COX-1 activity, but the water extract did not affect the NO production or COX activities. Flavonoids were isolated and purified from the ethanol extract of bee pollen, and identified at least five flavonoids and their glycosides. It is suggested that the ethanol extract of bee pollen show a potent anti-inflammatory activity and its effect acts via the inhibition of NO production, besides the inhibitory activity of COX-2. Some flavonoids included in bee pollen may partly participate in some of the anti-inflammatory action. The bee pollen would be beneficial not only as a dietary supplement but also as a functional food.


1,8-Bis(silylamido)naphthalene complexes of magnesium and zinc synthesised through alkane elimination reactions.
The reactions between magnesium or zinc alkyls and 1,8-bis(triorganosilyl)diaminonaphthalenes afford the 1,8-bis(triorganosilyl)diamidonaphthalene complexes with elimination of alkanes. The reaction between 1,8-C10H6(NSiMePh2H)2 and one or two equivalents of MgnBu2 affords two complexes with differing coordination environments for the magnesium; the reaction between 1,8-C10H6(NSiMePh2H)2 and MgnBu2 in a 1 : 1 ratio affords 1,8-C10H6(NSiMePh2)2{Mg(THF)2} (1), which features a single magnesium centre bridging both ligand nitrogen donors, whilst treatment of 1,8-C10H6(NSiR3H)2 (R3 = MePh2, iPr3) with two equivalents of MgnBu2 affords the bimetallic complexes 1,8-C10H6(NSiR3)2{nBuMg(THF)}2 (R3 = MePh22, R3 = iPr33), which feature four-membered Mg2N2 rings. Similarly, 1,8-C10H6(NSiiPr3)2{MeMg(THF)}2 (4) and 1,8-C10H6(NSiMePh2)2{ZnMe}2 (5) are formed through reactions with the proligands and two equivalents of MMe2 (M = Mg, Zn). The reaction between 1,8-C10H6(NSiMePh2H)2 and two equivalents of MeMgX affords the bimetallic complexes 1,8-C10H6(NSiMePh2)2(XMgOEt2)2 (X = Br 6; X = I 7). Very small amounts of [1,8-C10H6(NSiMePh2)2{IMg(OEt2)}]2 (8), formed through the coupling of two diamidonaphthalene ligands at the 4-position with concomitant dearomatisation of one of the naphthyl arene rings, were also isolated from a solution of 7.


Revision total elbow arthroplasty for prosthetic fractures.
Fractures of total elbow arthroplasty components are uncommon, and the literature provides little guidance regarding the management and outcomes of treatment of these complications. The goal of this report was to investigate the prevalence and management of fractures of ulnar and humeral components following total elbow arthroplasty and to review our experience with cement-within-cement reconstruction for revision following such fractures. Between 1979 and 2003, twenty-four patients with a total of twenty-seven fractured total elbow arthroplasty components (seventeen ulnar and ten humeral) of different designs presented to our institution. Twenty-six implants underwent subsequent revision elbow arthroplasty at our institution. Fourteen of those revisions were done with a cement-within-cement technique, and twelve, with traditional methods. Twenty-one patients (twenty-three implants) were available for final follow-up, and data that had been acquired prospectively and entered into the institutional arthroplasty database were reviewed retrospectively. At the time of final follow-up, the Mayo Elbow Performance Score (MEPS) was calculated and preoperative, postoperative, and most recent radiographs were examined for bone loss, bushing wear, and integrity of the bone-cement interface. The prevalences of humeral and ulnar component fracture following primary total elbow arthroplasties performed at our institution were 0.65% and 1.2%, respectively. At a mean of 5.1 years following revisions for those fractures, the MEPS was excellent for eight patients, good for five, fair for six, and poor for two. The average MEPS was 82 points following the revision total elbow arthroplasties done with the cement-within-cement technique and 78 points following the revisions done with the traditional method of cement removal and insertion of a revision component. Complications included seven intraoperative cortical perforations; five nerve injuries, two of which were permanent; three triceps avulsions; and one deep infection. Implant fractures following total elbow arthroplasty are uncommon. They occur for several reasons, such as notch sensitivity, component design, and high stresses due to bone deficiency. Revision techniques, such as cement-within-cement reimplantation, are reliable for relieving pain and restoring function; however, the rate and spectrum of complications are a cause for concern. Therapeutic Level IV.


[Data on prevalence of hypertension and blood pressure in Turkey: Systematic review, meta-analysis and meta-regression of epidemiological studies on cardiovascular risk factors].
Cardiovascular risc factors may show significant changes over the years. A systematic review and meta-analysis of epidemiological studies conducted in Turkey was performed to assess the latest profile and temporal changes in cardiovascular risk factors. Presented here are the data on hypertension (HT) and blood pressure (BP). Ovid Medline, the Web of Science Core Collection, and the Turkish Academic Network and Information Center (ULAKBIM) were searched for epidemiological studies conducted in Turkey during the last 15 years. In addition, the web pages of the Ministry of Health, the Turkish Statistical Institute, and associations of cardiology, nephrology, and endocrinology were searched for appropriate studies. Regional studies were excluded. The studies included were assessed with a bias score developed by our team, then categorized as having a low risk or a high risk of bias. The crude values of HT prevalence and BP were pooled using a random effects model. Meta-regression was performed to explain heterogeneity and to assess temporal changes. The agreement between the 2 authors on the selection and bias scoring of the studies was perfect (Kappa ≥0.95). There were 7 (n=73218) studies providing HT prevalence data, and 8 (n=75879) studies with BP data. The heterogeneity between the studies was high. Meta-analysis of the studies with a low risk of bias indicated that the crude prevalence of HT is higher in women, but that BP levels were similar in both sexes. The HT prevalence and BP value decreased between 2003 and 2012; however, the number of hypertensives stabilized at approximately 15 million, and the number of uncontrolled hypertensives, despite some decrease, was around 11 million. Despite some improvement, HT is still an important public health problem in Turkey.


Towards a two-body neuroscience.
Recent work from our interdisciplinary research group has revealed the emergence of inter-brain synchronization across multiple frequency bands during social interaction.1 Our findings result from the close collaboration between experts who study neural dynamics and developmental psychology. The initial aim of the collaboration was to combine knowledge from these two fields in order to move from a classical one-brain neuroscience towards a novel two-body approach. A new technique called hyperscanning has made it possible to study the neural activity of two individuals simultaneously. However, this advanced methodology was not sufficient in itself. What remained to be found was a way to promote real-time reciprocal social interaction between two individuals during brain recording and analyze the neural and behavioral phenomenon from an inter-individual perspective. Approaches used in infancy research to study nonverbal communication and coordination, between a mother and her child for example, have so far been poorly applied to neuroimaging experiments. We thus adapted an ecological two-body experiment inspired by the use of spontaneous imitation in preverbal infants. Numerous methodological and theoretical problems had to be overcome, ranging from the choice of a common time-unit for behavioral and brain recordings to the creation of algorithms for data processing between distant brain regions in different brains. This article will discuss the underlying issues and perspectives involved in elucidating the pathway from individual to social theories of cognition.


Role of cell cohesion in Myxococcus xanthus fruiting body formation.
Dsp mutants of Myxococcus xanthus have a complex phenotype with abnormal cell cohesion, social motility, and development. All three defects are the result of a single mutation in the dsp locus, a region of DNA about 14 kilobases long. Cohesion appears to play a central role in social motility, since nonsocial mutants exhibit weak agglutination or, in the case of Dsp cells, no agglutination (L. J. Shimkets, J. Bacteriol. 166:837-841, 1986). However, Dsp cells can be agglutinated by cohesive strains of M. xanthus. This provided the opportunity to examine the role of cohesion during development by comparing the developmental phenotype of Dsp cells with that of Dsp cells mixed with cohesive strains. Dsp mutants were unable to complete any of the developmental behaviors: aggregation, fruiting body formation, developmental autolysis, and sporulation. Contact with cohesive strains seemed to restore some developmental characteristics to the Dsp cells. When allowed to develop with wild-type cells, Dsp cells accumulated in fruiting bodies and underwent developmental autolysis, but did not form a significant portion of the spore population. Igl mutants, which may be similar to the previously described frizzy mutants, are cohesive strains that are unable to form fruiting bodies. Mixing Igl cells with Dsp cells under developmental conditions resulted in fruiting body formation, although the Dsp cells were unable to form significant levels of myxospores. In spite of their inability to sporulate under developmental conditions, Dsp mutants did not appear to be defective in the sporulation process. In fact, they formed normal levels of myxospores in response to the chemical inducer glycerol.


Fever and respiratory symptoms after welding on painted steel.
Electric-arc welding generates particles and gases that can induce chronic bronchitis and airway obstruction. In this case report two welders are described who had fever, spirometric deterioration, and bronchial hyperreactivity after welding steel painted with chloro-containing polymer lacquer. Pyrolysis of this paint releases many different compounds, for example, hydrogen chloride and complex chlorinated compounds.


Clinical management of transsexual subjects.
Transsexual subjects are individuals who have a desire to live and be accepted as a member of the opposite sex, usually accompanied by a sense of discomfort with, or inappropriateness of, one's anatomic sex, and a wish to have surgery and hormonal treatment to make one's body as congruent as possible with one's preferred sex. They seek to develop the physical characteristics of the desired gender, and should undergo an effective and safe treatment regimen. The goal of treatment is to rehabilitate the individual as a member of society in the gender he or she identifies with. Sex reassignment procedures necessary for the treatment of transsexual patients are allowed in our country, at Medical Services that have a multidisciplinary team composed of a psychologist, a social worker, a psychiatrist, an endocrinologist and surgeons (gynecologists, plastic surgeons, and urologists). Patients must be between 21 to 75 years old and in psychological and hormonal treatment for at least 2 years. Testosterone is the principal agent used to induce male characteristics in female transsexual patients, and the estrogen is the chosen hormone used to induce the female sexual characteristics in male transsexual patients. Based on our 15 years of experience, we can conclude that testosterone and estradiol treatment in physiological doses are effective and safe in female and male transsexual patients, respectively.


Occurrence of Bacterial Leaf Spot of Escarole Caused by Pseudomonas cichorii in the Everglades Agricultural Area of Southern Florida.
In the fall of 1997, 1998, and 2000, a leaf spot disease of escarole (Cichorium endivia L.) was widespread among commercial plantings in the Everglades Agricultural Area (EAA), south and east of Lake Okeechobee, FL. Symptoms consisted of dry, dark gray-to-black lesions that expanded to ≈4 cm in diameter. Concentric rings were often observed in mature lesions. Growers and scouts in the area consistently identified this disease as Alternaria leaf spot, because the symptoms closely resembled Alternaria leaf spots seen on a number of other vegetables. Prolific bacterial streaming occurred when cut portions of lesions were observed microscopically. A fluorescent bacterium was consistently isolated when a sterile inoculation needle was pushed through lesions. Eight bacterial strains were isolated, restreaked to obtain pure cultures, and characterized. All strains were aerobic, gram-negative rods that were oxidase positive and arginine dihydrolase negative. Negative reactions were recorded for levan formation and rotting of potato slices. All strains utilized glucose, mannitol, and m-tartrate and were negative for sucrose, sorbitol, benzoate, d-arabinose, l-rhamnose, and cellobiose. Results for utilization of D-aspartate were variable. Based on these results, the causal agent of bacterial leaf spot of escarole was identified as Pseudomonas cichorii. Greenhouse-grown plants of escarole, cv. Full Heart, and Cos lettuce, cv. Tall Guzmaine, were mistinoculated with a suspension (107 CFU/ml) of each test strain from escarole and P. cichorii strain Pc28, originally isolated from celery (1). Plants were bagged for 3 days after inoculation. Symptoms characteristic of this disease were evident on escarole inoculated with all test strains and Pc28 6 days after inoculation. Pure cultures of P. cichorii were recovered from lesions on King's B medium. Three test strains produced mild leaf spot symptoms in Cos lettuce, but the symptoms were distinctly different from those associated with the common bacterial leaf spot of lettuce in Florida caused by Xanthomonas campestris pv. vitians (2). To our knowledge, this is the first report of P. cichorii causing this unusual target spot symptom on escarole in the EAA. References: (1) K. Pernezny et al. Plant Dis. 78:917, 1994. (2) K. Pernezny et al. Plant Dis. 79:359, 1995.


Reaccessing an occluded radial artery: a "proximal entry" technique.
Radial artery occlusion (RAO) is an infrequent but important consequence of transradial access. It prevents subsequent use of the same radial artery for coronary angiography and intervention. We describe a new "proximal entry" technique in 3 cases of RAO, which allowed successful completion of the procedures. This technique should add to the armamentarium of a radial operator allowing for reaccessing the radial artery. (J Interven Cardiol 2011;24:378-381).


Ontogenetic changes in limb postures and their impact on effective limb length in baboons (Papio cynocephalus).
Digitigrade hand and foot postures and extended elbows and knees are considered adaptations to running in cursorial mammals because they increase effective limb lengths (ELLs). However, the relationship between digitigrady and ELL in primates is not well understood. We documented the ontogeny of limb postures in baboons to better understand the function of digitigrady during walking. We hypothesized that the hand and foot would become more elevated and the elbow and knee more extended, leading to increased relative ELLs throughout ontogeny. Longitudinal kinematic data were collected on four infant yellow baboons (Papio cynocephalus) as they aged from two to nine months, and again at two to three years. Hand/foot postures, elbow/knee angles, relative fore/hind limb ELLs, and dimensionless velocity were measured for 404 symmetrical walking strides. Digitigrade hand and foot postures were preferred at all ages. The elbow extended slightly and the knee flexed slightly with age. Elevated proximal hands, extended elbows, and extended knees were associated with long relative ELLs. For a given age, relative hind limb ELL was longer than relative forelimb ELL. In the forelimb, digitigrade hand postures and extended elbows function to increase relative ELL at slow walking velocity. Increased forelimb ELL may be an attempt to equalize forelimb and hind limb ELLs in baboons with an absolutely longer hind limb. Pedal digitigrady is not a main contributing factor to hind limb ELL. Results suggest that manual and pedal digitigrady in terrestrial cercopithecoids does not function to increase velocity.


Diaphragmatic fatigue in unanesthetized adult sheep.
We studied diaphragmatic muscle function during inspiratory flow resistive (IFR) loaded breathing in unanesthetized sheep. We measured the change in transdiaphragmatic pressure (dPdi) and arterial blood gas tensions and recorded diaphragmatic electromyogram (EMG) from electrodes implanted on the muscle. We found that, with IFR loads less than 150 cmH2O X l-1 X s, dPdi and the integrated EMG increased, reached a plateau, and were maintained at high levels. The centroid frequency (fc) of the EMG power spectrum did not consistently change. With IFR loads greater than 150 cmH2O X l-1 X s, O2 was administered to prevent hypoxia, cyanosis, and agitation. With these loads, dPdi increased severalfold above base line, reached a plateau, and then started to decrease. Arterial PCO2 increased sharply at the time when dPdi decreased. The integrated EMG (iEMG) and fc started to decrease gradually 10-20 min before dPdi started to decrease. We conclude that 1) the diaphragm is capable of generating large pressures for prolonged periods with no evidence of fatigue; 2) with very high IFR loads, mechanical failure of the diaphragm can occur in the unanesthetized awake sheep; 3) diaphragmatic fatigue is associated with acute hypercapnia and therefore failure of the entire respiratory pump; and 4) a decrease in iEMG and a concommitant shift in the power spectrum density towards lower frequencies precede the mechanical failure of the diaphragm.


Impact of a Social Media Group Page on Undergraduate Medical Physiology Learning.
To investigate the impact of associating classroom learning of medical physiology with a Facebook group page in an all-women medical college of a conservative small city in Pakistan. Qualitative interpretivist study using semi-structured interviews. Women Medical College Abbottabad, Pakistan, from March to December 2014. Aclosed Facebook study group was established at a local medical college in Pakistan. It was used to upload learning resources and initiate discussions, coordinated with classroom lectures of physiology. Thirteen semistructured interviews were conducted with volunteer students according to a standard protocol. Five major themes were identified. Facebook group is something new and exciting; it motivated self-study, research, collaborative learning and improved class attendance. Convenience of easily accessible resources allowed the students to concentrate on the lecture rather than note taking. It was easier to communicate with the instructor through Facebook than face to face. Lurkers were also learning. High achievers who had adapted to the current didactic system of teaching were less receptive of the collaborative learning and favored teaching geared towards exam preparation. Using social media for e-learning in undergraduate medical education can enhance the student learning experience, especially in resource-limited regions where Information and communication technology is not an integrated part of the teaching process.


Grape seed proanthocyanidin extract ameliorates monosodium iodoacetate-induced osteoarthritis.
Osteoarthritis (OA) is an age-related joint disease that is characterized by degeneration of articular cartilage and chronic pain. Oxidative stress is considered one of the pathophysiological factors in the progression of OA. We investigated the effects of grape seed proanthocyanidin extract (GSPE), which is an antioxidant, on monosodium iodoacetate (MIA)-induced arthritis of the knee joint of rat, which is an animal model of human OA. GSPE (100 mg/kg or 300 mg/kg) or saline was given orally three times per week for 4 weeks after the MIA injection. Pain was measured using the paw withdrawal latency (PWL), the paw withdrawal threshold (PWT) and the hind limb weight bearing ability. Joint damage was assessed using histological and microscopic analysis and microcomputerized tomography. Matrix metalloproteinase-13 (MMP13) and nitrotyrosine were detected using immunohistochemistry. Administration of GSPE to the MIA-treated rats significantly increased the PWL and PWT and this resulted in recovery of hind paw weight distribution (P < 0.05). GSPE reduced the loss of chondrocytes and proteoglycan, the production of MMP13, nitrotyrosine and IL-1β and the formation of osteophytes, and it reduced the number of subchondral bone fractures in the MIA-treated rats. These results indicate that GSPE is antinociceptive and it is protective against joint damage in the MIA-treated rat model of OA. GSPE could open up novel avenues for the treatment of OA.


Urinary incontinence in women is not exclusively a medical problem: a population-based study on urinary incontinence and general living conditions.
The aim of the study was to analyse differences in general health and general living conditions between women with and without urinary incontinence (UI). This cross-sectional population-based study was conducted in Orebro County, Sweden. A public health questionnaire, "Life and Health", was sent to a randomly selected sample of the population. The questionnaire consisted of 87 questions on broad aspects of general and psychiatric health. An additional questionnaire was enclosed for those respondents who reported experiencing UI. The data were analysed using binary logistic regression. The final study population constituted 4609 women, 1332 of whom had completed both questionnaires. The remaining 3277 had completed only the Life and Health questionnaire. Effect measures were odds ratios (ORs) with corresponding 95% confidence intervals (CIs). Statistically significant associations were found between UI and the occurrence of musculoskeletal pain (OR 1.45, 95% CI 1.20-1.76), fatigue and sleeping disorders (OR 1.59, 95% CI 1.30-1.95), feelings of humiliation (OR 1.29, 95% CI 1.12-1.50), financial problems (OR 1.36, 95% CI 1.11-1.66), and reluctance to seek medical care (OR 1.43, 95% CI 1.21-1.68). UI among women is commonly associated with a number of different psychosocial problems as well as an expressed feeling of vulnerability.


In silico-labeled ghost cytometry.
Characterization and isolation of a large population of cells are indispensable procedures in biological sciences. Flow cytometry is one of the standards that offers a method to characterize and isolate cells at high throughput. When performing flow cytometry, cells are molecularly stained with fluorescent labels to adopt biomolecular specificity which is essential for characterizing cells. However, molecular staining is costly and its chemical toxicity can cause side effects to the cells which becomes a critical issue when the cells are used downstream as medical products or for further analysis. Here, we introduce a high-throughput stain-free flow cytometry called in silico-labeled ghost cytometry which characterizes and sorts cells using machine-predicted labels. Instead of detecting molecular stains, we use machine learning to derive the molecular labels from compressive data obtained with diffractive and scattering imaging methods. By directly using the compressive 'imaging' data, our system can accurately assign the designated label to each cell in real time and perform sorting based on this judgment. With this method, we were able to distinguish different cell states, cell types derived from human induced pluripotent stem (iPS) cells, and subtypes of peripheral white blood cells using only stain-free modalities. Our method will find applications in cell manufacturing for regenerative medicine as well as in cell-based medical diagnostic assays in which fluorescence labeling of the cells is undesirable.


T wave alternans in an in vitro canine tissue model of Brugada syndrome.
Macroscopic T wave alternans (TWA) associated with increased occurrence of ventricular arrhythmias has been reported in patients with Brugada syndrome. However, the mechanisms in this syndrome are still unclear. We evaluated the hypothesis that TWA in Brugada syndrome was caused by the dynamic instability and heterogeneity of action potentials (APs) in the right ventricle. Using an optical mapping system, we mapped APs on the epicardium or transmural surfaces of 28 isolated and arterially perfused canine right ventricular preparations having drug-induced Brugada syndrome (in micromol/l: 2.5-15 pinacidil, 5.0 terfenadine, and 5.0-13 pilsicainide). Bradycardia at cycle length (CL) of 2,632 +/- 496 ms (n = 19) induced alternating deep and shallow T waves in the transmural electrocardiogram. Compared with the shallow T waves, deep T waves were associated with epicardial APs having longer durations and larger domes. Adjacent regions having APs with alternating domes, with constant domes, and without domes coexisted simultaneously in the epicardium and caused TWA. In contrast to the alternating epicardial APs, midmyocardial and endocardial APs did not change during TWA. Alternans could be terminated by rapid (CL: 529 +/- 168 ms, n = 7) or very slow (CL: 3,000 ms, n = 7) pacing. The heterogeneic APs during TWA augmented the dispersion of repolarization both within the epicardium and from the epicardium to the endocardium and caused phase 2 reentry. In this drug-induced model of Brugada syndrome, heterogeneic AP contours and dynamic alternans in the dome of right ventricular epicardial, but not midmyocardial or endocardial, APs caused TWA and heightened arrhythmogenicity in part by increasing the dispersion of repolarization.


A dual role for the inducer in signalling by MalT, a signal transduction ATPase with numerous domains (STAND).
Signal transduction ATPases with numerous domains (STAND) are widespread proteins, whose activation involves inducer-dependent conversion of resting ADP-bound monomers into active ATP-bound multimers. This process notably comprises opening of the nucleotide-binding oligomerization domain (NOD), nucleotide exchange and NOD-mediated multimerization. How inducer binding to the sensor domain, whose structure is not conserved throughout the STAND family, causes protein activation remains unclear. We used MalT, an Escherichia coli transcription factor, as a STAND model system, to address this question by dissecting the signalling pathway in vitro. We have found that inducer binding to the sensor is the first step of the activation pathway. It both triggers opening of the NOD and makes the MalT multimer competent for binding promoter MalT sites via its DNA-binding domains. Based on available data, we proposed that inducer trigger of NOD opening is a conserved STAND feature, irrespective of the sensor structure. As discussed, an additional role for the inducer, as found for MalT, might pertain to other types of STANDs.


TGFBI (BIGH3) gene mutations in German families: two novel mutations associated with unique clinical and histopathological findings.
To report the clinical, histopathological and immunohistochemical findings of two novel mutations within the TGFBI gene. The genotype of 41 affected members of 16 families and nine sporadic cases was investigated by direct sequencing of the TGFBI gene. Clinical, histological and immunohistochemical characteristics of corneal opacification were reported and compared with the coding region changes in the TGFBI gene. A novel mutation Leu509Pro was detected in one family with a geographic pattern-like clinical phenotype. Histopathologically we found amyloid together with non-amyloid deposits and immunohistochemical staining of Keratoepithelin (KE) KE2 and KE15 antibodies. In two families and one sporadic case the novel mutation Gly623Arg with a late-onset, map-like corneal dystrophy was identified. Here amyloid and immunohistochemical staining of only KE2 antibodies occurred. Further, five already known mutations are reported: Arg124Cys Arg555Trp Arg124His His626Arg, Ala546Asp in 13 families and five sporadic cases of German origin. The underlying gene defect within the TBFBI gene was not identified in any of the four probands with Thiel-Behnke corneal dystrophy. The two novel mutations within the TGFBI gene add another two phenotypes with atypical immunohistochemical and histopathological features to those so far reported.


A Link between the Increase in Electroencephalographic Coherence and Performance Improvement in Operating a Brain-Computer Interface.
We study the relationship between electroencephalographic (EEG) coherence and accuracy in operating a brain-computer interface (BCI). In our case, the BCI is controlled through motor imagery. Hence, a number of volunteers were trained using different training paradigms: classical visual feedback, auditory stimulation, and functional electrical stimulation (FES). After each training session, the volunteers' accuracy in operating the BCI was assessed, and the event-related coherence (ErCoh) was calculated for all possible combinations of pairs of EEG sensors. After at least four training sessions, we searched for significant differences in accuracy and ErCoh using one-way analysis of variance (ANOVA) and multiple comparison tests. Our results show that there exists a high correlation between an increase in ErCoh and performance improvement, and this effect is mainly localized in the centrofrontal and centroparietal brain regions for the case of our motor imagery task. This result has a direct implication with the development of new techniques to evaluate BCI performance and the process of selecting a feedback modality that better enhances the volunteer's capacity to operate a BCI system.


Activation of the Nuclear Erythroid 2-Related Factor 2 Antioxidant Responsive Element (Nrf2-ARE) Signaling Pathway Alleviates Acute Graft-Versus-Host Disease by Reducing Oxidative Stress and Inhibiting Infiltration of Inflammatory Cells in an Allogeneic Stem Cell Transplantation Mouse Model.
BACKGROUND Acute graft-versus-host disease (aGVHD) limits the wider application of hematopoietic stem cell transplantation (HSCT). We explored the relationship between the Nrf2-ARE signaling pathway and aGVHD and identified effective and efficient therapeutic targets for the prevention and management of aGVHD following HSCT. MATERIAL AND METHODS C57BL/6 and BALB/c mice were used to establish the aGVHD model. The bone marrow and spleen mononuclear cells were separated from the donor mice and injected into the caudal vein of recipient mice that had undergone total body irradiation (TBI, 8 Gy). Sulforaphane (SFN) was used to activate the Nrf2-ARE signaling pathway. RESULTS The long-term survival rate of the SFN group was higher than that of the control group (40% vs. 0%, p<0.05, n=10). There were worse pathological changes and a greater infiltration of inflammatory cells in the liver, small intestine, and lung tissues of the control group. Furthermore, the Nrf2, NQO1, and HO-1 mRNA and protein levels were higher in the small intestines of the SFN group than in the control group (p<0.05, n=4). CONCLUSIONS The Nrf2-ARE signaling pathway plays a vital role in preventing aGVHD in an HSCT mouse model by regulating the expression of the downstream antioxidant genes NQO1 and HO-1 and by inhibiting the local inflammatory reaction.


Dipolar versus octupolar triphenylamine-based fluorescent organic nanoparticles as brilliant one- and two-photon emitters for (bio)imaging.
Two related triphenylamine-based dipolar and octupolar fluorophores are used to prepare aqueous suspensions of fluorescent organic nanoparticles (FONs) via the reprecipitation method. The obtained spherical nanoparticles (30-40 nm in diameter) are fluorescent in aqueous solution (up to 15% fluorescence quantum yield) and exhibit extremely high one- and two-photon brightness, superior to those obtained for quantum dots. Despite the two chromophores showing similar fluorescence in solution, the fluorescence of FONs made from the octupolar derivative is significantly red-shifted compared to that generated by the dipolar FONs. In addition, the maximum two-photon absorption cross section of the FONs made from the octupolar derivative is 55% larger than that of the dipolar derivative FONs. The experimental observations provide evidence that the different molecular shape (rodlike versus three-branched) and charge distribution (dipolar versus octupolar) of the two chromophores strongly affect the packing inside the nanoparticles as well as their spectroscopic properties and colloidal stability in pure water. The use of these FONs as probes for biphotonic in-vivo imaging is investigated on Xenopus laevis tadpoles to test their utilization for angiography. When using FONs made from the octupolar dye, the formation of microagglomerates (2-5 μm scale) is observed in vivo, with subsequent lethal occlusion of the blood vessels. Conversely, the nanoparticles of the dipolar dye allow acute imaging of blood vessels thanks to their suitable size and brightness, while no toxic effect is observed. Such a goal cannot be achieved with the dissolved dye, which permeates the vessel walls.


GaAs Clusters in the Quantum Size Regime: Growth on High Surface Area Silica by Molecular Beam Epitaxy.
Molecular beam epitaxy has been used to grow microcrystalline clusters of gallium arsenide (GaAs) in the size range from 2.5 to 60 nanometers on high-purity, amorphous silica supports. High-resolution transmission electron microscopy reveals that clusters as small as 3.5 nanometers have good crystalline order with a lattice constant equal to that of bulk GaAs. Study of the microcrystallite surfaces by x-ray photoelectron spectroscopy shows that they are covered with a shell (1.0 to 1.5 nanometers thick) of native oxides of gallium and arsenic (Ga(2)O(3) and As(2)O(3)), whose presence could explain the low luminescence efficiency of the clusters. Optical absorption spectra of the supported GaAs are consistent with the blue-shifted band edge expected for semiconductor microcrystallites in the quantum size regime.


Regulatory Framework for Clinical Decision Support Software: Present Uncertainty and Prospective Proposition.
US regulators have been slow to provide meaningful guidance to industry participants on the issue of clinical decision support (CDS) software. It is crucial that regulators soon clarify the differences between regulated medical devices and unregulated health management software that nevertheless has the potential to affect patient care. Future CDS regulation in the United States should aim to reduce ambiguity by establishing detailed and simple criteria for manufacturers to use in deciding if a CDS product will be regulated. Clear standards will help ensure the safety of CDS that is brought to market. In addition, clarification will facilitate technological innovation, delivering clinical benefits to needy patients. To this end, the regulatory framework implemented in the United States with respect to CDS should consider the "substantial dependence" standard.


Quality of life in MPN comes of age as a therapeutic target.
BCR-ABL-negative myeloproliferative neoplasms include primary myelofibrosis, polycythemia vera, and essential thrombocythemia. Clonal stem cell proliferation and dysregulated JAK/STAT molecular pathways characterize these hematologic malignancies. Symptoms experienced by patients are heterogeneous including excessive and disabling fatigue, early satiety, anorexia, pruritus, bone pain, night sweats, cachexia, abdominal pain and discomfort, and cognitive complaints. Patients also experience impaired quality of life along with decreased overall survival. New targeted drug therapies, including JAK2 inhibitors, have demonstrated remarkable success in alleviating the myeloproliferative neoplasm (MPN) symptomatic burden, reducing splenomegaly and improving quality of life while offering overall survival benefit. Within the USA, FDA approval has only been granted to use JAK2 inhibitors in intermediate- to high-risk myelofibrosis. However, given that low-prognostic-scoring patients have been shown to have considerable symptomology, there is a possibility that lower-risk patients may benefit from therapy. More than ever, the need for accurate MPN symptom burden assessment and subsequent addition of targeted therapies is critical in the treatment of MPNs. This article discusses the role of MPN symptom burden and quality of life as therapeutic targets in the context of recent MPN clinical advances.


Risk factors and outcomes of intravenous tissue plasminogen activator and endovascular thrombectomy utilization amongst pediatrics acute ischemic stroke.
Pediatric stroke is a debilitating disease. There are several risk factors predisposing children to this life-threatening disease. Although, published literature estimates a relatively high incidence of pediatric stroke, treatment guidelines on intravenous tissue plasminogen activator and endovascular thrombectomy utilization remain a dilemma. There is a lack of large population-based studies and clinical trials evaluating the efficacy and safety outcomes associated with these treatments in this unique population. We sought to determine the prevalence of risk factors, concurrent utilization of intravenous tissue plasminogen activator and endovascular thrombectomy, and associated outcomes in pediatric stroke hospitalizations. We performed a retrospective analysis of the Nationwide Inpatient Sample data (2003-2014) in pediatric (1-21 years of age) acute ischemic stroke hospitalizations using ICD-9-CM codes. The multivariable survey logistic regression model was weighted to account for sampling strategy, evaluate predictors of hemorrhagic conversion, and treatment outcomes (mortality, morbidity, and discharge disposition) amongst pediatric stroke hospitalizations. In this analysis, 9109 patients between 1 and 21 years of age were admitted during 2003-2014 for acute ischemic stroke. Of these 9109 patients, 119 (1.30%) received endovascular thrombectomy alone, 256 (2.82%) intravenous recombinant tissue plasminogen activator, and 69 (0.75%) both endovascular thrombectomy and intravenous recombinant tissue plasminogen activator. We found overall high prevalence of conditions like epilepsy (19.59%), atrial septal defect (11.76%), sickle cell disease (8.63%), and moyamoya disease (5.41%) in pediatric acute ischemic stroke patients. Unadjusted analysis showed high prevalence of all-cause in-hospital mortality in combined endovascular thrombectomy and intravenous recombinant tissue plasminogen activator utilization group, and higher prevalence of hemorrhagic conversion and morbidity in endovascular thrombectomy utilization group compared to other groups (p < 0.0001). Multivariate adjusted analysis showed that children with endovascular thrombectomy utilization (aOR: 19.19; 95% CI: 2.50-147.29, p = 0.005), intravenous recombinant tissue plasminogen activator utilization (aOR: 8.85; 95% CI: 1.92-40.76, p = 0.005), and both (endovascular thrombectomy and intravenous recombinant tissue plasminogen activator) utilization (aOR: 7.55; 95% CI: 1.16-49.31, p = 0.035) had higher odds of hemorrhagic conversion compared to no-treatment group. We found various risk factors associated with pediatric stroke. The early identification can be useful to formulate preventive strategies and influence the incidence of pediatric stroke. Our study results showed that use of intravenous recombinant tissue plasminogen activator and endovascular thrombectomy increase risk of mortality and hemorrhagic conversion, but we suggest to have more clinical studies to evaluate the idea candidates for utilization of intravenous recombinant tissue plasminogen activator and endovascular thrombectomy based on risk: benefit ratio.


Cardiopulmonary and Gastrointestinal Manifestations of Eosinophil- associated Diseases and Idiopathic Hypereosinophilic Syndromes: Multimodality Imaging Approach.
Eosinophil-associated diseases (EADs) are a diverse group of disorders characterized by an increase in circulating or tissue eosinophils. Cardiopulmonary and gastrointestinal system involvement can be due to primary EAD with no known cause or can be secondary to known systemic disease. The cardiopulmonary spectrum of EADs comprises simple pulmonary eosinophilia, acute eosinophilic pneumonia, chronic eosinophilic pneumonia, Churg-Strauss syndrome, allergic bronchopulmonary aspergillosis, bronchocentric granulomatosis, parasitic infections, and idiopathic hypereosinophilic syndrome. Eosinophilic gastrointestinal disorders include eosinophilic esophagitis, eosinophilic gastroenteritis, and eosinophilic colitis. Diagnosis is often challenging and requires a combination of clinical and imaging features along with laboratory findings. The absolute eosinophil count in peripheral blood and the percentage of eosinophils in bronchoalveolar lavage fluid are crucial in evaluation of various eosinophilic lung diseases. Although chest radiography is the initial imaging modality used in suspected cases of pulmonary EAD, multidetector computed tomography may demonstrate more characteristic pulmonary patterns, nodules, and subtle parenchymal abnormalities. Barium esophagography is used to assess mucosal abnormalities and the length and diameter of esophageal strictures. Magnetic resonance imaging is superior in providing valuable information in select patients, especially in evaluation of cardiac and gastrointestinal system involvement. Many patients require a multimodality imaging approach to enable diagnosis, guide treatment, and assess treatment response. Knowledge of the clinical features and imaging findings of the spectrum of EADs involving the lungs, heart, and gastrointestinal tract permits optimal patient care.


Repair of temporomandibular joint disc perforation using a synovial membrane flap in Macaca fascicularis monkeys: light and electron microscopy studies.
Previous studies have demonstrated that experimentally produced perforations in the discs of Macaca fascicularis monkeys lead to osteoarthrosis. Synovial membrane hyperplasia also was demonstrated in monkey and human joints with disc perforations. The hypothesis was advanced that a synovial flap obtained from within the affected joint would be the most appropriate tissue to repair chronic disc perforation. To test this hypothesis, four adult M fascicularis monkeys were anesthetized and 4- to 6-mm perforations were made in the posterolateral aspects of the avascular discs bilaterally. The wounds were sutured leaving the perforations open, and the animals were fed their normal diet. After 4 weeks, one joint in each monkey was reopened and a repair was performed using a double-layered flap from the synovial lining of the superior and inferior recesses. Four weeks after repair, the animals were killed and the temporomandibular joints (TMJs) were removed en bloc and decalcified. The joints were sectioned into lateral, middle, and medial sections and were photographed using a stereomicroscope and then processed for light and electron microscopy. The same processing was done to four intact joints that were used as controls. Eight weeks following perforation, the joint components showed degenerative changes consistent with osteoarthritis. Close to the perforations the disc showed loss of collagen, vacuolation of extracellular matrix, accumulation of dense proteoglycan-like material, and the appearance within the disc of type A or macrophage-like cells of the synovium. The discal tissue away from the perforation showed high cellularity and vascularity. The temporal and condylar surfaces showed denudation, fibrillation, osteophytes, and chondrocytic clustering, all characteristics of osteoarthrosis. The surgically repaired discs were intact and the articular surfaces showed no degenerative changes. Discal collagen was restored and appearance of myofibroblasts and elastogenesis were a consistent feature of the repaired disc. The vascularity of the condylar cartilage of the repaired joints appeared similar to that of embryonic cartilage. The reversibility of the degenerative alterations following discal repair in this experimental model should provide the basis for a rational and useful method for surgical repair of TMJ disc perforation using intraarticular synovial tissue.


Psychopharmacological Treatment in the RAISE-ETP Study: Outcomes of a Manual and Computer Decision Support System Based Intervention.
The Recovery After an Initial Schizophrenia Episode-Early Treatment Program compared NAVIGATE, a comprehensive program for first-episode psychosis, to clinician-choice community care over 2 years. Quality of life and psychotic and depressive symptom outcomes were found to be better with NAVIGATE. Compared with previous comprehensive first-episode psychosis interventions, NAVIGATE medication treatment included unique elements of detailed first-episode-specific psychotropic medication guidelines and a computerized decision support system to facilitate shared decision making regarding prescriptions. In the present study, the authors compared NAVIGATE and community care on the psychotropic medications prescribed, side effects experienced, metabolic outcomes, and scores on the Adherence Estimator scale, which assesses beliefs related to nonadherence. Prescription data were obtained monthly. At baseline and at 3, 6, 12, 18, and 24 months, participants reported whether they were experiencing any of 21 common antipsychotic side effects, vital signs were obtained, fasting blood samples were collected, and the Adherence Estimator scale was completed. Over the 2-year study period, compared with the 181 community care participants, the 223 NAVIGATE participants had more medication visits, were more likely to receive a prescription for an antipsychotic and more likely to receive one conforming to NAVIGATE prescribing principles, and were less likely to receive a prescription for an antidepressant. NAVIGATE participants experienced fewer side effects and gained less weight; other vital signs and cardiometabolic laboratory findings did not differ between groups. Adherence Estimator scores improved in the NAVIGATE group but not in the community care group. As part of comprehensive care services, medication prescription can be optimized for first-episode psychosis, contributing to better outcomes with a lower side effect burden than standard care.


Emergence of Gold-Mesoporous Silica Hybrid Nanotheranostics: Dox-Encoded, Folate Targeted Chemotherapy with Modulation of SERS Fingerprinting for Apoptosis Toward Tumor Eradication.
Strategically fabricated theranostic nanocarrier delivery system is an unmet need in personalized medicine. Herein, this study reports a versatile folate receptor (FR) targeted nanoenvelope delivery system (TNEDS) fabricated with gold core silica shell followed by chitosan-folic acid conjugate surface functionalization by for precise loading of doxorubicin (Dox), resembled as Au@SiO2 -Dox-CS-FA. TNEDS possesses up to 90% Dox loading efficiency and internalized through endocytosis pathway leading to pH and redox-sensitive release kinetics. The superior FR-targeted cytotoxicity is evaluated by the nanocarrier in comparison with US Food and Drug Administration (FDA)-approved liposomal Dox conjugate, Lipodox. Moreover, TNEDS exhibits theranostic features through caspase-mediated apoptosis and envisages high surface plasmon resonance enabling the nanoconstruct as a promising surface enhanced Raman scattering (SERS) nanotag. Minuscule changes in the biochemical components inside cells exerted by the TNEDS along with the Dox release are evaluated explicitly in a time-dependent fashion using bimodal SERS/fluorescence nanoprobe. Finally, TNEDS displays superior antitumor response in FR-positive ascites as well as solid tumor syngraft mouse models. Therefore, this futuristic TNEDS is expected to be a potential alternative as a clinically relevant theranostic nanomedicine to effectively combat neoplasia.


Bayesian Evaluation of inequality-constrained Hypotheses in SEM Models using Mplus.
Researchers in the behavioural and social sciences often have expectations that can be expressed in the form of inequality constraints among the parameters of a structural equation model resulting in an informative hypothesis. The question they would like an answer to is "Is the Hypothesis Correct" or "Is the hypothesis incorrect?". We demonstrate a Bayesian approach to compare an inequality-constrained hypothesis with its complement in an SEM framework. The method is introduced and its utility is illustrated by means of an example. Furthermore, the influence of the specification of the prior distribution is examined. Finally, it is shown how the approach proposed can be implemented using Mplus.


Phenylmethimazole abrogates diet-induced inflammation, glucose intolerance and NAFLD.
Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of both metabolic and inflammatory diseases and has become the leading chronic liver disease worldwide. High-fat (HF) diets promote an increased uptake and storage of free fatty acids (FFAs) and triglycerides (TGs) in hepatocytes, which initiates steatosis and induces lipotoxicity, inflammation and insulin resistance. Activation and signaling of Toll-like receptor 4 (TLR4) by FFAs induces inflammation evident in NAFLD and insulin resistance. Currently, there are no effective treatments to specifically target inflammation associated with this disease. We have established the efficacy of phenylmethimazole (C10) to prevent lipopolysaccharide and palmitate-induced TLR4 signaling. Because TLR4 is a key mediator in pro-inflammatory responses, it is a potential therapeutic target for NAFLD. Here, we show that treatment with C10 inhibits HF diet-induced inflammation in both liver and mesenteric adipose tissue measured by a decrease in mRNA levels of pro-inflammatory cytokines. Additionally, C10 treatment improves glucose tolerance and hepatic steatosis despite the development of obesity due to HF diet feeding. Administration of C10 after 16 weeks of HF diet feeding reversed glucose intolerance, hepatic inflammation, and improved hepatic steatosis. Thus, our findings establish C10 as a potential therapeutic for the treatment of NAFLD.


Indications, limitations and maneuvers to enable extended hepatectomy: current trends.
The liver is a solid organ with a wide variety of primary benign or malignant tumors as well as metastatic lesions. Surgical resection of these tumors remains the only curative modality. Several limitations, however, do not allow the performance of these operations. This review evaluates the indications and limitations regarding these extended hepatic resections, as well as describing all the manipulations that increase the candidates for such operations. A thorough review of the literature was performed in order to define indications for extended hepatectomy, as well as to present all methods that contribute to increasing the volume of the future remnant liver. The role of portal vein ligation, portal vein embolization, two-stage hepatectomy, and in situ liver transection are evaluated in the setting of indications and results. Extended hepatectomies are a necessity due to oncological reasons. All methods developed in order to increase the volume of the remnant liver are safe and efficient. in situ liver transection is a novel and revolutionary two-step procedure for extended hepatic resections. Further clinical studies are required to estimate long-term results and the oncological basis of this technique.


Toll-like receptors 2 and 4 in ischemic stroke: outcome and therapeutic values.
Stroke triggers an intense inflammatory response that could be a consequence of Toll-like receptors (TLRs) activation. However, the clinical significance and the therapeutic possibilities of TLR in stroke is not completely clear. In this study, we analyze the association between the expression of TLR2 and TLR4, inflammatory molecules and endogenous ligands, and clinical outcome of ischemic stroke patients, and we test the potential of TLR2/TLR4 and their endogenous ligands as therapeutic targets. For this purpose, we included 110 patients with ischemic stroke finding that TLR2 and TLR4 are independently associated to poor outcome and correlated with higher serum levels of interleukin (IL)1β, IL6, tumor necrosis factor α, and VCAM1, and that TLR4 was independently associated to lesion volume. In addition, we have developed an in vitro model to test the potential therapeutic value of blocking TLR2/TLR4 or their endogenous ligands. Cultured cells (monocytes and human umbilical vein endothelial cells) were treated with serum from ischemic stroke patients, showing a strong inflammatory response that was blocked when TLR2/4 or cellular fibronectin (cFN) or HSP60 were blocked. In conclusion, TLR2 and TLR4 are associated to outcome in stroke patients and TLR2/4 or their endogenous ligands, cFN/HSP60 could be new therapeutic targets for ischemic stroke.


Functional mobility discriminates nonfallers from one-time and frequent fallers.
Given that 90% of hip fractures result from a fall, individuals who fall frequently are more likely to be at greater risk for fracture than one-time fallers. Our aim was to determine whether performance variables associated with injurious falls could be used to distinguish frequent fallers from both one-time fallers and nonfallers. A total of 157 men and women (77.4-5.4 years) were recruited and categorized into one of the following three groups based on falls status over the previous 12 months: nonfallers (n = 48), one-time fallers (n = 56), and frequent fallers (more than one fall) (n = 53). All subjects were evaluated on functional mobility and lower extremity strength and power. Using multivariate analysis of covariance with height as a covariate, nonfallers were significantly faster than both one-time and frequent fallers during the Get Up and Go (a test involving lower extremity strength and power, and mobility) and faster than one-time fallers on the Tandem Gait (p < .01). There were no significant differences between groups for other mobility variables or for laboratory measures of strength and power. Because one-time and frequent fallers were similar on all measures. they were grouped as "fallers" in discriminant analysis. The Get Up and Go discriminated between the fallers and nonfallers with a final Wilks's Lambda of .900 (p < .001) and correctly classified 72.4% of fallers and nonfallers before crossvalidation and 71.2% of the cases after validation. Given that the Get Up and Go discriminates between fallers and nonfallers and is associated with lower extremity strength and power, fall prevention strategies should focus on improving both functional mobility and lower extremity strength and power.


Randomized controlled trial: Multimodal Anxiety and Social Skill Intervention for adolescents with autism spectrum disorder.
Anxiety is common among adolescents with autism spectrum disorders (ASD) and may amplify the core social disability, thus necessitating combined treatment approaches. This pilot, randomized controlled trial evaluated the feasibility and preliminary outcomes of the Multimodal Anxiety and Social Skills Intervention (MASSI) program in a sample of 30 adolescents with ASD and anxiety symptoms of moderate or greater severity. The treatment was acceptable to families, subject adherence was high, and therapist fidelity was high. A 16 % improvement in ASD social impairment (within-group effect size = 1.18) was observed on a parent-reported scale. Although anxiety symptoms declined by 26 %, the change was not statistically significant. These findings suggest MASSI is a feasible treatment program and further evaluation is warranted.


Nanosecond-scale shift-and-dump Mach-Zehnder switch.
We present a Mach-Zehnder-based optical switch with novel electrooptic shift-and-dump phase shifters that have no residual amplitude modulation. As a result, the switch can have a very high extinction ratio with no overhead in power dissipation or insertion loss compared to standard electrooptic Mach-Zehnder switches. We fabricate the switch in an all-digital silicon photonic platform that monolithically integrates the actuation and control electronics together with the photonics. The switch demonstrates an extinction ratio >33 dB, insertion loss <1.2 dB, and nanosecond-scale transients.


Computational methods to predict the reactivity of nanoparticles through structure-property relationships.
Innovative biomedical techniques operational at the nanoscale level are being developed in therapeutics, including advanced drug delivery systems and targeted nanotherapy. Given the large number of nanoparticles that are being developed for possible biomedical use, the use of computational methods in the assessment of their properties is of key importance. Among the in silico methods, quantum mechanics is still used rarely in the study of nanostructured particles. This review provides an overview of some of the main quantum mechanics methods that are already used in the assessment of chemicals. Furthermore, classical tools used in the chemistry field are described, to show their potential also in the pharmacological field. The current status of computational methods in terms of availability and applicability to nanoparticles, and recommendations for further research are highlighted. The in silico modelling of nanoparticles can assist in targeting and filling gaps in knowledge on the effects of these particular particles. Computational models of the behaviour of nanoparticles in biological systems, including simulation models for predicting intermolecular interactions and harmful side effects, can be highly valuable in screening candidate particles for potential biomedical use in diagnostics, imaging and drug delivery.


Long-range and targeted ectopic recombination between the two homeologous chromosomes 11 and 12 in Oryza species.
Whole genome duplication (WGD) and subsequent evolution of gene pairs have been shown to have shaped the present day genomes of most, if not all, plants and to have played an essential role in the evolution of many eukaryotic genomes. Analysis of the rice (Oryza sativa ssp. japonica) genome sequence suggested an ancestral WGD ∼50-70 Ma common to all cereals and a segmental duplication between chromosomes 11 and 12 as recently as 5 Ma. More recent studies based on coding sequences have demonstrated that gene conversion is responsible for the high sequence conservation which suggested such a recent duplication. We previously showed that gene conversion has been a recurrent process throughout the Oryza genus and in closely related species and that orthologous duplicated regions are also highly conserved in other cereal genomes. We have extended these studies to compare megabase regions of genomic (coding and noncoding) sequences between two cultivated (O. sativa, Oryza glaberrima) and one wild (Oryza brachyantha) rice species using a novel approach of topological incongruency. The high levels of intraspecies conservation of both gene and nongene sequences, particularly in O. brachyantha, indicate long-range conversion events less than 4 Ma in all three species. These observations demonstrate megabase-scale conversion initiated within a highly rearranged region located at ∼2.1 Mb from the chromosome termini and emphasize the importance of gene conversion in cereal genome evolution.


ATM-NF-kappaB connection as a target for tumor radiosensitization.
Ionizing radiation (IR) plays a key role in both areas of carcinogenesis and anticancer radiotherapy. The ATM (ataxia-telangiectasia mutated) protein, a sensor to IR and other DNA-damaging agents, activates a wide variety of effectors involved in multiple signaling pathways, cell cycle checkpoints, DNA repair and apoptosis. Accumulated evidence also indicates that the transcription factor NF-kappaB (nuclear factor-kappaB) plays a critical role in cellular protection against a variety of genotoxic agents including IR, and inhibition of NF-kappaB leads to radiosensitization in radioresistant cancer cells. NF-kappaB was found to be defective in cells from patients with A-T (ataxia-telangiectasia) who are highly sensitive to DNA damage induced by IR and UV lights. Cells derived from A-T individuals are hypersensitive to killing by IR. Both ATM and NF-kappaB deficiencies result in increased sensitivity to DNA double strand breaks. Therefore, identification of the molecular linkage between the kinase ATM and NF-kappaB signaling in tumor response to therapeutic IR will lead to a better understanding of cellular response to IR, and will promise novel molecular targets for therapy-associated tumor resistance. This review article focuses on recent findings related to the relationship between ATM and NF-kappaB in response to IR. Also, the association of ATM with the NF-kappaB subunit p65 in adaptive radiation response, recently observed in our lab, is also discussed.


IGF-I treatment in adults with type 1 diabetes: effects on glucose and protein metabolism in the fasting state and during a hyperinsulinemic-euglycemic amino acid clamp.
Type 1 diabetes is associated with abnormalities of the growth hormone (GH)-IGF-I axis. Such abnormalities include decreased circulating levels of IGF-I. We studied the effects of IGF-I therapy (40 microg x kg(-1) x day(-1)) on protein and glucose metabolism in adults with type 1 diabetes in a randomized placebo-controlled trial. A total of 12 subjects participated, and each subject was studied at baseline and after 7 days of treatment, both in the fasting state and during a hyperinsulinemic-euglycemic amino acid clamp. Protein and glucose metabolism were assessed using infusions of [1-13C]leucine and [6-6-2H2]glucose. IGF-I administration resulted in a 51% rise in circulating IGF-I levels (P < 0.005) and a 56% decrease in the mean overnight GH concentration (P < 0.05). After IGF-I treatment, a decrease in the overnight insulin requirement (0.26+/-0.07 vs. 0.17+/-0.06 U/kg, P < 0.05) and an increase in the glucose infusion requirement were observed during the hyperinsulinemic clamp (approximately 67%, P < 0.05). Basal glucose kinetics were unchanged, but an increase in insulin-stimulated peripheral glucose disposal was observed after IGF-I therapy (37+/-6 vs. 52+/-10 micromol x kg(-1) x min(-1), P < 0.05). IGF-I administration increased the basal metabolic clearance rate for leucine (approximately 28%, P < 0.05) and resulted in a net increase in leucine balance, both in the basal state and during the hyperinsulinemic amino acid clamp (-0.17+/-0.03 vs. -0.10+/-0.02, P < 0.01, and 0.25+/-0.08 vs. 0.40+/-0.06, P < 0.05, respectively). No changes in these variables were recorded in the subjects after administration of placebo. These findings demonstrated that IGF-I replacement resulted in significant alterations in glucose and protein metabolism in the basal and insulin-stimulated states. These effects were associated with increased insulin sensitivity, and they underline the major role of IGF-I in protein and glucose metabolism in type 1 diabetes.


Physician-delivered interventions for smoking cessation: strategies for increasing effectiveness.
If physicians and other health-care providers were able to facilitate long-term cessation in 1 of every 10 smokers--a safe estimate based on the outcomes of randomized physician-delivered intervention studies--almost 4 million smokers would become former smokers. Evidence from randomized trials and observational studies demonstrates that physicians who intervene with smokers have an impact on their cigarette-smoking behavior. Greater smoking cessation occurs as physician interventions become more intensive and contacts more frequent. Adding modalities such as counseling, self-help booklets, and nicotine-containing chewing gum appears to augment the effectiveness of advice alone. The consistent demonstration of the need for follow-up and the possible use of several modalities is not unlike the demonstrated components of effective overall management approaches to such medical problems as hypertension. Surveys have indicated that physicians often do not intervene because they experience a low success rate with smokers. Educational programs have demonstrated substantial success in training physicians to counsel smokers; therefore, new goals for medical education, house-staff training, and continuing medical education need to include the development of skills and office management practices that can be used by providers to facilitate health-promoting behaviors among their patients. This article reviews the impact of physician-delivered smoking interventions on smokers, physician attitudes toward intervention, and physicians' reported intervention practices. It identifies those strategies that have been demonstrated to be effective in an out-patient office setting and emphasizes the need for every smoker to be considered a candidate for intervention.


Inhibition of microRNA-29b reduces murine abdominal aortic aneurysm development.
MicroRNAs (miRs) regulate gene expression at the posttranscriptional level and play crucial roles in vascular integrity. As such, they may have a role in modifying abdominal aortic aneurysm (AAA) expansion, the pathophysiological mechanisms of which remain incompletely explored. Here, we investigate the role of miRs in 2 murine models of experimental AAA: the porcine pancreatic elastase (PPE) infusion model in C57BL/6 mice and the AngII infusion model in Apoe-/- mice. AAA development was accompanied by decreased aortic expression of miR-29b, along with increased expression of known miR-29b targets, Col1a1, Col3a1, Col5a1, and Eln, in both models. In vivo administration of locked nucleic acid anti-miR-29b greatly increased collagen expression, leading to an early fibrotic response in the abdominal aortic wall and resulting in a significant reduction in AAA progression over time in both models. In contrast, overexpression of miR-29b using a lentiviral vector led to augmented AAA expansion and significant increase of aortic rupture rate. Cell culture studies identified aortic fibroblasts as the likely vascular cell type mediating the profibrotic effects of miR-29b modulation. A similar pattern of reduced miR-29b expression and increased target gene expression was observed in human AAA tissue samples compared with that in organ donor controls. These data suggest that therapeutic manipulation of miR-29b and its target genes holds promise for limiting AAA disease progression and protecting from rupture.


High resolution mass spectrometry for studying the interactions of cisplatin with oligonucleotides.
Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR MS) has been used to probe the interaction of the anticancer drug cisplatin with oligonucleotides. The binding kinetics, the nature of the adducts formed, and the location of the binding site within the specifically designed double-stranded DNA oligonucleotides, ds(GTATTGGCACGTA) and ds(GTACCGGTGTGTA), were determined by recording mass spectra over time and/or employing tandem mass spectrometry (MS/MS). The FT-ICR MS studies show that binding to DNA takes place via a [Pt(NH 3) 2Cl] (+) intermediate prior to formation of bifunctional [Pt(NH 3) 2] (2+) adducts. Tandem MS reveals that the major binding sites correspond to GG and GTG, the known preferred binding sites for cisplatin, and demonstrates the preference for binding to guanosine within the oligonucleotide. The obtained results are discussed and compared to published data obtained by other mass spectrometric techniques, NMR spectroscopy and X-ray crystallography.


A ruthenium-nitrosyl-functionalized nanoplatform for the targeting of liver cancer cells and NIR-light-controlled delivery of nitric oxide combined with photothermal therapy.
The development of light-controlled nitric oxide (NO)-releasing nanoplatforms that are capable of specifically targeting liver cancer cell lines and delivering an optimal amount of NO can significantly affect liver cancer therapy. In this study, a multifunctional nanoplatform {N-GQDs@Ru-NO@Gal} (1) for the near-infrared (NIR) light-responsive release of NO, consisting of a NO donor (Ru-NO) and a liver-targeting galactose derivative (Gal) covalently attached to N-doped graphene quantum dots (N-GQDs), was reported. Nanoplatform 1 preferentially targeted liver cancer cells over normal cells and instantly released NO as well as exhibited a prominent photothermal effect upon NIR irradiation at 808 nm, thereby leading to efficient anti-tumor efficacy. {N-GQDs@Ru-NO@Gal} with a small size (<10 nm), good biocompatibility, and fluorescent-tracing properties represents a unique example of a multifunctional NO-releasing nanoplatform that combines photodynamic and photothermal therapies for the targeted treatment of liver cancer. Hence, the developed nanoplatform demonstrates potential for applications in NO-mediated multimodal phototherapy in the near future.


Novel carbamate derivatives of 4-beta-amino-4'-O-demethyl-4-desoxypodophyllotoxin as inhibitors of topoisomerase II: synthesis and biological evaluation.
A novel series of carbamate derivatives of 4-beta-amino-4'-O-demethyl-4-desoxypodophyllotoxin were synthesized. Their effect on human DNA topoisomerase II and antiproliferative activity was evaluated. Compounds 4a-c, 4g, 4j and 4k are topoisomerase II poisons that induce double-stranded breaks in DNA and exhibit increased cytotoxicity compared to etoposide.


An intensive follow-up does not change survival of patients with clinical stage I endometrial cancer.
The clinical benefit of an intensive follow-up protocol in endometrial cancer patients is still uncertain. One hundred and thirty-three patients underwent initial abdominal surgery for clinical stage I endometrial cancer between January 1988 and December 1997 and were periodically followed-up until April 1999 or until death. After surgery, 89 patients received postoperative adjuvant treatment. Periodical surveillance included physical examination, vaginal smear and abdominal-pelvic ultrasound every 3-4 months for the first 2 years from surgery, every 6 months for the next 3 years and yearly thereafter. Chest X-ray was performed every 6 months for the first 2 years, every year for the next 3 years and with individually increasing intervals afterwards. An abdominal-pelvic CT scan was carried out yearly for 5 years. Twenty-four patients (18.0%) developed recurrent disease after a median time of 17.5 months (range, 6-64 months). Five-year actuarial disease-free survival was 81.2% in the whole series, and in detail 94.2% in the subset of patients with FIGO stage Ia grade 1 or 2 endometrioid adenocarcinoma, or stage Ib grade 1 endometrioid adenocarcinoma (low-risk), compared to 76.0 (p = 0.0472) in the subset of patients with stage Ia grade 3 endometrioid adenocarcinoma, stage Ib grade 2 or 3 endometrioid adenocarcinoma, stage equal to or greater than Ic endometrioid adenocarcinoma any grade, and aggressive histologies (high-risk). The site of recurrent disease was local in 6 (25.0%) patients, distant in 17 (70.8%), and local plus distant in 1 (4.2%). Eleven (45.8%) recurrences were symptomatic and 13 (54.2%) were asymptomatic. The median survival after recurrence was 10 months. Survival was longer in patients who relapsed after 17.5 months from initial surgery when compared to those who relapsed earlier (p = 0.02). Conversely, survival after recurrence was not related to patient characteristics at diagnosis, such as FIGO stage, tumor grade, myometrial invasion, histologic type, and lymph node status. It is noteworthy that survival was similar in asymptomatic women, in whom the relapse was occasionally detected by follow-up examinations, and in symptomatic ones. An intensive surveillance protocol seems to have no significant impact on the outcome of patients with clinical stage I endometrial cancer. Simplified follow-up programs tailored for patient subsets with different recurrence risk are required.


Gene regulatory networks and developmental plasticity in the early sea urchin embryo: alternative deployment of the skeletogenic gene regulatory network.
Cell fates in the sea urchin embryo are remarkably labile, despite the fact that maternal polarity and zygotic programs of differential gene expression pattern the embryo from the earliest stages. Recent work has focused on transcriptional gene regulatory networks (GRNs) deployed in specific embryonic territories during early development. The micromere-primary mesenchyme cell (PMC) GRN drives the development of the embryonic skeleton. Although normally deployed only by presumptive PMCs, every lineage of the early embryo has the potential to activate this pathway. Here, we focus on one striking example of regulative activation of the skeletogenic GRN; the transfating of non-skeletogenic mesoderm (NSM) cells to a PMC fate during gastrulation. We show that transfating is accompanied by the de novo expression of terminal, biomineralization-related genes in the PMC GRN, as well as genes encoding two upstream transcription factors, Lvalx1 and Lvtbr. We report that Lvalx1, a key component of the skeletogenic GRN in the PMC lineage, plays an essential role in the regulative pathway both in NSM cells and in animal blastomeres. MAPK signaling is required for the expression of Lvalx1 and downstream skeletogenic genes in NSM cells, mirroring its role in the PMC lineage. We also demonstrate that Lvalx1 regulates the signal from PMCs that normally suppresses NSM transfating. Significantly, misexpression of Lvalx1 in macromeres (the progenitors of NSM cells) is sufficient to activate the skeletogenic GRN. We suggest that NSM cells normally deploy a basal mesodermal pathway and require only an Lvalx1-mediated sub-program to express a PMC fate. Finally, we provide evidence that, in contrast to the normal pathway, activation of the skeletogenic GRN in NSM cells is independent of Lvpmar1. Our studies reveal that, although most features of the micromere-PMC GRN are recapitulated in transfating NSM cells, different inputs activate this GRN during normal and regulative development.


Relationships Between Physical Testing and Match Activity Profiles Across the Australian Football League Participation Pathway.
Purpose: To establish levels of association between physical fitness and match activity profiles of players in the Australian Football League (AFL) participation pathway. Methods: Players (N = 287, range 10.9-19.1 y) were assessed on 20-m sprint, AFL agility, vertical jump and running vertical jump, 20-m multistage fitness test (MSFT), and Athletic Abilities Assessment. Match activity profiles were obtained from global positioning system measures: relative speed, maximal velocity, and relative high-speed running. Results: Correlational analyses revealed moderate relationships between sprint (r = .32-.57, P ≤ .05) and jump test scores (r = .34-.78, P ≤ .05) and match activity profiles in Local U12, Local U14, National U16, and National U18s, except jump tests in National U18s. AFL agility was also moderate to strongly associated in Local U12, Local U14, Local U18, and National U16s (r = .37-.87, P ≤ .05) and strongly associated with relative speed in Local U18s (r = .84, P ≤ .05). Match relative speed and high-speed running were moderate to strongly associated with 20-m MSFT in Local U14, Local U18, and National U18s (r = .41-.95, P ≤ .05) and Athletic Abilities Assessment in Local U12 and Local U18s (r = .35-.67, P ≤ .05). Match activity profile demands increased between Local U12 and National U16s, then plateaued. Conclusions: Physical fitness relates more strongly to match activity profiles in younger adolescent and national-level players. Recruiters should consider adolescent physical fitness and match activity profiles as dynamic across the AFL participation pathway.


Perceiving Locations of Moving Objects Across Eyeblinks.
Eyeblinks cause disruption of visual input that generally goes unnoticed. It is thought that the brain uses active suppression to prevent awareness of the gaps, but it is unclear how suppression would affect the perception of dynamic events when visual input changes across the blink. Here, we addressed this question by studying the perception of moving objects around eyeblinks. In Experiment 1 (N = 16), we observed that when motion terminates during a blink, the last perceived position is shifted forward from its actual last position. In Experiment 2 (N = 8), we found that motion trajectories were perceived as more continuous when the object jumped backward during the blink, canceling a fraction of the space that it traveled. This suggests subjective underestimation of blink duration. These results reveal the strategies used by the visual system to compensate for disruptions and maintain perceptual continuity: Time elapsed during eyeblinks is perceptually compressed and filled with extrapolated information.


Future projections of total hip and knee arthroplasty in the UK: results from the UK Clinical Practice Research Datalink.
To estimate the future rate of primary total hip (THR) or knee (TKR) replacement in the UK to 2035 allowing for changes in population demographics and obesity. Using age/gender/body mass index (BMI)-specific incidence rates from a population-based cohort study of 50,000 THR and 45,609 TKR patients from the UK Clinical Practice Research Datalink (CPRD) between 1991 and 2010, we projected future numbers of THR and TKR using two models: a static, estimated rate from 2010 applied to population growth forecasts to 2035, and a log-linear rate extrapolation over the same period. Both scenarios used population forecast data from the UK Office for National Statistics (ONS). Assuming rates of THR and TKR for 2010, and given projected population changes in age, gender and BMI, the number of THRs and TKRs performed in the UK in 2035 is estimated to be, respectively: 95,877 and 118,666. By comparison, an exponential extrapolation of historical rates using a log-linear model produces much higher estimates of THR and TKR counts in 2035 at 439,097 and 1,219,362 respectively. Projected counts were higher for women than men. Assuming a changing (rather than fixed) future BMI distribution increases TKRs by 2035 but not THRs. Using historical rates and population forecasts we have projected the number of THR/TKR operations in the UK up to 2035. This study will inform policymakers requiring estimates of future demand for surgery. Incorporating future forecasts for BMI into projections of joint replacement may be more relevant for TKR rather than THR.


Identification of a novel clade of human immunodeficiency virus type 1 in Democratic Republic of Congo.
The high genetic heterogeneity of HIV-1 in the Democratic Republic of Congo (DRC) constitutes a real challenge for the development of vaccines to counter the spread of the HIV-1 epidemic. It is important to continue to monitor the epidemic by studying the circulating strains and their impact on the overall spread. As part of the ongoing effort to study the global distribution of HIV-1 subtypes and circulating recombinant forms (CRFs), here we describe a new phylogenetic clade of HIV-1 by the analysis of two full-length sequences (83CD003 and 90CD121E12) collected from two individuals at a 7-year interval (1983 and 1990, respectively). One of the two sequences (90CD121E12) was obtained from a vertically infected, 12-month-old baby in Kimpese, rural DRC, an area with low and stable seroprevalence of HIV-1 in women attending antenatal clinics. The two sequences are genetically similar by 95% of their full genome and topologically form a distinct cluster that is equidistant from the existing subtypes (A through K) by the analysis of both the full genome and subgenomic regions. Furthermore, they share several other genetic features, including an additional pair of cysteine residues, predictive of an extra disulfide bridge, in the V4 loop of gp120. This new clade is currently rare, spreading at a slower pace than the other subtypes found in the DRC region. Pending the identification of at least one partial length sequence of the same lineage from another patient who is epidemiologically unlinked to those described here, this clade is not yet named as a subtype as per the recommendation of the nomenclature committee.


Green tea extract as food antioxidant. Synergism and antagonism with α-tocopherol in vegetable oils and their colloidal systems.
The antioxidant effects of α-tocopherol (TOH) in combination with green tea extract (GTE), the green tea polyphenol (-)-epicatechin (EC) or the isomeric (+)-catechin (C), were investigated using different lipid systems based on high linoleic sunflower oil: bulk oil, o/w-emulsion and a phosphatidylcholine-based liposome system. Both polyphenols as well as TOH were efficient antioxidants in all systems when used alone, as detected by the formation of free radicals and conjugated dienes and by oxygen consumption. Strong synergistic effect was found for the combination of TOH and GTE in a methyl linoleate o/w-emulsion and in the pure bulk oil, while only an additive effect was observed in a liposome system. The synergism was already evident for the tendency for radical formation in the bulk oil as detected by electron spin resonance (ESR) spectroscopy. On the contrary, combinations of TOH with either EC or C showed clear synergistic effects in both heterogeneous systems, but antagonistic or additive effects in bulk oil. GTE may accordingly be used to protect both vegetable oils and their emulsions against oxidation through enhancement of the activity of their endogenous antioxidants, while GTE is less efficient in the protection of phospholipids as in liposomes.


Tetherless near-infrared control of brain activity in behaving animals using fully implantable upconversion microdevices.
Many nanomaterials can be used as sensors or transducers in biomedical research and they form the essential components of transformative novel biotechnologies. In this study, we present an all-optical method for tetherless remote control of neural activity using fully implantable micro-devices based on upconversion technology. Upconversion nanoparticles (UCNPs) were used as transducers to convert near-infrared (NIR) energy to visible light in order to stimulate neurons expressing different opsin proteins. In our setup, UCNPs were packaged in a glass micro-optrode to form an implantable device with superb long-term biocompatibility. We showed that remotely applied NIR illumination is able to reliably trigger spiking activity in rat brains. In combination with a robotic laser projection system, the upconversion-based tetherless neural stimulation technique was implemented to modulate brain activity in various regions, including the striatum, ventral tegmental area, and visual cortex. Using this system, we were able to achieve behavioral conditioning in freely moving animals. Notably, our microscale device was at least one order of magnitude smaller in size (∼100 μm in diameter) and two orders of magnitude lighter in weight (less than 1 mg) than existing wireless optogenetic devices based on light-emitting diodes. This feature allows simultaneous implantation of multiple UCNP-optrodes to achieve modulation of brain function to control complex animal behavior. We believe that this technology not only represents a novel practical application of upconversion nanomaterials, but also opens up new possibilities for remote control of neural activity in the brains of behaving animals.


Fertility Potential in Adult Hypospadias.
Hypospadias is a congenital anomaly of the urogenital tract characterized by abnormal location of the external urethral meatus over ventral aspect of penis. The ideal time to correct primary hypospadias is when aged 6-12 months. However, in some developing countries, such as ours, this anomaly may be left untreated until adulthood. There are multiple risk factors responsible for development of this anomaly, out of which paternal sub fertility is one of them. As the child grows into adulthood, fertility status becomes an important issue, frequently raised by patients. To evaluate the fertility potential of adult hypospadiac patients and to rule out the effect of age of surgical correction over fertility potential. Seventy three adult patients of hypospadias were prospectively evaluated, out of which 43 were operated during adulthood. All patients underwent measurement of penile length and circumference in both flaccid and erect positions along with testicular volume, serum LH, FSH and testosterone and semen analysis. A set of questionnaire was given to all the patients which included assessment of erectile function (IIEF-5), ejaculatory function, strength of libido and level of satisfaction after sexual intercourse. Results were compared with an age matched control group of 70 healthy person. Out of 73 patients with a mean age of 23.73 years, 14(19.17%) had proximal and rest 59(80.82%) had distal type of hypospadias. Mean penile length in both type of hypospadiac patients under both flaccid and erect conditions (7.92±1.33 and 9.62±1.31cm) were significantly shorter than those of control (10.78±0.94 and 13.15±1.15 cm) (p<0.001). In spite of short penile length, the level of satisfaction of all patients and their partner after penetrating intercourse were comparable to control (p>0.05). The strength of libido (p>0.05) was comparable with control in both type of hypospadiac patients; however IIEF-5 scores was poor in the proximal type of hypospadias. Semen volume (ml), sperm concentration (mill/ml), active sperm motility (%), and normal sperm morphology were comparable between distal hypospadiac group and control (p>0.05), however these parameters were poor in proximal type. The serum FSH and LH levels were significantly higher and serum testosterone level was significantly lower in hypospadiac patients than control (p <0.001). However, no difference in testicular size was found. The patients who were operated during childhood had shorter penile length compared to patients operated during adulthood. Fertility potential parameters in distal type of hypospadias were comparable with control. However the proximal type had poor erectile function and semen quality. Patients operated in either childhood or in adulthood, there was no significant difference in fertility potential.


Memantine in patients with frontotemporal lobar degeneration: a multicentre, randomised, double-blind, placebo-controlled trial.
Memantine has been used off-label to treat frontotemporal lobar degeneration (FTD). A previous 26-week open-label study suggested a transient, modest benefit on neuropsychiatric symptoms as measured by the neuropsychiatric inventory (NPI). We aimed to determine whether memantine is an effective treatment for FTD. We did a randomised, parallel group, double-blind, placebo-controlled trial of 20 mg memantine taken orally daily for 26 weeks in patients with FTD. Participants met Neary criteria for behavioural variant FTD (bvFTD) or semantic dementia and had characteristic brain atrophy. Use of acetylcholinesterase inhibitors was prohibited. Individuals were randomly assigned to receive either memantine or matched placebo tablets (1:1) in blocks of two and four patients. All patients and study personnel were masked to treatment assignment. Primary endpoints were the change in total NPI score and clinical global impression of change (CGIC) score after 26 weeks and were analysed by intention to treat. This study is registered with Clinicaltrials.gov, number NCT00545974. Of 100 patients screened, 81 were randomly assigned to receive memantine (39 patients) or placebo (42 patients). Five (6%) patients discontinued, and 76 completed the 26-week treatment. Enrolment numbers were lower than planned because of many patients' preference to take memantine or cholinesterase inhibitors off-label rather than participate in a clinical trial. Memantine treatment had no effect on either the NPI (mean difference 2·2, 95% CI -3·9 to 8·3, p=0·47) or CGIC (mean difference 0·0, -0·4 to 0·4, p=0·90) after 26 weeks of treatment. Memantine was generally well tolerated; however, patients in the memantine group had more frequent cognitive adverse events (six patients) than those in the placebo group (one). Memantine treatment showed no benefit in patients with FTD. These data do not support memantine use in FTD. Forest Research Institute.


[Reflections on the past, present and future of minimally invasive surgery].
So-called "minimally invasive surgery" aims to contribute to reducing the effects of surgical trauma and its consequences. A milestone in the development of this concept has been the generalisation of techniques of the videoendoscopic approach in numerous surgical procedures. Outstanding amongst these is laparoscopy, which makes it possible to carry out different abdominal surgical techniques while guaranteeing maximum respect for the peritoneal surface and the abdominal wall itself. This is translated into lower morbidity and mortality and better recovery by the patients. For videoendoscopic access to become consolidated as the first option against the traditional or open approach, it is necessary that two requisites be met: the indication of surgery must be the same irrespective of the approach, and the results in terms of efficiency, safety and cost must be similar or superior. In the immediate future, with the increase in the experience of surgical teams and the improvement of technological capacity, there will be a growth in the number of procedures susceptible to approach using this technique.


Treatment of As(V) and As(III) by electrocoagulation using Al and Fe electrode.
A batch electrocoagulation (EC) process with bipolar electrode and potentiodynamic polarization tests with monopolar systems were investigated as methods to explore the effects of electrode materials and initial solution pH on the As(V) and As(III) removal. The results displayed that the system with Al electrode has higher reaction rate during the initial period from 0 to 25 minutes than that of Fe electrode for alkaline condition. The pH increased with the EC time because the As(V) and As(III) removal by either co-precipitation or adsorption resulted in that the OH positions in Al-hydroxide or Fe-hydroxide were substituted by As(V) and As(III). The pH in Fe electrode system elevate higher than that in Al electrode because the As(V) removal substitutes more OH position in Fe-hydroxide than that in Al-hydroxide. EC system with Fe electrode can successfully remove the As(III) but system with Al electrode cannot because As(III) can strongly bind to the surface of Fe-hydroxide with forming inner-sphere species but weakly adsorb to the Al-hydroxide surface with forming outer-sphere species. The acidic solution can destroy the deposited hydroxide passive film then allow the metallic ions liberate into the solution, therefore, the acidic initial solution can enhance the As(V) and As(III) removal. The over potential calculation and potentiodynamic polarization tests reveal that the Fe electrode systems possess higher over potential and pitting potential than that of Al electrode system due to the fast hydrolysis of and the occurrence of Fe-hydroxide passive film.


Distinct patterns of microsatellite instability are seen in tumours of the urinary tract.
To date, two forms of microsatellite instability (MSI) have been described in human cancer. MSI typical of hereditary nonpolyposis colon cancer (HNPCC), is due to deficient DNA mismatch repair (MMR) and is defined with mono- and dinucleotide repeat microsatellites. A second variety of instability is best seen at selective tetranucleotide repeats (EMAST; elevated microsatellite alterations at select tetranucleotides). While MSI occurs infrequently in bladder cancers, EMAST is common. Sporadic tumours with the largest proportion showing MSI are those found most frequently in HNPCC kindreds. While bladder cancer is not frequently seen in HNPCC, upper urinary tract tumours (UTTs) are. Having previously found a low frequency of MSI in bladder cancer, we sought to determine the relative levels of MSI and EMAST in transitional cell carcinoma (TCC) of the upper and lower urinary tracts. Microsatellite analysis was performed at 10 mono- and dinucleotide and eight tetranucleotide loci, in 89 bladder and 71 UTT TCC. Contrasting patterns of instability were seen in urinary tumours. In bladder cancer, MSI was rare and EMAST was common. The presence of EMAST was not related to tumour grade, stage, subsequent outcome or immunohistochemical expression of the MMR proteins. In UTT, while MSI occurred frequently, EMAST was seen less frequently than in bladder cancer. When TCC of the upper and lower urinary tracts are compared, MSI-H is more frequent in UTT and EMAST more frequent in bladder cancer. Our findings show that, as for colorectal cancer, the pattern of MSI varies with location in the urinary tract. In addition, we have confirmed that MSI and EMAST are discrete forms of MSI, and that the presence of EMAST does not affect tumour phenotype.


Structural Model of the Bilitranslocase Transmembrane Domain Supported by NMR and FRET Data.
We present a 3D model of the four transmembrane (TM) helical regions of bilitranslocase (BTL), a structurally uncharacterized protein that transports organic anions across the cell membrane. The model was computed by considering helix-helix interactions as primary constraints, using Monte Carlo simulations. The interactions between the TM2 and TM3 segments have been confirmed by Förster resonance energy transfer (FRET) spectroscopy and nuclear magnetic resonance (NMR) spectroscopy, increasing our confidence in the model. Several insights into the BTL transport mechanism were obtained by analyzing the model. For example, the observed cis-trans Leu-Pro peptide bond isomerization in the TM3 fragment may indicate a key conformational change during anion transport by BTL. Our structural model of BTL may facilitate further studies, including drug discovery.


Successful by Chance? The Power of Mixed Models and Neutral Simulations for the Detection of Individual Fixed Heterogeneity in Fitness Components.
Heterogeneity in fitness components consists of fixed heterogeneity due to latent differences fixed throughout life (e.g., genetic variation) and dynamic heterogeneity generated by stochastic variation. Their relative magnitude is crucial for evolutionary processes, as only the former may allow for adaptation. However, the importance of fixed heterogeneity in small populations has recently been questioned. Using neutral simulations (NS), several studies failed to detect fixed heterogeneity, thus challenging previous results from mixed models (MM). To understand the causes of this discrepancy, we estimate the statistical power and false positive rate of both methods and apply them to empirical data from a wild rodent population. While MM show high false-positive rates if confounding factors are not accounted for, they have high statistical power to detect real fixed heterogeneity. In contrast, NS are also subject to high false-positive rates but always have low power. Indeed, MM analyses of the rodent population data show significant fixed heterogeneity in reproductive success, whereas NS analyses do not. We suggest that fixed heterogeneity may be more common than is suggested by NS and that NS are useful only if more powerful methods are not applicable and if they are complemented by a power analysis.