Compositional and Interfacial Engineering Yield High-Performance and Stable p-i-n Perovskite Solar Cells and Mini-Modules.
Through the optimization of the perovskite precursor composition and interfaces to selective contacts, we achieved a p-i-n-type perovskite solar cell (PSC) with a 22.3% power conversion efficiency (PCE). This is a new performance record for a PSC with an absorber bandgap of 1.63 eV. We demonstrate that the high device performance originates from a synergy between (1) an improved perovskite absorber quality when introducing formamidinium chloride (FACl) as an additive in the "triple cation" Cs0.05FA0.79MA0.16PbBr0.51I2.49 (Cs-MAFA) perovskite precursor ink, (2) an increased open-circuit voltage, VOC, due to reduced recombination losses when using a lithium fluoride (LiF) interfacial buffer layer, and (3) high-quality hole-selective contacts with a self-assembled monolayer (SAM) of [2-(9H-carbazol-9-yl)ethyl]phosphonic acid (2PACz) on ITO electrodes. While all devices exhibit a high performance after fabrication, as determined from current-density voltage, J-V, measurements, substantial differences in device performance become apparent when considering longer-term stability data. A reduced long-term stability of devices with the introduction of a LiF interlayer is compensated for by using FACl as an additive in the metal-halide perovskite thin-film deposition. Optimized devices maintained about 80% of the initial average PCE during maximum power point (MPP) tracking for >700 h. We scaled the optimized device architecture to larger areas and achieved fully laser patterned series-interconnected mini-modules with a PCE of 19.4% for a 2.2 cm2 active area. A robust device architecture and reproducible deposition methods are fundamental for high performance and stable large-area single junction and tandem modules based on PSCs.


Simplified Septal Stabilization in Closed-Approach Low-Septal-Resection Dorsal Preservation Rhinoplasty.
Septal fixation is a basic step in low-septal-resection dorsal preservation rhinoplasty. Inadequate septal stabilization can lead to supratip depression or more severe saddle nose deformity. This paper presents a simple surgical maneuver to stabilize quadrangular septal cartilage instead of suture fixation to the anterior nasal spine. Thirty patients who underwent closed-approach low-septal-resection dorsal preservation rhinoplasty between July and December 2021 were included in this retrospective study. Depending on the surgical maneuver performed to stabilize quadrangular septal cartilage, the patients were divided into 2 groups as follows: (1) a group in which the septum was stabilized with transfixion sutures (the transfixion suture group) and (2) a group in which the septum was fixed to the anterior nasal spine with suture (the anterior nasal spine suture fixation group). Standardized postoperative 12-month lateral-view photographs were scanned for the presence of supratip depression or saddle nose deformity that may indicate insufficient septum stabilization. Supratip depression was observed in 1 patient in the transfixion suture group (n = 16) and in 1 patient in the anterior nasal spine suture fixation group (n = 14; P > 0.05). No saddle nose deformity was observed in either group. Transfixion sutures seem effective in providing septal stabilization to prevent supratip depression or saddle nose deformity in closed-approach low-septal-resection dorsal preservation rhinoplasty. Transfixion sutures can be used for septal stabilization in closed-approach rhinoplasty, allowing the surgeon to take advantage of the ease of placement.


Extending the linear-quadratic model for large fraction doses pertinent to stereotactic radiotherapy.
Ongoing clinical trials designed to explore the use of extracranial stereotactic radiosurgery (ESR) for different tumour sites use large doses per fraction (15, 20, 30 Gy or even larger). The question of whether the linear-quadratic (LQ) model is appropriate to describe radiation response for such large fraction doses has been raised and has not been answered definitively. It has been proposed that mechanism-based models, such as the lethal-potentially lethal (LPL) model, could be more appropriate for such large fraction/acute doses. However, such models are not well characterized with clinical data and they are generally not easy to use. The purpose of this work is to modify the LQ model to more accurately describe radiation response for high fraction/acute doses. A new parameter is introduced in the modified LQ (MLQ) model. The new parameter introduced is characterized based both on in vitro cell survival data of several human tumour cell lines and in vivo animal iso-effect curves. The MLQ model produces a better fit to the iso-effect data than the LQ model. For a high single dose irradiation, the prediction of the MLQ is consistent with that from the LPL model. Unlike the LPL model, the MLQ model retains the simplicity of the LQ model and uses the well-characterized alpha and beta parameters. This work indicates that the standard LQ model can lead to erroneous results when used to calculate iso-effects with large fraction doses, such as those used for ESR. We present a solution to this problem.


High-throughput functional annotation of novel gene products using document clustering.
Gene products differentially expressed in healthy vs. diseased tissues may be considered drug targets since the change in their expression level can be related to the cause and progression of the disease studied. A significant portion of the proteins produced by these genes will be unknown and consequently their function must be characterised. The experimental elucidation of biochemical function must be supported by computational tools which can help predicting the possible function of a given protein from its amino acid sequence. We have designed a high-throughput system which automatically analyses amino acid sequences deduced from differentially represented cDNA clones. The system attempts to assign a biological function to protein sequences by carrying out searches in sequence databanks and by locating functionally relevant motifs in the query sequences. The results delivered by the various prediction methods consist of the annotations of matching sequences and/or motifs, which are free-format texts written by humans and therefore may describe the same concept with synonymous words. It is desirable to present the results in such a way that the annotations describing the same biological function are grouped together. To this end we devised an algorithm that enables the hierarchical clustering of free-format documents based on their contents. The system is capable of detecting and flagging conflicting annotations, and will speed up the interpretation of the function prediction results.


Population-level comparative effectiveness of laparoscopic versus open radical nephrectomy for patients with kidney cancer.
Because there is limited population-based evidence supporting the comparative effectiveness of laparoscopic radical nephrectomy (LRN) after its widespread adoption, we compared trends in hospital-based outcomes among patients with kidney cancer treated with LRN or open radical nephrectomy (ORN). Using linked SEER-Medicare data, the authors identified patients with kidney cancer who were treated with LRN or ORN from 2000 through 2005. The authors measured 4 primary outcomes: intensive care unit (ICU) admission, prolonged length of stay, 30-day hospital readmission, and in-hospital mortality. The authors then estimated the association between surgical approach and each outcome, adjusting for patient demographics, tumor characteristics, and year of surgery. The authors identified 2108 (26%) and 5895 (74%) patients treated with LRN and ORN, respectively. Patients treated with LRN were more likely to be white, female, of higher socioeconomic position, and to have tumor sizes of ≤4 cm (all P < .05). The adjusted probability of ICU admission and prolonged length of stay was 41% and 46% lower, respectively, for patients undergoing LRN (P < .001). Although uncommon for both groups, the adjusted probability of in-hospital mortality was 51% higher (2.3% vs 1.5%, P = .04) for patients treated with a laparoscopic approach. At a population level, patients treated with LRN have a lower likelihood of ICU admission and prolonged length of stay, supporting the convalescence benefits of laparoscopy. In-hospital mortality, however, was higher among patients treated with LRN. The latter finding suggests a potentially unanticipated consequence of this technique and highlights the need for long-term monitoring during and after the widespread adoption of new surgical technologies.


GRF elevates cytosolic free calcium concentration in rat anterior pituitary cells.
The effect of human growth hormone-releasing factor (GRF) on intracellular free calcium concentration ([Ca2+]i) was examined in rat anterior pituitary cells. The [Ca2+]i was monitored directly by means of the intracellularly trapped fluorescent indicator, fura-2. GRF rapidly elevated [Ca2+]i, reaching a new plateau within approximately 30 s. The half-maximally effective concentration of GRF was approximately 130 pM. GRF produced a maximal increase in [Ca2+]i by approximately 120 nM. The GRF (2 nM)-induced elevation of [Ca2+]i was abolished by removal of extracellular calcium (Ca2+ omitted, 2 mM EGTA). The GRF (2 nM)-caused rise in [Ca2+]i was largely reduced in the presence of the calcium channel blockers Mg2+ (31.2 mM) or nifedipine (1 microM). An increase in [Ca2+]i by approximately 60 nM was elicited by the addition of prostaglandin E2 (1 microM), which can stimulate growth hormone secretion independent of GRF receptors. These data indicate that GRF elevates the [Ca2+]i, possibly in somatotrophs; this GRF-induced increase in [Ca2+]i may depend on an influx of extracellular Ca2+, largely through Mg2+- and nifedipine-sensitive calcium channels.


Evi5 promotes collective cell migration through its Rab-GAP activity.
Membrane trafficking has well-defined roles during cell migration. However, its regulation is poorly characterized. In this paper, we describe the first screen for putative Rab-GTPase-activating proteins (GAPs) during collective cell migration of Drosophila melanogaster border cells (BCs), identify the uncharacterized Drosophila protein Evi5 as an essential membrane trafficking regulator, and describe the molecular mechanism by which Evi5 regulates BC migration. Evi5 requires its Rab-GAP activity to fulfill its functions during migration and acts as a GAP protein for Rab11. Both loss and gain of Evi5 function blocked BC migration by disrupting the Rab11-dependent polarization of active guidance receptors. Altogether, our findings deepen our understanding of the molecular machinery regulating endocytosis and subsequently cell signaling during migration.


Lesson of the month 2: Autoimmune sequelae of anti-GAD antibodies - thinking outside the box.
A 52 year-old female with no significant medical problems presented with left-sided weakness, unsteady gait and speech disturbance. It was thought that she had neuro-inflammation and she remained clinically stable. Several years later, she was diagnosed with latent autoimmune diabetes of adulthood. Her neurological symptoms deteriorated and she was admitted into hospital. The cerebrospinal fluid was normal, as were an array of blood tests. Imaging tests, including magnetic resonance imaging, computerised tomography and positron emission tomography scans were normal. However, her anti-glutamic acid decarboxylase antibody serum level, which had been taken in the diabetes outpatient clinic, returned at 2,000,000 IU/mL (normal range 0-10). This led to the diagnosis of glutamic acid decarboxylase (GAD) positive cerebellar ataxia. She was treated with plasma exchange and intravenous immunoglobulins and over next 12 weeks her symptoms improved. Our case highlights the need for appropriate treatment of patients with GAD positive cerebellar ataxia to achieve good outcomes.


Immunochemistry of mammalian cholinesterases.
Advances in the study of cholinesterase biology have been facilitated by the development of polyclonal and monoclonal antibodies to acetylcholinesterase (AChE) (EC 220.127.116.11) and butyrylcholinesterase (BuChE) (EC 22.214.171.124) in several laboratories. Our work has focused on murine monoclonal antibodies to the mammalian enzymes. Two dozen antibodies are now in hand, with primary specificity for the AChE of human red blood cells, rabbit brain, and rat brain, and for the BuChE of human plasma. These antibodies exhibit a restricted but useful range of affinities for other mammalian cholinesterases of corresponding types. Several applications are described, including an analysis of BuChE phylogeny within the higher primates, an immunodisplacement assay of AChE in normal human red blood cells and cells from patients with paroxysmal nocturnal hemoglobinuria, a study of immunochemical differences between membrane-associated and soluble AChE of rabbit brain, and initial work on the immunofluorescence cytochemistry of the rat brain.


Development of a Genetic System for Marinobacter atlanticus CP1 (sp. nov.), a Wax Ester Producing Strain Isolated From an Autotrophic Biocathode.
Here, we report on the development of a genetic system for Marinobacter sp. strain CP1, previously isolated from the Biocathode MCL community and shown to oxidize iron and grow as a cathodic biofilm. Sequence analysis of the small and large subunits of the 16S rRNA gene of CP1, as well as comparison of select conserved proteins, indicate that it is most closely related to Marinobacter adhaerens HP15 and Marinobacter sp. ES.042. In silico DNA-DNA hybridization using the genome-to-genome distance calculator (GGDC) predicts CP1 to be a new species of Marinobacter described here as Marinobacter atlanticus. CP1 is competent for transformation with plasmid DNA using conjugation with Escherichia coli donor strain WM3064 and constitutive expression of green fluorescent protein (GFP) is stable in the absence of antibiotic selection. Targeted double deletion mutagenesis of homologs for the M. aquaeoli fatty acyl-CoA reductase (acrB) and fatty aldehyde reductase (farA) genes resulted in a loss of production of wax esters; however, single deletion mutants for either gene resulted in an increase in total wax esters recovered. Genetic tools presented here for CP1 will enable further exploration of wax ester synthesis for biotechnological applications, as well as furthering our efforts to understand the role of CP1 within the Biocathode MCL community.


[Photosensitivity in primary and secondary epilepsies].
A retrospective study was performed on 34 patients with photosensitivity detected on the electroencephalogram. This group was compared to an aleatory sample, with 218 patients. The objectives were to evaluate the photosensitivity and: type of epilepsy, age of onset of seizures, sex ratio, frequency of seizures, and family history.


An Andrographolide from Helichrysum caespitium (DC.) Sond. Ex Harv., (Asteraceae) and Its Antimicrobial, Antiquorum Sensing, and Antibiofilm Potentials.
Helichrysum caespititium (DC.) Sond. Ex Harv., (Asteraceae) is a medicinal plant indigenous to South Africa. Its non-polar extracts exhibit significant antimicrobial and, in particular, antigonorrheal activity. This study aimed at isolating and purifying the active antigonorrheal compound from its chloroform extract and validating its inhibition potential on quorum sensing (QS) and biofilm formation of multi-drug resistant (MDR) pathogens. Phytochemical investigation of aerial parts of H. caespititium afforded a diterpene lactone (CF6). The effect of CF6 on violacein production and biofilm formation was studied using in vitro quantitative violacein inhibition (Chromobacterium violaceum) and biofilm formation (Streptococcus pyogenes, Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae, Neisseria gonorrhoeae, and Pseudomonas aeruginosa). The structure of CF6 was characterized using FTIR, NMR, and UPLC-MS data accordingly, as 10-methyl-8-(propan-17-ylidene)naphthalen-9-yl)-11-vinyl-14-hydroxyfuran-16-one. The susceptibility testing of the pathogens against CF6 revealed Neisseria gonorrhoeae was noticeably susceptible with a MIC value of 60 µg/mL, while Streptococcus pyogenes and Staphylococcus aureus showed MIC of 125 µg/mL. All gram-negative pathogens, Escherichia coli, Klebsiella pneumonia and Pseudomonas aeruginosa were inhibited at 250 µg/mL. CF6 also inhibited the production of violacein by 51.88% at 250 µg/mL and prevented cell attachment by 40.76-81.18%, with N. gonorrhoeae being highly prohibited from forming biofilm. In conclusion, 10-methyl-8-(propan-17-ylidene)naphthalen-9-yl)-11-vinyl-14-hydroxyfuran-16-one is the first of its kind to be isolated from the non-polar (chloroform) extract of South African Helichrysum caespititium with antigonorrheal, antimicrobial, antiquorum sensing, and antibiofilm properties. The compound may serve as a drug candidate against MDR pathogens.


Low SO2 emission from CFB co-firing MSW and bituminous.
Influence of co-firing rate on SO2 emission from co-firing municipal solid waste (MSW) and bituminous containing high amount of sulfur (1.79%) was studied in a 0.15 MWt circulating fluidized bed (CFB). The temperature selected is 1123 K, typical for MSW incineration using CFB. The particle concentration in the dilution zone of the furnace, the alkali metal concentration and sulfate concentration in the recirculating ash and fly ash, and flue gas composition were determined. The results showed that the addition of MSW leads to a significant decrease in SO2 emission. Concentration of SO2 in flue gas decreased to 0 with the co-firing rate greater than 51%. This reduction in SO2 emission is attributed both to the high particle concentration in the dilution zone of the furnace, the high content of alkali metals in the bed material, and to the comparatively high concentration of HCI in flue gas during co-firing of MSW and bituminous.


The Hyper-Pract Study : a multicentre survey on the accuracy of the echocardiographic assessment of hypertensive left ventricular hypertrophy in clinical practice.
Left ventricular hypertrophy (LVH) assessed by echocardiography has a relevant impact in clinical decision making in hypertensive patients. We investigated the precision and accuracy of hypertensive LVH determination in current clinical practice by a regional-based survey. The study included 211 patients with essential hypertension consecutively attending six hospital outpatient hypertension clinics in the northern Italian region of Lombardy; all subjects had undergone an echocardiographic examination for hypertension-related problems in a non-academic or research ultrasound laboratory within 2 years. The original echocardiographic report was examined to ascertain whether the diagnosis of LVH was based on calculation of left ventricular (LV) mass according to validated formulae and indexed to body size (primary outcome) and whether LV geometrical patterns and indices of diastolic function were provided (secondary outcome). A total of 211 echocardiograms performed by 120 physicians operating in 73 different hospital and out-of-hospital ultrasound laboratories were collected. Absolute LV mass, LV mass index and relative wall thickness were calculated in 45.5%, 24.6% and 12.3% of the cases, respectively. Parameters of LV diastolic filling were measured in two-thirds of the cases and estimation of E/A ratio was provided by less than 20% of the examinations. This study shows that a large majority of echocardiographic examinations, routinely performed in hypertensive subjects in order to detect cardiac damage, do not report qualifying data on LV mass, LV geometry and diastolic function. These results indicate that a quantitative assessment of LVH and LV function is rarely provided in clinical practice.


CT evaluation of small pulmonary vessels area in patients with COPD with severe pulmonary hypertension.
Severe pulmonary hypertension (PH) is very uncommon in COPD, and a distinct phenotype has been hypothesised. We aimed to evaluate whether CT can help to recognise this condition non-invasively by measuring small pulmonary vessels. Patients with COPD who underwent pulmonary function tests, unenhanced CT of the chest and right heart catheterisation (RHC) during a period of stability were included in the study. From 105 included patients, 20 patients with COPD with severe PH (mean pulmonary arterial pressure, mPAP>35 mm Hg) were compared with 20 FEV1-matched and age-matched patients with COPD with mild or without PH (mPAP<35 mm Hg). The percentage of total cross-sectional area of vessels less than 5 mm(2) normalised by lung area (%CSA<5) and 5-10 mm(2) (%CSA5-10), the mean number of cross-sectioned vessels (CSNs) and bronchial wall thickness (WT) were measured on CT examination and compared between groups. Paw scores combining PaO2 measurement and CT parameters best correlated with mPAP were compared by receiver operating characteristic analysis to predict severe PH in COPD. Patients with severe PH COPD had higher %CSA and CSN values than those of patients with COPD without severe PH. Using multiple regression analysis, %CSA<5 and WT were the best predictors of mPAP in patients with and without severe PH, respectively. A score combining %CSA<5, PaO2 and WT best predicted severe PH in patients with COPD. CT measurements of small vessels support a distinct vessel-related phenotype in patients with COPD with severe PH, and combined with WT and PaO2 parameters in the paw score, which may offer a non-invasive tool to select patients for RHC.


Current and emerging therapies in multiple sclerosis: a systematic review.
Multiple sclerosis (MS) is a potentially disabling chronic autoimmune neurological disease that mainly affects young adults. Our understanding of the pathophysiology of MS has significantly advanced in the past quarter of a century. This has led to the development of many disease-modifying therapies (DMTs) that prevent exacerbations and new lesions in patients with relapsing remitting MS (RRMS). So far there is no drug available that can completely halt the neurodegenerative changes associated with the disease. It is the purpose of this review to provide concise information regarding mechanism of action, indications, side effects and safety of Food and Drug Administration and European Medicines Agency approved agents for MS, emerging therapies, and drugs that can be considered for off-label use in MS.


Association of Kawasaki disease with tropospheric winds in Central Chile: is wind-borne desert dust a risk factor?
It has been found that Kawasaki disease (KD) cases diagnosed in Japan, Hawaii and San Diego, USA increase when tropospheric wind patterns arrive from central Asia, suggesting a common, wind-borne causal agent. We analyzed KD cases hospitalized in Santiago, Chile to look for associations with local, regional and large scale meteorological variables. We compiled monthly data of KD incidence rates, local meteorological variables, large scale wind patterns and several El Niño Southern Oscillation (ENSO) indices for 2001-2010; we considered standardized anomalies in all analyses and used linear time series models to account for data autocorrelation. We found that meteorological variables explain 38% of variance in KD rates. A unit increase in northerly wind at 3 lagged months, temperature at 1 and 3 lagged months and monthly change of ENSO 4 index are associated with changes in KD rates of 0.203 (95% CI 0.049-0.358), 0.181 (95% CI 0.014-0.347), 0.192 (95% CI 0.030-0.353) and -0.307 (95% CI -0.458-0.156), respectively. These results are robust when northerly wind level is changed or when a shorter period (2005-2010) is used to estimate model parameters. We found a statistical association of KD at Santiago, Chile with tropospheric, northerly wind patterns suggesting that dust transported from the Atacama Desert could include a causative agent. A novel result is that ENSO dynamics also explain part of KD variability with a decrease in KD when La Niña is dissipating or El Niño is on the rise; hence climate scale dynamics might be taken into account in future studies worldwide - at least as a potential explanatory variable that may confound KD seasonality on a global scale.


Communications Skills in the Pharmacy Profession: A Cross Sectional Survey of UK Registered Pharmacists and Pharmacy Educators.
Objectives: To determine UK pharmacists' experiences of their current communication skills and undergraduate training and to identify communication skills training and teaching at UK schools of pharmacy. Methods: Two surveys were developed. The first survey was sent to UK practicing pharmacists examining their current communication skills and interest in behavioural counselling techniques such as Motivational Interviewing (MI). A second survey was sent to all UK Schools of Pharmacy investigating communication skills training and teaching. Results: In the first survey pharmacists reported low satisfaction with their undergraduate communication skills training. A convenience sample of 109 UK pharmacists responded to the first survey. Forty-four per cent (n = 48) of the respondents stated that they continued their professional development in communication skills after an undergraduate degree. Seventy (65.4%) were not familiar with behavioural counselling techniques such as MI. The most common patient consultation delivered by pharmacists was around adherence to medicine 22.4% (n = 50). Pharmacists expressed a need for further training in clinical areas such as mental health 25.7% (n = 80). Results from the second survey to pharmacy schools showed that Schools of Pharmacy response rate was 60% (18/30). All 18 schools stated that they teach health behaviour change consultation skills and this is mostly delivered by a clinical pharmacist. Teaching communication skills was mostly delivered as role play with peers (n = 17). Conclusion: This first national survey of communication skills training in Schools of Pharmacy shows that newer graduates have received more communication training compared to older graduates, however pharmacists' respondents still felt that they were under prepared for behaviour change patient consultations. MI training would be welcomed by those. Practice Implications: Structured courses in communication skills, including behavioural change techniques, are needed for practicing UK pharmacists.


Medical management of acute non-specific low back pain: comparison of different medical treatments, one center's retrospective analysis.
Within the developed countries, low back pain and related ailments represent one of the most relevant conditions, affecting both health and socio-economic systems. Non-specific acute low back pain (nsALBP) could represent either an isolated event or the presenting symptom of an underlying condition. Its management is usually medical and radiological investigations should be avoided. However, a general agreement on the best pharmacological treatment is still missing. In the present study, we retrospectively collected patients' data from the institutional database. Two different medical treatments were recognized and groups consequently set. Outcomes were the clinical status, measured using the visual analogue scale (VAS) score for back pain, the use rate of rescue drugs, side effects related to medical treatment, compliance to the treatment, and global satisfaction. The pharma blending of Tramadol 75 mg and Dexketoprofen 25 mg (available blended in a single tablet), resulted effective in the nsALBP management, with less side effects and rescue-drug use along with a higher compliance. Furthermore, patient satisfaction in this treatment group was significatively higher. Many different medical treatments have been investigated and reported in nsALBP management during the last decades. Associations of different drugs are the most common protocols, even though there is no general agreement. Tramadol and Dexketoprofen provide a good clinical result, fewer side effects and a long-lasting and more effective painkiller action, reducing the use of rescue drugs. Moreover, our results suggest that a single tab may provide a higher compliance rate.


Lower extremity pain after sexual intercourse: a case report of embolization due to femorofemoral bypass graft occlusion.
We describe a case of recurrent thromboembolism to the femoral-popliteal circulation in a patient with prior femorofemoral bypass graft placement. Two separate embolic events occurred, each within a short time after sexual intercourse. Normal circulation to the lower extremity was restored via percutaneous laser-assisted balloon angioplasty, but the source of emboli was corrected surgically via removal of the occluded femorofemoral graft. We propose that distal thrombosis in a patient with prior femorofemoral bypass may indicate an occluded graft as a source of embolization; therefore, consideration should be given to removal of the graft.


Pharmacologic therapy for type 2 diabetes mellitus.
Type 2 diabetes mellitus is a chronic metabolic disorder that results from defects in both insulin secretion and insulin action. An elevated rate of basal hepatic glucose production in the presence of hyperinsulinemia is the primary cause of fasting hyperglycemia; after a meal, impaired suppression of hepatic glucose production by insulin and decreased insulin-mediated glucose uptake by muscle contribute almost equally to postprandial hyperglycemia. In the United States, five classes of oral agents, each of which works through a different mechanism of action, are currently available to improve glycemic control in patients with type 2 diabetes. The recently completed United Kingdom Prospective Diabetes Study (UKPDS) has shown that type 2 diabetes mellitus is a progressive disorder that can be treated initially with oral agent monotherapy but will eventually require the addition of other oral agents, and that in many patients, insulin therapy will be needed to achieve targeted glycemic levels. In the UKPDS, improved glycemic control, irrespective of the agent used (sulfonylureas, metformin, or insulin), decreased the incidence of microvascular complications (retinopathy, neuropathy, and nephropathy). This review examines the goals of antihyperglycemic therapy and reviews the mechanism of action, efficacy, nonglycemic benefits, cost, and safety profile of each of the five approved classes of oral agents. A rationale for the use of these oral agents as monotherapy, in combination with each other, and in combination with insulin is provided.


Short longitudinal versus transverse skin incision for carotid endarterectomy: impact on cranial and cervical nerve injuries and esthetic outcome.
Nerve injuries, wound complications and especially poor cosmetic results still have an important impact on the carotid endarterectomy (CEA) morbidity. Introduction of the mini skin incision in clinical practice seems to be safe with reduction in postoperative pain and superficial and cranial nerves lesions, and better aesthetics outcomes. The objective of this retrospective study was to compare the results between the short longitudinal with the short transverse cervical incision and to evaluate their impact on cranial and cervical nerves and aesthetic outcomes. From January 2007 to December 2009 266 patients underwent 300 consecutive primary CEA procedures. Two-hundred nineteen patients were submitted to short longitudinal cervical incision (group A), in eighty one a short transverse cervical skin incision (group B) was performed. The average of skin incision was about 4-5.5 cm. In all cases a preoperative CEA duplex ultrasounds (US) assisted skin marking was carried out. All patients were submitted to the general anesthesia with Remifentanyl conserved consciousness. Routinely synthetic patch and selective policy intraluminal shunts were used. Incisions were extended when shunts were required or in case of high carotid bifurcation. Preoperative and postoperative cranial nerves evaluation was always performed and a questionnaire about the satisfaction of the aesthetic outcome was proposed to all patients to the discharge and six months follow-up. Stroke/TIA, death, wound complications, cranial and cervical nerves injuries and restenosis rate were reported and analyzed through statistical analysis (χ2 and Student's t test). The 30 days mortality was 0.3% (1/300). The TIA rate was 0.91% in group A and 1.2 % in group B (P>0.9). Wound complications were 1.8% and 1.2 % respectively (P>0.1). No statistically differences were reported in the incidence of cranial and cervical nerves injuries between the two groups (P>0.9). No difference in restenosis rate was detected (P>0.9). In case of lengthening of the incision for high internal carotid (ICA) stenosis and especially to the need of shunt deployment, the longitudinal approach showed unequivocally to be easier and safer. No differences were achieved between short longitudinal and transverse incision in term of stroke, wound complications or nerves impairment. A good cosmetic outcome was gained in both groups. The Duplex US skin markings pre-CEA permitted localization and limits of the plaque with appropriate short incision. A longitudinal cervical approach is to prefer as can lead to an easier proximal and distal lengthening in cases of atherosclerotic extension of the plaque and shunt deployment.


Absorption, disposition and pharmacokinetics of solid lipid nanoparticles.
Solid lipid nanoparticles (SLNs) are primarily composed of solid lipids, which thus impart to them some of the fundamental properties of these lipids, including biocompatibility, biodegradability and low-toxicity. SLNs represent a unique class of colloidal drug delivery systems that possess the advantages of both the "soft" drug carriers such as emulsions and liposomes and polymeric nanoparticles. In this review, we will provide an overview on the absorption, disposition and pharmacokinetics of SLNs. The lipidic nature, as well as the relatively small particle size, of SLNs ensures sufficient affinity with the biomembranes, and results in improved absorption by either of the oral, transdermal, pulmonary, nasal, ocular, rectal or buccal route. One special aspect of oral SLNs is the enhanced lymphatic absorption by either the chylomicron-association pathway or the M cell uptaking pathway. Intravenous SLNs are predominantly uptaken by the liver or spleen following opsonization by the complementary system. Modification of SLN surface with PEGs chains will mask the hydrophobic surface and divert SLNs to non-hepatic and non-splenic organs, while ligand-modification will achieve active targeting to specific tissues or organs. Degradation of SLNs is primarily based on the degradation of the lipids themselves by lipase. Pharmacokinetics reflects the effect of the lipidic vehicles of SLNs on in vivo disposition of the loaded drugs.


[Effect of angular accelerations on the sensory and motor components of fixation eye movements].
The effect of angular accelerations on the eye fixation function and concomitant sensory reactions was investigated under special conditions. An illusion of target distortion towards the rapid component of the vestibular nystagmus developed in these situations. Changes in the eye fixation movements and "sensation of target" were coordinated and depended on the direction of the vestibular nystagmus. The findings indicate that during an exposure to angular accelerations the stability of target perceptions is disturbed and objectively recorded errors of its fixation by the optic apparatus are made.


Transcription of genes near the sspE locus of the Bacillus subtilis genome.
The yfhP, yfhQ (mutY homologue), yfhS and yfhR (oxidoreductase homologue) genes, which are located upstream of the sspE locus, have been identified in the Bacillus subtilis genome. Transcriptional analysis showed that yfhP, yfhQ and yfhR are transcribed during the exponential growth phase, and sspE is monocistronically transcribed in the late sporulation phase and co-transcribed with yfhQ and/or yfhR during exponential growth. However, SspE was not translated during this period. Northern blot and primer extension analyses indicated that yfhS is transcribed by E sigma E during sporulation. No significant difference between wild-type and yfhS mutant strains was found in the rate of sporulation or germination, the heat tolerance of spores or the transcription of the sspE locus during sporulation. The transcription of the yfhP and yfhQ-yfhR-sspE loci increased 2.5- and 5.3-fold in a yfhP-deficient strain compared to the wild-type strain at t-2 (2 h before initiation of sporulation). In addition, transcription corresponding to the yfhR-sspE loci increased more than twofold with maximum values observed at t-1.5. These results suggest that YfhP may act as a negative regulator for the transcription of yfhQ, yfhR, sspE and yfhP.


Rapid restoration of normal endothelial functions in genetically hyperlipidemic mice by a synthetic mediator of reverse lipid transport.
Endothelial dysfunction is a major pathophysiological consequence of hypercholesterolemia and other conditions. We examined whether a synthetic mediator of lipid transport from peripheral tissues to the liver (ie, the "reverse" pathway) could restore normal endothelial function in vivo. Using assays of macrovascular and microvascular function, we found that genetically hypercholesterolemic apolipoprotein E knockout mice exhibited key endothelial impairments. Treatment of the mice for 1 week with daily intravenous bolus injections of large "empty" phospholipid vesicles, which accelerate the reverse pathway in vivo, restored endothelium-dependent relaxation, leukocyte adherence, and endothelial expression of vascular cell adhesion molecule-1 to normal or nearly normal levels. These changes occurred despite the long-standing hyperlipidemia of the animals and the persistence of high serum concentrations of cholesterol-rich atherogenic lipoproteins during the treatment. Our results indicate that dysfunctional macrovascular and microvascular endothelium in apolipoprotein E knockout mice can recover relatively quickly in vivo and that accelerated reverse lipid transport may be a useful therapy.


Hospitalizations for vaccine preventable pneumonias in patients with inflammatory bowel disease: a 6-year analysis of the Nationwide Inpatient Sample.
Pneumonias are among the most common causes of hospitalization among inflammatory bowel disease (IBD) patients. Guidelines published in 2004 advocate vaccination against Streptococcus pneumoniae and influenza virus. We sought to examine trends in hospitalizations for vaccine preventable pneumonias among IBD patients since the availability of published guidelines, and to identify whether Haemophilus influenzae is a causative organism for pneumonia hospitalizations among IBD patients. This cross-sectional study on the Nationwide Inpatient Sample was used to identify admissions for pneumonias in patients with IBD between 2004 and 2009. A multivariate logistic regression analysis was performed comparing IBD patients to controls, accounting for potential confounders. There were more admissions for S. pneumoniae pneumonia than influenza virus or H. influenzae (787, 393, and 183 respectively). Crohn's disease (CD) as well as ulcerative colitis (UC) patients did not demonstrate increased adjusted odds of hospitalization for S. pneumoniae pneumonia (1.08; confidence interval [CI] 0.99-1.17 compared to 0.93; CI 0.82-1.06 respectively). Increased adjusted odds for hospitalization for pneumonias due to influenza virus were seen among UC patients in the bottom quartile of income (1.86; CI 1.46-2.37). Adjusted odds for H. influenzae pneumonia admission in patients with UC and CD patients were increased compared to controls (1.42; CI 1.13-1.79 and 1.28; CI 1.06-1.54, respectively). The study identified lowest income UC patients as having higher adjusted odds, and these patients should be targeted for influenza virus vaccination. Additionally, H. influenzae may be another vaccine preventable cause for pneumonia among IBD patients.


N-Cadherin is a prospective cell surface marker of human mesenchymal stem cells that have high ability for cardiomyocyte differentiation.
Mesenchymal stem cells (MSCs) are among the most promising sources of stem cells for regenerative medicine. However, the range of their differentiation ability is very limited. In this study, we explored prospective cell surface markers of human MSCs that readily differentiate into cardiomyocytes. When the cardiomyogenic differentiation potential and the expression of cell surface markers involved in heart development were analyzed using various immortalized human MSC lines, the MSCs with high expression of N-cadherin showed a higher probability of differentiation into beating cardiomyocytes. The differentiated cardiomyocytes expressed terminally differentiated cardiomyocyte-specific markers such as α-actinin, cardiac troponin T, and connexin-43. A similar correlation was observed with primary human MSCs derived from bone marrow and adipose tissue. Moreover, N-cadherin-positive MSCs isolated with N-cadherin antibody-conjugated magnetic beads showed an apparently higher ability to differentiate into cardiomyocytes than the N-cadherin-negative population. Quantitative polymerase chain reaction analyses demonstrated that the N-cadherin-positive population expressed significantly elevated levels of cardiomyogenic progenitor-specific transcription factors, including Nkx2.5, Hand1, and GATA4 mRNAs. Our results suggest that N-cadherin is a novel prospective cell surface marker of human MSCs that show a better ability for cardiomyocyte differentiation.


Bedside detection of brain ischemia using intracerebral microdialysis: subarachnoid hemorrhage and delayed ischemic deterioration.
Intracerebral microdialysis has been demonstrated to be a useful method for detection of brain ischemia in experimental models and in patients. We have applied new mobile microdialysate analysis equipment that allows a bedside comparison of changes in neurochemistry with the neurological status of the patient. Ten patients with severe aneurysmal subarachnoid hemorrhage (that is, with a high risk of vasospasm and a high risk of subsequent ischemic deficits) were selected. Microdialysis catheters were inserted into the temporal and subfrontal cortex at the end of aneurysm surgery. Samples, collected hourly for 4 to 11 days, were analyzed immediately at the bedside for glucose, lactate, and glycerol and later for pyruvate and glutamate. The patients' neurological status was monitored constantly, and daily recordings of blood flow velocities were performed using transcranial Doppler sonography. Concentrations of the measured substances varied widely. Individual analyses revealed that patients with uneventful clinical courses generally demonstrated low and stable levels of the different metabolites, and those with signs of cerebral ischemia demonstrated various patterns of neurochemical changes. Lactate and glutamate seemed to be sensitive markers of impending ischemia, and increased glycerol levels were associated with severe ischemic deficits. Obtaining the microdialysis data directly at the bedside seemed to be of great advantage when relating the values to other clinical findings. Bedside intracerebral microdialysis monitoring of patients with subarachnoid hemorrhage and signs of delayed ischemia revealed dramatic changes in extracellular concentrations of glucose, lactate, and glycerol that could be directly correlated to the clinical status of the patients. These findings emphasize the potential of microdialysis in neurosurgical intensive care patients.


The non-random occurrence of Robertsonian fusion in the house mouse.
Chromosomal rearrangements such as Robertsonian (Rb) fusions constitute a major phenomenon in the evolution of genome organization in a wide range of organisms. Although proximate mechanisms for the formation of Rb fusion are now well identified, the evolutionary forces that drive chromosomal evolution remain poorly understood. In the house mouse, numerous chromosomal races occur in nature, each defined by a unique combination of Rb fusions. Among the 106 different Rb fusions that were reported from natural populations, the low involvement of chromosome 19 in Rb fusions is striking, prompting the question of the randomness of chromosomal involvement in Rb fusions. We uncover a significant quadratic relationship between chromosome size and probability of fusing, which has never previously been in this species. It appears that fusions involving chromosome 19 are not particularly infrequent, given the expected low fusion probability associated with the chromosome's size. The results are discussed, assessing selective processes or constraints that may operate on chromosome size.


Family Strain Questionnaire - Short Form for nurses and general practitioners.
Our paper presents an instrument for recognising the psychological problems of caregivers: the short form of a previously validated questionnaire, the Family Strain Questionnaire. Individuals caring for chronic patients frequently suffer from psychological problems, which are underestimated by medical professionals and, consequently, are not adequately treated. Therefore, clinical nurses, general practitioners and the members of home care teams have to recognise the psychological problems of caregivers. To do so, they need to quickly measure the problem's severity quickly and track it over time, without a specific training in psychological diagnosis. Survey. Principal caregivers (n = 811) completed the Family Strain Questionnaire in its original form (semi-structured interview plus 44 dichotomous items, administrable in about 20 minutes), aimed at investigating the subjective perception of emotional burden, problems in social involvement, the need for more information about the disease, satisfaction with family relationships and thoughts about death. Data were analysed using the Rasch model for the reduction of items. Thirty items were selected and reanalysed in a new sample of 40 caregivers. The thirty items selected showed very good fit statistics and maintained the diagnostic qualities of the original form. They thus compose the Family Strain Questionnaire - Short Form that caregivers can complete in about five minutes. This brief measure can indicate the severity of stress and allows categorisation of caregivers by psychological risk, which is also represented by a graphic tool. This study confirms that the Family Strain Questionnaire - Short Form offers an initial measure of caregivers' psychological status, regardless of the patient's disease and allows professionals to monitor it over time with a rapid and effective instrument. Clinical nurses, general practitioners and homecare teams should find the Family Strain Questionnaire - Short Form useful for assessing caregiving strain. The instrument is quick and easy to use and does not require any sophisticated psychological training.


[Specific binding of progesterone to the proteins of human endometrial cells].
A specific complex of protein-receptor with hormone, which had a sedimentation coefficient 3.8S, was formed in cell nuclei on incubation of endometrial tissue from pregnant woman with 3H-progestrone at 37 degrees C in vitro. In cell cytoplasm of endometrium the progesterone-protein complex was observed which sedimented at 6.8S and 4.2S. Progesterone was accumulated mainly in nuclei; lower concentrations of the hormone were found in cell cytoplasm of endometrium. Fractions of mitochondria, microsomes and ribosomes also bound the hormone but less distinct as compared with the nuclei. The formation of cytoplasmic complex of progesterone with protein-receptor occurred on incubation of endometrial cytoplasmic fraction with 3h-progesterone at 4 degrees C.


Chemical constituents and biological activities of Cirsium leucopsis, C. sipyleum, and C. eriophorum.
Two endemic Cirsium species, C. leucopsis DC. and C. sipyleum O. Schwarz, and C. eriophorum (L.) Scop. growing in Turkey were investigated to establish their secondary metabolites, fatty acid compositions, and antioxidant and anticholinesterase potentials. Spectroscopic methods were used to elucidate the structures of thirteen known compounds (p-hydroxy-benzoic acid, vanillic acid, cis-epoxyconiferyl alcohol, syringin, balanophonin, 1'-O-methyl-balanophonin, apigenin, kaempferol-3- O-β-D-glucopyranoside, kaempferol-3-O-α-L-rhamnopyranoside, taraxasterol, taraxasterol acetate, β-sitosterol, β-sitosterol-3-O-β-D-glucopyranoside). cis-Epoxyconiferyl alcohol and 1'-O-methyl- balanophonin were isolated for the first time from Cirsium species. Palmitic acid (47.1%) was found to be the main fatty acid of C. leucopsis, linoleic acid in both C. sipyleum (42.1%) and C. eriophorum (37.8 %). Assays of β-carotene bleaching, scavenging of 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radicals, 2,2-azinobis (3-ethylbenzothiazoline-6-sulfonic acid) diammonium (ABTS) cation radicals, and superoxide anion radicals, as well as cupric reducing antioxidant capacity (CUPRAC) were used to determine the antioxidant activities of the extracts and isolated compounds. Vanillic acid, balanohonin, and kaempferol-3-O-aαL-rhamnopyranoside exhibited strong antioxidant activity. Taraxa-terol was a potent inhibitor of acetyl- and butyrylcholinesterase activity, respectively.


Treatment with anti-T-lymphocyte antibodies prevents induction of insulitis in mice given multiple doses of streptozocin.
The importance of T-lymphocytes in the induction of insulitis and hyperglycemia in certain strains of mice treated with multiple subdiabetogenic doses of streptozocin has been a matter of controversy. To understand the role of T-lymphocytes, we treated thymectomized BALB/c ByJ mice with five daily doses of streptozocin (45 mg/kg) and determined the effect of treatment with monoclonal antibodies against T-lymphocyte subsets on the development of diabetes and insulitis. Hyperglycemia (mean glucose of 321 +/- 29 vs. 167 +/- 15 mg/dl in controls) and insulitis were induced in BALB/c ByJ mice given streptozocin. Thy1.2+, L3T4, and Lyt2+ cells were all identified within the islets of diabetic mice. There was a relative paucity of L3T4+ cells and an overabundance of Lyt2+ cells compared with the frequency of these cells found in lymphatic tissues or peripheral blood. Treatment with anti-L3T4 or anti-Lyt2 monoclonal antibodies caused a reduction in splenic T-lymphocyte subsets and attenuated the hyperglycemia to 212 +/- 14 and 197 +/- 16 mg/dl (P less than .001 and .01), respectively, compared with controls and prevented the insulitis induced by streptozocin. Our studies support the hypothesis that an immune response is important to the development of multi-low-dose streptozocin diabetes and indicate that treatment with monoclonal antibodies against the L3T4+ or Lyt2+ T-lymphocyte subsets can attenuate this process.


HTS-compatible beta-lactamase transcriptional reporter gene assay for interrogating the heat shock response pathway.
Moderate environmental and physiological stressors are known to initiate protective heat shock response (HSR) leading to cell survival. HSR is largely mediated by the activation of heat shock factor (HSF), resulting in increased heat shock protein expression. Dysregulation of the HSR signaling has been associated with various diseases including cancer, inflammation and neurodegenerative disorders. Compounds that can modulate HSR have been pursued for the treatment of these diseases. To facilitate the discovery of HSR modulators, we developed a high-throughput amenable betalactamase transcriptional reporter gene assay for monitoring the function of HSF. HeLa cells were engineered to express the beta-lactamase reporter under the control of HSF response elements (HSE) present in the HSP70 gene promoter. The HSE-beta lactamase (HSE-bla) reporter gene assay was validated by using HSF-specific siRNAs and known small molecule modulators. Taking the advantage of fluorescence resonance energy transfer (FRET)-based cell permeable betalactamase substrate, this assay can be miniaturized into 1536-well format. Our results demonstrate that the assay is robust and can be applied to high-throughput screening (HTS) for modulators of HSR.


A method for estimating population sex ratio for sage-grouse using noninvasive genetic samples.
Population sex ratio is an important metric for wildlife management and conservation, but estimates can be difficult to obtain, particularly for sexually monomorphic species or for species that differ in detection probability between the sexes. Noninvasive genetic sampling (NGS) using polymerase chain reaction (PCR) has become a common method for identifying sex from sources such as hair, feathers or faeces, and is a potential source for estimating sex ratio. If, however, PCR success is sex-biased, naively using NGS could lead to a biased sex ratio estimator. We measured PCR success rates and error rates for amplifying the W and Z chromosomes from greater sage-grouse (Centrocercus urophasianus) faecal samples, examined how success and error rates for sex identification changed in response to faecal sample exposure time, and used simulation models to evaluate precision and bias of three sex assignment criteria for estimating population sex ratio with variable sample sizes and levels of PCR replication. We found PCR success rates were higher for females than males and that choice of sex assignment criteria influenced the bias and precision of corresponding sex ratio estimates. Our simulations demonstrate the importance of considering the interplay between the sex bias of PCR success, number of genotyping replicates, sample size, true population sex ratio and accuracy of assignment rules for designing future studies. Our results suggest that using faecal DNA for estimating the sex ratio of sage-grouse populations has great potential and, with minor adaptations and similar marker evaluations, should be applicable to numerous species.


Normative values and determinants of physical capacity in individuals with spinal cord injury.
We reanalyzed data from five studies with similar or identical methodology performed by our laboratory to define normative values and determinants of physical capacity in individuals with tetraplegia and paraplegia. Each study consisted of a graded wheelchair exercise test to determine peak oxygen uptake and maximal power output and could additionally include a wheelchair sprint test to determine short-term (anaerobic) power output and/or an isometric strength test. The combined subject population included 166 individuals (20 women), varying considerably for age, body mass, lesion level, time since injury, and activity level. Ranges in physical capacity parameters were extensive and normative values for individuals with tetraplegia and paraplegia were established. These physical capacity norms could be used for evaluation of fitness status and training or therapeutic interventions. Multiple regression procedures indicated that 48-80% of the variance in physical capacity could be explained by lesion level and completeness, activity level, gender, age, body mass, and time since injury. Although physical capacity is largely determined by factors that cannot be altered, such as lesion level, age, and gender, changeable factors such as activity level and body mass play an additional role.


VASE: Variational Assorted Surprise Exploration for Reinforcement Learning.
Exploration in environments with continuous control and sparse rewards remains a key challenge in reinforcement learning (RL). One of the approaches to encourage more systematic and efficient exploration relies on surprise as an intrinsic reward for the agent. We introduce a new definition of surprise and its RL implementation named variational assorted surprise exploration (VASE). VASE uses a Bayesian neural network as a model of the environment dynamics and is trained using variational inference, alternately updating the accuracy of the agent's model and policy. Our experiments show that in continuous control sparse reward environments, VASE outperforms other surprise-based exploration techniques.


Gastric impaction in captive crocodiles (Crocodilus niloticus).
Five crocodiles kept in captivity for more than 4 years died within a period of 4 days. A post mortem examination of one showed that it had died from gastric impaction which had resulted from the feeding of guinea pigs. It was thought that the high ratio of hair to flesh in guinea pigs together with daily feeding cause the impaction.


The transformational potential of molecular radiomics.
Conventional radiomics in nuclear medicine involve hand-crafted and computer-assisted regions of interest. Recent developments in artificial intelligence (AI) have seen the emergence of AI-augmented segmentation and extraction of lower order traditional radiomic features. Deep learning (DL) affords the opportunity to extract abstract radiomic features directly from input tensors (images) without the need for segmentation. These fourth-order, high dimensional radiomics produce deep radiomics and are well suited to the data density associated with the molecular nature of hybrid imaging. Molecular radiomics and deep molecular radiomics provide insights beyond images and quantitation typical of semantic reporting. While the application of molecular radiomics using hand-crafted and computer-generated features is integrated into decision-making in nuclear medicine, the acceptance of deep molecular radiomics is less universal. This manuscript aims to provide an understanding of the language and principles associated with radiomics and deep radiomics in nuclear medicine.


More than a small adult brain: Lessons from chemotherapy-induced cognitive impairment for modelling paediatric brain disorders.
Childhood is recognised as a period of immense physical and emotional development, and this, in part, is driven by underlying neurophysiological transformations. These neurodevelopmental processes are unique to the paediatric brain and are facilitated by augmented rates of neuroplasticity and expanded neural stem cell populations within neurogenic niches. However, given the immaturity of the developing central nervous system, innate protective mechanisms such as neuroimmune and antioxidant responses are functionally naïve which results in periods of heightened sensitivity to neurotoxic insult. This is highly relevant in the context of paediatric cancer, and in particular, the neurocognitive symptoms associated with treatment, such as surgery, radio- and chemotherapy. The vulnerability of the developing brain may increase susceptibility to damage and persistent symptomology, aligning with reports of more severe neurocognitive dysfunction in children compared to adults. It is therefore surprising, given this intensified neurocognitive burden, that most of the pre-clinical, mechanistic research focuses exclusively on adult populations and extrapolates findings to paediatric cohorts. Given this dearth of age-specific research, throughout this review we will draw comparisons with neurodevelopmental disorders which share comparable pathways to cancer treatment related side-effects. Furthermore, we will examine the unique nuances of the paediatric brain along with the somatic systems which influence neurological function. In doing so, we will highlight the importance of developing in vitro and in vivo paediatric disease models to produce age-specific discovery and clinically translatable research.


Racial disparity in the utilization of implantable-cardioverter defibrillators among patients with prior myocardial infarction and an ejection fraction of <or=35%.
Age-adjusted sudden cardiac death rates are highest for black patients compared with other racial groups. The prophylactic implantation of an implantable cardioverter-defibrillator (ICD) provides a significant reduction in sudden cardiac death and overall mortality in patients after myocardial infarctions with significant left ventricular systolic dysfunction. The purpose of this study was to determine whether black patients with left ventricular systolic dysfunction were less likely than white patients to receive ICDs for the primary prevention of sudden cardiac death. Data from the National Registry to Advance Heart Health (ADVANCENT) were analyzed to determine which patients with histories of myocardial infarctions and ejection fractions<or=35% received ICDs for the primary prevention of sudden cardiac death. Multivariate logistic regression was used to evaluate the association of patients' race with ICD implantation. Overall, 7,830 patients were identified as eligible candidates for ICDs. Black patients (n=660) were younger, more often women, had less education, had more co-morbidities, and had a lower mean ejection fraction compared with white patients (n=7,170). More than 90% of the study population were insured, and approximately 88% of participants in the registry were enrolled by cardiologists. Blacks were significantly less likely than whites to receive ICDs (30% vs 41%, p<0.001). This difference in ICD use persisted after adjusting for demographics, clinical characteristics, and socioeconomic factors (odds ratio 0.62, 95% confidence interval 0.50 to 0.75, p<0.001). In conclusion, among patients at an increased risk for sudden cardiac death, blacks were significantly less likely to receive ICDs than whites.


Restrictions and limitations after pelvic floor surgery: what's the evidence?
A common concern regarding pelvic floor surgery is the relatively high risk of recurrence. In an effort to minimize this risk, many surgeons instruct their patients to avoid certain activities during the healing process so as not to damage the repair before proper healing has occurred. However, many of these restrictions have been historically based on little to no hard evidence. The purpose of this review is to present the latest evidence-based recommendations regarding restrictions and limitations after pelvic floor surgery. The current review covers postoperative activities that could impact proper healing of a vaginal incision and of the strength of the reconstruction itself. It also looks at safety of the patient and those around her as she heals. Topics include pelvic rest, swimming, lifting exercising, working, and driving. Observational research suggests that many unavoidable activities of daily living may have as great, if not an even greater, risk of impacting the healing process than many of the modifiable activity restrictions that are commonly imposed on patients. This may explain why recent clinical trials show no greater problem with healing in patients randomized to less strict postoperative restrictions than the standard. Although further research is necessary, it appears that patients are more satisfied with less strict postoperative limitations, and this less restrictive activity may not have any significant negative impact on the healing process.


Genetic diversity and structure of baobab (Adansonia digitata L.) in southeastern Kenya.
Baobab (Adansonia digitata L.) is an iconic tree of African savannahs. Its multipurpose character and nutritional composition of fruits and leaves offer high economic and social potential for local communities. There is an urgent need to characterize the genetic diversity of the Kenyan baobab populations in order to facilitate further conservation and domestication programmes. This study aims at documenting the genetic diversity and structure of baobab populations in southeastern Kenya. Leaf or bark samples were collected from 189 baobab trees in seven populations distributed in two geographical groups, i.e. four inland and three coastal populations. Nine microsatellite loci were used to assess genetic diversity. Overall, genetic diversity of the species was high and similarly distributed over the populations. Bayesian clustering and principal coordinate analysis congruently divided the populations into two distinct clusters, suggesting significant differences between inland and coastal populations. The genetic differentiation between coastal and inland populations suggests a limited possibility of gene flow between these populations. Further conservation and domestications studies should take into consideration thegeographical origin of trees and more attention should be paid to morphological characterization of fruits and leaves of the coastal and inland populations to understand the causes and the impact of the differentiation.


Processes evaluation of coverage and compliance to a round of mass drug administration with DEC and Albendazole for the control of lymphatic filariasis in Puducherry, India.
Mass drug administration (MDA) with annual single dose of DEC and Albendazole is being carried out in India to achieve the National Health Policy goal of elimination of lymphatic filariasis by 2015. The study was conducted in the districts of the Union territory of Puducherry for processes evaluation of round of MDA conducted in 2012. We have conducted household surveys to assess the coverage of drug distribution and consumption, also to identify the reasons for non compliance and to make necessary recommendations for improving programme implementation. Cluster sampling method was followed for the household survey by circulating pre-tested questionnaire. Statistically sufficient numbers of samples were collected in all clusters of districts which are geographically separated. There was a significant variation between reported and assessed coverage. The coverage was comparable between the districts but significantly higher in rural areas compared to urban areas that may be due to acceptability of the drug by the rural people. Above 52% of target population have consumed the drug and consumption was significantly higher in the rural areas. Mahe region recorded a low consumption rate of between 19-42% in different wards, this may be due to misconception of people of Mahe that drugs which are given free of cost are of low quality. Selective intake of albendazole was noticed in Mahe.


Epidemiological study of a developmentally and culturally sensitive preschool intervention to improve school readiness of children in Addis Ababa, Ethiopia.
Early childhood is a dynamic period of physical, psychosocial and cognitive development, where age appropriate intervention during the preschool years influences psychosocial, behavioural and academic achievement of children. This study evaluated the impact of a comprehensive preschool intervention on psychosocial, cognitive and behavioural school preparedness among children in Addis Ababa, Ethiopia. Employing a cluster-sampling design, 150 preschool children who received the basic preschool curriculum (non-intervention) were compared with 100 randomly selected children who received a comprehensive preschool curriculum (intervention) using the Early Development Instrument (EDI) in five domains. Sample t-tests compared means of domain scores. Binary logistic regression analysed proportions of vulnerability in domains and overall. There were no group differences in gender, age, special need status or child's first language. Intervention children had higher domain scores on social competence (mean difference 0.67 (SE=0.26)), emotional maturity (mean difference 0.77 (SE=0.29)), language and cognitive development (mean difference 0.67 (SE=0.40)), communication and general knowledge (mean difference 0.82 (SE=0.34)). Accounting for confounding variables, intervention children had a lower chance of overall vulnerability to domain problems (adjusted OR (AOR)=0.38; 95% CI 0.13 to 1.15), language and cognitive development (AOR=0.21; 95% CI 0.03 to 1.64), and social competence (AOR=0.20; 95% CI 0.08 to 0.45). The comprehensive intervention was associated with better outcomes on early childhood development across four domains. It is recommended to extend this programme to other areas of Ethiopia, where children do not have appropriate school preparation, to reduce risk of school dropout, negative personal and societal outcomes.


Factors influencing women's decisions to drink alcohol during pregnancy: findings of a qualitative study with implications for health communication.
Despite Australian guidelines advising abstinence from alcohol during pregnancy, a relatively high number of Australian women continue to drink alcohol while pregnant. While some call for greater advocacy of the need for abstinence, others have expressed concern that abstinence messages may be harmful to pregnant women and their unborn babies due to the anxiety they could provoke. We present findings on women's deliberations over drinking alcohol during pregnancy, particularly their emotional dimensions, to inform debates about public health messages and practitioner-patient discussions regarding alcohol use during pregnancy. Semi-structured face-to-face interviews were conducted with 40 women in their homes. Our sample comprised women aged 34-39, drawn from the Australian Longitudinal Study on Women's Health, living in the Greater Brisbane Area who were pregnant, or had recently given birth, in 2009. An inductive qualitative framework analysis approach was used to identify and interpret themes explaining why pregnant women choose to drink or not. Women generally described drinking small amounts of alcohol during pregnancy as being a low risk activity and talked about the importance of alcohol to their social lives as a reason for continuing to drink or finding abstinence a burden; sensitisation to the judgements of others was not widespread. Women predominantly assessed the risk of their drinking in terms of the kinds of alcoholic beverages consumed rather than alcohol content. In reflecting on the advice they recalled receiving, women described their healthcare practitioners as being relaxed about the risks of alcohol consumption. The significance of alcohol to women's identity appeared to be an important reason for continued alcohol use during pregnancy among otherwise risk averse women. Anxiety about alcohol consumption during pregnancy was not widespread. However, obstetricians were an important mediator of this. Health messages that dispel the notion that wine is a "healthy" choice of alcoholic beverage, that provide women with strategies to help them avoid drinking, that advise the broader public not to pressure women to drink if they do not want to, and educate women about the effects of ethanol on maternal and fetal bodies, should be considered.


Congenital choanal atresia in North African infants.
Eleven cases of congenital choanal atresia seen over a period of 2 years are described. Its incidence in the community was 1 in 3100 births. Twenty-seven per cent of cases were missed at birth, suggesting an even higher incidence. The anomaly was significantly commoner in infants of younger mothers with less than four children (P less than or equal to 0.05). Maternal polyhydramnios was present in three cases (P less than or equal to 0.0001). The sex incidence was equivocal and three infants were of low birthweight. The atresia was bilateral in the majority of the cases, and associated congenital anomalies were present in five of the 11 infants. Five underwent surgery with no complications.


Acute myelopathy caused by a cervical synovial cyst.
Synovial cysts of the cervical spine, although they occur infrequently, may cause acute radiculopathy or myelopathy. Here, we report a case of a cervical synovial cyst presenting as acute myelopathy after manual stretching. A 68-year-old man presented with gait disturbance, decreased touch senses, and increased sensitivity to pain below T12 level. These symptoms developed after manual stretching 3 days prior. Computed tomography scanning and magnetic resonance imaging revealed a 1-cm, small multilocular cystic lesion in the spinal canal with cord compression at the C7-T1 level. We performed a left partial laminectomy of C7 and T1 using a posterior approach and completely removed the cystic mass. Histological examination of the resected mass revealed fibrous tissue fragments with amorphous materials and granulation tissue compatible with a synovial cyst. The patient's symptoms resolved after surgery. We describe a case of acute myelopathy caused by a cervical synovial cyst that was treated by surgical excision. Although cervical synovial cysts are often associated with degenerative facet joints, clinicians should be aware of the possibility that these cysts can cause acute neurologic symptoms.


[Sensitization to ascaris lumbricoides and asthma severity in children].
There is little information concerning asthma severity and sensitization to Ascaris lumbricoides in pediatric patients. The relationship between sensitization to Ascaris lumbricoides and asthma severity in 219 patients with a high prevalence of parasitic exposure (IgE antibodies) was studied by using linear, multivariate and logistic regression. Sensitization to Ascaris lumbricoides was associated with positive skin tests for aeroallergens, increased total serum IgE, increased eosinophils, reductions in FEV1 and FEV1/FVC ratio, increased airway Methacholine, bronchodilator responsiveness, and hospitalizations for asthma in the past year. Sensitization to Ascaris lumbricoides is associated with increased severity of asthma among Romanian children. This association is mediated by a high degree of atopy among the asthma children sensitized to Ascaris lumbricoides and belonging to a population with a low prevalence of helminthiasis.


Tuberous sclerosis complex: Hamartin and tuberin expression in renal cysts and its discordant expression in renal neoplasms.
Tuberous sclerosis complex (TSC) results from mutation of TSC1 or TSC2 that encode for hamartin and tuberin. It affects the kidneys often in advance of extra-renal stigmata. We studied 14 TSC cases, and 4 possible TSC cases with multiple angiomyolipomas (AMLs) for hamartin and tuberin protein expression to determine if the staining profile could predict mutation status or likelihood of TSC with renal-limited disease. The 18 cases included 15 nephrectomies and 1 section of 6 TSC-associated renal cell carcinomas (RCC). Controls included the non-neoplastic kidney in 5 tumor nephrectomies, 4 sporadic cases of AML and 6 clear cell RCCs. In the 14 TSC cases, 9 had AMLs, 9 had RCCs, 5 had polycystic kidney disease and 8 had eosinophilic cysts (EC) lined by large eosinophilic cells. The controls and study cases showed luminal staining of proximal tubules (PT) and peripheral membrane staining in distal tubules/collecting ducts for hamartin and cytoplasmic staining for tuberin. Eosinophilic cysts had a luminal PT-like stain with hamartin and a cytoplasmic reaction for tuberin. Hamartin stained myoid cells in all AMLs. Tuberin was negative in all but 1AML, an epithelioid AML. All but 1 RCC were positive for tuberin; 13 RCCs (7 TSC/6 non-TSC) were negative for hamartin and 4 showed a weak reaction. We conclude that the ECs of TSC are proximal tubule-derived. The hamartin and tuberin staining profiles of AMLs and most RCCs are reciprocal precluding prediction of the mutation in TSC, and fail to predict if a patient with multifocal AML has TSC.


[Development of the method of RNA labeling in vitro using the terminal transferase with the purpose to obtain hybridization probes].
A possibility to use terminal transferase to obtain hybridized RNA-probes has been investigated. Optimal conditions of the reaction proceeding were elaborated on the model objects--RNA of the phage MS2: 200 mM of potassium cacodylate, pH 7.2, 1 mM CoCl2, 1 mM DTT, under the considerable surplus of the enzyme. The elaborated method was used to determine the area of early genes of cyanophage LPP-3. With this purpose total RNA preparations were isolated from cyanobacterium Plectonema boryanum CALU 465. The above preparations were labeled by means of terminal transferase and [alpha-32P] ATP and used as the probes in hybridization with the DNA restriction fragments of LPP-3. Proceeding from the results of Southern-blots, a conclusion was made, that the KpnI-fragment of genome of cyanophage LPP3 10 kb in size includes the early genes. A possibility of practical use of the developed method is discussed.


Gay identity, interpersonal violence, and HIV risk behaviors: an empirical test of theoretical relationships among a probability-based sample of urban men who have sex with men.
The highest absolute number of new HIV infections and AIDS cases still occur among men who have sex with men (MSM). Numerous theoretical approaches have been used to understand HIV risk behaviors among MSM; however, no theoretical model examines sexual risk behaviors in the context of gay identity and interpersonal violence. Using a model testing predictive correlational design, the theoretical relationships between childhood sexual abuse, adverse early life experiences, gay identity, substance use, battering, aversive emotions, HIV alienation, cue-to-action triggers, and HIV risk behaviors were empirically tested using confirmatory factor analysis and structural equation modeling. The relationships between these constructs are complex, yet childhood sexual abuse and gay identity were found to be theoretically associated with HIV risk behaviors. Also of importance, battering victimization was identified as a key mediating variable between childhood sexual abuse, gay identity, and adverse early life experiences and HIV risk behaviors among urban MSM.


[Lamotrigine in the adult-onset epilepsy: efficacy and long-term safety].
LTG is a new antiepileptic drug that is nowadays very often used in epileptic patients. To determine efficacy and safety of Lamotrigine (LTG) in the first five years after its marketing in patients at a third level university hospital, as well as its impact on the management of classic antiepileptic drugs (AED). We reviewed retrospectively our Epilepsy Unit Database. One hundred patients were treated with LTG in a 5-year period. Efficacy was evaluated comparing seizure frequency in a 6-month period before and after LTG. The type of epilepsy, side effects, blood levels and concomitant treatments were considered in the analysis. LTG was effective in all groups of epileptic patients studied. Eighteen percent of patients became seizure-free. Seventeen percent of patients improved more than 50%. Fifty-seven percent of patients remained treated with LTG after four years of follow-up. Side effects were mild, but frequent; only four patients discontinued LTG because of adverse effects. Serum levels were usually high, but showed no relation with clinical efficacy. The mean number of AED taken per patient increased. LTG is a safe an effective drug in epilepsy. It has a clear impact in the management of the epileptic patients.


Automated Gas Chromatography Peak Alignment: A Deep Learning Approach using Greedy Optimization and Simulation.
The clinical significance of volatile organic compounds (VOC) in detecting diseases has been established over the past decades. Gas chromatography (GC) devices enable the measurement of these VOCs. Chromatographic peak alignment is one of the important yet challenging steps in analyzing chromatogram signals. Traditional semi-automated alignment algorithms require manual intervention by an operator which is slow, expensive and inconsistent. A pipeline is proposed to train a deep-learning model from artificial chromatograms simulated from a small, annotated dataset, and a postprocessing step based on greedy optimization to align the signals.Clinical Relevance- Breath VOCs have been shown to have a significant diagnostic power for various diseases including asthma, acute respiratory distress syndrome and COVID-19. Automatic analysis of chromatograms can lead to improvements in the diagnosis and management of such diseases.


Expression of yeast INM1 encoding inositol monophosphatase is regulated by inositol, carbon source and growth stage and is decreased by lithium and valproate.
Inositol monophosphatase plays a vital role in the de novo biosynthesis of inositol and in the phosphoinositide second messenger signalling pathway. We cloned the Saccharomyces cerevisiae open reading frame (ORF) YHR046c (termed INM1), which encodes inositol monophosphatase, characterized the protein Inm1p and analysed expression of the INM1 gene. INM1 was expressed in bacteria under the control of the lacZ promoter. The purified protein has inositol monophosphatase activity that is inhibited by the antibipolar drug lithium, but not valproate. In the inm1Delta:URA3 null mutant, inositol monophosphatase activity was reduced but not eliminated. The disruption had little effect on growth in the presence of lithium or valproate and no effect on growth in the absence of inositol. To characterize the regulation of INM1, we examined the effects of inositol, carbon source, growth phase, and the antibipolar drugs lithium and valproate on INM1 expression using an INM1-lacZ reporter gene. Unlike all other phospholipid biosynthetic enzyme-encoding genes studied, which contain the UASINO regulatory element, INM1 expression is increased in the presence of inositol. In addition, INM1 expression was repressed during growth in glycerol and derepressed as glucose-grown cells entered stationary. Both lithium and valproate, which cause a decrease in intracellular inositol, effect a decrease in INM1 expression. A model is presented to account for regulation of INM1 expression.


The transcription factor FoxB mediates temporal loss of cellular competence for notochord induction in ascidian embryos.
In embryos of the ascidian Halocynthia roretzi, the competence of isolated presumptive notochord blastomeres to respond to fibroblast growth factor (FGF) for induction of the primary notochord decays by 1 hour after cleavage from the 32- to 64-cell stage. This study analyzes the molecular mechanisms responsible for this loss of competence and provides evidence for a novel mechanism. A forkhead family transcription factor, FoxB, plays a role in competence decay by preventing the induction of notochord-specific Brachyury (Bra) gene expression by the FGF/MAPK signaling pathway. Unlike the mechanisms reported previously in other animals, no component in the FGF signal transduction cascade appeared to be lost or inactivated at the time of competence loss. Knockdown of FoxB functions allowed the isolated cells to retain their competence for a longer period, and to respond to FGF with expression of Bra beyond the stage at which competence was normally lost. FoxB acts as a transcription repressor by directly binding to the cis-regulatory element of the Bra gene. Our results suggest that FoxB prevents ectopic induction of the notochord fate within the cells that assume a default nerve cord fate, after the stage when notochord induction has been completed. The merit of this system is that embryos can use the same FGF signaling cascade again for another purpose in the same cell lineage at later stages by keeping the signaling cascade itself available. Temporally and spatially regulated FoxB expression in nerve cord cells was promoted by the ZicN transcription factor and absence of FGF/MAPK signaling.


Reducing costs while maintaining quality in endovascular neurosurgical procedures.
As medical costs continue to rise during a time of increasing medical resource utilization, both hospitals and physicians must attempt to limit superfluous health care expenses. Neurointerventional treatment has been shown to be costly, but it is often the best treatment available for certain neuropathologies. The authors studied the effects of 3 policy changes designed to limit the costs of performing neurointerventional procedures at the University of Michigan. The authors retrospectively analyzed the costs of performing neurointerventional procedures during the 6-month periods before and after the implementation of 3 cost-saving policies: 1) the use of an alternative, more economical contrast agent, 2) standardization of coil prices through negotiation with industry representatives to receive economies of scale, and 3) institution of a feedback method to show practitioners the costs of unused products per patient procedure. The costs during the 6-month time intervals before and after implementation were also compared with costs during the most recent 6-month time period. The policy requiring use of a more economical contrast agent led to a decrease in the cost of contrast usage of $42.79 per procedure for the first 6 months after implementation, and $137.09 per procedure for the most current 6-month period, resulting in an estimated total savings of $62,924.31 for the most recent 6-month period. The standardized coil pricing system led to savings of $159.21 per coil after the policy change, and $188.07 per coil in the most recent 6-month period. This yielded total estimated savings of $76,732.56 during the most recent 6-month period. The feedback system for unused items decreased the cost of wasted products by approximately $44.36 per procedure in the 6 months directly after the policy change and by $48.20 per procedure in the most recent 6-month period, leading to total estimated savings of $22,123.80 during the most recent 6-month period. According to extrapolation over a 1-year period, the 3 policy changes decreased costs by an estimated $323,561.34. Simple cost-saving policies can lead to substantial reductions in costs of neurointerventional procedures while maintaining high levels of quality and growth of services.


The rarity of cryptococcosis in Northern California: the 10-year experience of a large defined population.
The incidence of clinically manifest cryptococcosis was determined among over one million subscribers to the Kaiser-Permanente Medical Care Program in Northern California during the 10-year period 1971-1980. A total of 10 persons developed the disease, of whom two had no underlying immunosuppressive disease or therapy. The overall incidence was 0.8 per million persons per year; for nonimmunosuppressed individuals the incidence was estimated to be 0.2 per million per year. Incidence increased with age into the seventh decade of life and was greater in men than in women. The overall case fatality rate was 40 per cent. The data are not consistent with the view that cryptococcosis usually occurs in persons without obvious predisposing factors.


Bladder Leiomyoma.
Leiomyoma of the bladder is a very rare disorder that accounts for 0.43% of all bladder neoplasms. Although the pathophysiology of the bladder leiomyoma is unknown, there are some theories in it. The patients can be asymptomatic; and clinical symptoms, when present, are associated with the tumor size and location. Imaging techniques such as ultrasonography, intravenous urography, computed tomography, and magnetic resonance imaging are helpful but definitive diagnosis is made by histopathological examination. Surgical resection of tumor with transurethral, open, laparoscopic and robotic approaches is the main treatment. We present a case of leiomyoma of the bladder in an adult male patient.


Regulatory networks contributing to psoriasis susceptibility.
The non-involved, healthy-looking skin of psoriatic patients displays inherent characteristics that make it prone to develop typical psoriatic symptoms. Our primary aim was to identify genes and proteins that are differentially regulated in the non-involved psoriatic and the normal epidermis, and to discover regulatory networks responsible for these differences. A cDNA microarray experiment was performed to compare the gene expression profiles of 4 healthy and 4 psoriatic non-involved epidermis samples in response to T-cell lymphokine induction in organotypic cultures. We identified 61 annotated genes and another 11 expressed transcripts that were differentially regulated in the psoriatic tissues. Bioinformatics analysis suggested that the regulation of cell morphology, development and cell death is abnormal, and that the metabolism of small molecules and lipids is differentially regulated in psoriatic epidermis. Our results indicate that one of the early steps of psoriasis pathogenesis may be the abnormal regulation of IL-23A and IL-1B genes in psoriatic keratinocytes.


Scaling of geometric phase versus band structure in cluster-Ising models.
We study the phase diagram of a class of models in which a generalized cluster interaction can be quenched by an Ising exchange interaction and external magnetic field. The various phases are studied through winding numbers. They may be ordinary phases with local order parameters or exotic ones, known as symmetry protected topologically ordered phases. Quantum phase transitions with dynamical critical exponents z=1 or z=2 are found. In particular, the criticality is analyzed through finite-size scaling of the geometric phase accumulated when the spins of the lattice perform an adiabatic precession. With this study, we quantify the scaling behavior of the geometric phase in relation to the topology and low-energy properties of the band structure of the system.


Substitution of the D1-Asn87 site in photosystem II of cyanobacteria mimics the chloride-binding characteristics of spinach photosystem II.
Photoinduced water oxidation at the O2-evolving complex (OEC) of photosystem II (PSII) is a complex process involving a tetramanganese-calcium cluster that is surrounded by a hydrogen-bonded network of water molecules, chloride ions, and amino acid residues. Although the structure of the OEC has remained conserved over eons of evolution, significant differences in the chloride-binding characteristics exist between cyanobacteria and higher plants. An analysis of amino acid residues in and around the OEC has identified residue 87 in the D1 subunit as the only significant difference between PSII in cyanobacteria and higher plants. We substituted the D1-Asn87 residue in the cyanobacterium Synechocystis sp. PCC 6803 (wildtype) with alanine, present in higher plants, or with aspartic acid. We studied PSII core complexes purified from D1-N87A and D1-N87D variant strains to probe the function of the D1-Asn87 residue in the water-oxidation mechanism. EPR spectra of the S2 state and flash-induced FTIR spectra of both D1-N87A and D1-N87D PSII core complexes exhibited characteristics similar to those of wildtype Synechocystis PSII core complexes. However, flash-induced O2-evolution studies revealed a decreased cycling efficiency of the D1-N87D variant, whereas the cycling efficiency of the D1-N87A PSII variant was similar to that of wildtype PSII. Steady-state O2-evolution activity assays revealed that substitution of the D1 residue at position 87 with alanine perturbs the chloride-binding site in the proton-exit channel. These findings provide new insight into the role of the D1-Asn87 site in the water-oxidation mechanism and explain the difference in the chloride-binding properties of cyanobacterial and higher-plant PSII.


Androgen deprivation therapy for prostate cancer is associated with cardiovascular morbidity and mortality: a meta-analysis of population-based observational studies.
There is no consensus regarding whether androgen deprivation therapy (ADT) is associated with cardiovascular disease (CVD) and cardiovascular mortality (CVM). The objective of this study was to determine the role of ADT for prostate cancer (PCa) in development of cardiovascular events (CVD and CVM). We performed a meta-analysis from population-based observational studies comparing ADT vs control aimed at treating PCa in patients with PCa, reporting either CVD or CVM as outcome. Publications were searched using Medline, Embase, Cochrane Library Central Register of observational studies database up to May 31th 2014, and supplementary searches in publications from potentially relevant journals. 6 studies were identified with a total of 129,802 ADT users and 165,605 controls investigating the relationship between ADT and CVD. The incidence of CVD was 10% higher in ADT groups, although no significant association was observed (HR = 1.10, 95%CIs: 1.00-1.21; P = 0.06). For different types of ADT, CVD was related with gonadotropin-releasing hormone (GnRH) (HR = 1.19, 95%CIs: 1.04-1.36; P<0.001) and GnRH plus oral antiandrogen (AA) (HR = 1.46, 95%CIs: 1.03-2.08; P = 0.04), but not with AA alone or orchiectomy. For CVM, 119,625 ADT users and 150,974 controls from 6 eligible studies were included, pooled results suggested that ADT was associated with CVM (HR = 1.17, 95%CIs: 1.04-1.32; P = 0.01). Significantly increased CVM was also detected in GnRH and GnRH plus AA groups. When patients received other treatments (e.g. prostatectomy and radiotherapy) were ruled out of consideration, more increased CVD (HR = 1.19, 95%CIs: 1.08-1.30; P<0.001) and CVM (HR = 1.30, 95%CIs: 1.13-1.50; P<0.001) were found in men treated with ADT monotherapy. ADT is associated with both CVD and CVM. Particularly, GnRH alone and GnRH plus AA can significantly increase the incidence of cardiovascular events in patients with PCa.


The translational expression of ABCA2 and ABCA3 is a strong prognostic biomarker for multidrug resistance in pediatric acute lymphoblastic leukemia.
The aim of this work was to study the correlation between the expressions of the ABCA2 and ABCA3 genes at the mRNA and protein levels in children with acute lymphoblastic leukemia (ALL) and the effects of this association on multidrug resistance (MDR). Sixty-nine children with de novo ALL and 25 controls were enrolled in the study. Mononuclear cells were isolated from the bone marrow. The mRNA levels of ABCA2 and ABCA3 were measured by real-time polymerase chain reaction (PCR). Samples with high mRNA levels were assessed for respective protein levels by Western blotting. Following the first year of treatment, persistent monoclonality of T-cell gamma receptors or immunoglobulin H (IgH) gene rearrangement was assessed and considered as the MDR. The tertiary structure of ABCA2 was predicted using Phyre2 and I-TASSER web systems and compared to that of ABCA3, which has been previously reported. Molecular docking was performed using DOCK 6.7. Real-time quantitative PCR (qRT-PCR) showed high levels of ABCA2 and ABCA3 mRNAs in 13 and 17 samples, respectively. Among them, five and eight individuals demonstrated high levels of ABCA2 and ABCA3, respectively. Response to chemotherapy was significantly decreased (P=0.001) when the mRNA and protein of both genes were overexpressed compared to individuals with high transcriptional levels of either ABCA2 or ABCA3 alone. Close similarity between ABCA2 and ABCA3 structures was revealed by protein tertiary structure prediction, whereas molecular docking analysis suggested similar binding of chemotherapy drugs and therefore a potentially similar role in determining the MDR. Our findings suggested, for the first time, that quantification of the protein level of ABCA2 and ABCA3 transporters had a prognostic impact on pediatric ALL MDR. Furthermore, the tertiary structure of ABCA2 was predicted for the first time, and docking analysis revealed a possible compensatory effect between ABCA2 and ABCA3 transporters, which may contribute to the efflux of cytotoxic drugs and, ultimately, to chemoresistance.


Potential anti-aging agents suppress the level of constitutive mTOR- and DNA damage- signaling.
Two different mechanisms are considered to be the primary cause of aging. Cumulative DNA damage caused by reactive oxygen species (ROS), the by-products of oxidative phosphorylation, is one of these mechanisms (ROS concept). Constitutive stimulation of mitogen- and nutrient-sensing mTOR/S6 signaling is the second mechanism (TOR concept). The flow- and laser scanning- cytometric methods were developed to measure the level of the constitutive DNA damage/ROS- as well as of mTOR/S6- signaling in individual cells. Specifically, persistent activation of ATM and expression of γH2AX in untreated cells appears to report constitutive DNA damage induced by endogenous ROS. The level of phosphorylation of Ser235/236-ribosomal protein (RP), of Ser2448-mTOR and of Ser65-4EBP1, informs on constitutive signaling along the mTOR/S6 pathway. Potential gero-suppressive agents rapamycin, metformin, 2-deoxyglucose, berberine, resveratrol, vitamin D3 and aspirin, all decreased the level of constitutive DNA damage signaling as seen by the reduced expression of γH2AX in proliferating A549, TK6, WI-38 cells and in mitogenically stimulated human lymphocytes. They all also decreased the level of intracellular ROS and mitochondrial trans-membrane potential ΔΨm, the marker of mitochondrial energizing as well as reduced phosphorylation of mTOR, RP-S6 and 4EBP1. The most effective was rapamycin. Although the primary target of each on these agents may be different the data are consistent with the downstream mechanism in which the decline in mTOR/S6K signaling and translation rate is coupled with a decrease in oxidative phosphorylation, (revealed by ΔΨm) that leads to reduction of ROS and oxidative DNA damage. The decreased rate of translation induced by these agents may slow down cells hypertrophy and alleviate other features of cell aging/senescence. Reduction of oxidative DNA damage may lower predisposition to neoplastic transformation which otherwise may result from errors in repair of DNA sites coding for oncogenes or tumor suppressor genes. The data suggest that combined assessment of constitutive γH2AX expression, mitochondrial activity (ROS, ΔΨm) and mTOR signaling provides an adequate gamut of cell responses to evaluate effectiveness of gero-suppressive agents.