Solvent dehydrated costal cartilage: evaluation in a rabbit model.
An experimental study has been performed on 30 New Zealand rabbits to compare autogenous cartilage harvested from the rabbits' auricles, bone graft harvested from the iliac crest of the rabbits, and the commercially available solvent dehydrated human costal cartilage (SDHCC) grafts, each measuring 1 x 1 cm. The grafts are divided into two groups, one group of grafts are inserted into pouches on the cranial bones subperiosteally and the other subfascially on the back of the animals. The grafts are evaluated on the 4th and the 12th weeks. No problems, such as dehiscence, hematoma, infection, erythema, flap necrosis, or graft exposition, occurred during the postoperative follow-up. SDHCC grafts are well tolerated and preserved by the host. They are infiltrated by the fibrous connective tissue and are firmly fixed to the surrounding structures. By the end of 12th week, the thickness of SDHCC grafts were not significantly different, compared with autogenous cartilage grafts, but both were thicker than the autogenous bone grafts. Viable chondrocytes and active cartilage development on SDHCC grafts were seen by the 4th week and chondrogenetic and osteogenetic activity on the 12th demonstrate the feasibility of clinical use of SDHCC grafts for soft and bony defects.


Predictors of osteoclast activity in patients with sickle cell disease.
Bone changes are common in sickle cell disease, but the pathogenesis is not fully understood. Tartrate-resistant acid phosphatase (TRACP) type 5b is produced by bone-resorbing osteoclasts. In other forms of hemolytic anemia, increased iron stores are associated with osteoporosis. We hypothesized that transfusional iron overload would be associated with increased osteoclast activity in patients with sickle cell disease. We examined tartrate-resistant acid phosphatase 5b concentrations in patients with sickle cell disease and normal controls of similar age and sex distribution at steady state. Serum tartrate-resistant acid phosphatase 5b concentration was measured using an immunocapture enzyme assay and plasma concentrations of other cytokines were assayed using the Bio-Plex suspension array system. Tricuspid regurgitation velocity, an indirect measure of systolic pulmonary artery pressure, was determined by echocardiography. Tartrate-resistant acid phosphatase 5b concentrations were higher in 58 adults with sickle cell disease than in 22 controls (medians of 4.4 versus 2.4 U/L, respectively; P=0.0001). Among the patients with sickle cell disease, tartrate-resistant acid phosphatase 5b independently correlated with blood urea nitrogen (standardized beta=0.40, P=0.003), interleukin-8 (standardized beta=0.30, P=0.020), and chemokine C-C motif ligand 5 (standardized beta=-0.28, P=0.031) concentrations, but not with serum ferritin concentration. Frequent blood transfusions (>10 units in life time) were not associated with higher tartrate-resistant acid phosphatase 5b levels in multivariate analysis. There were strong correlations among tartrate-resistant acid phosphatase 5b, alkaline phosphatase and tricuspid regurgitation velocity (r>0.35, P<0.001). Patients with sickle cell disease have increased osteoclast activity as reflected by serum tartrate-resistant acid phosphatase 5b concentrations. Our results may support a potential role of inflammation rather than increased iron stores in stimulating osteoclast activity in sickle cell disease. The positive relationships among tartrate-resistant acid phosphatase 5b, alkaline phosphatase and tricuspid regurgitation velocity raise the possibility of a common pathway in the pulmonary and bone complications of sickle cell disease.


New treatment for hepatitis C in chronic kidney disease, dialysis, and transplant.
The evidence that chronic hepatitis C plays a detrimental role in survival among patients on maintenance dialysis or renal transplant recipients promotes the antiviral treatment of hepatitis C virus (HCV) among chronic kidney disease patients. Also, it seems that HCV infection is associated with an increased risk of developing chronic kidney disease in the adult general population. Interferon-based regimens have provided limited efficacy and safety among chronic kidney disease patients, whereas the advent of the new direct-acting antivirals for the treatment of hepatitis C (launched over the past 5 years) has given the opportunity to reach sustained virologic response rates of 90% for many patient groups. Unfortunately, poor information exists regarding the antiviral treatment of hepatitis C in the chronic kidney disease population. The first published data on the treatment of hepatitis C among patients with chronic kidney disease (stage 4-5) and HCV genotype 1 regard the grazoprevir (NS3/4A protease inhibitor) and elbasvir (NS5A inhibitor) combination; excellent efficacy (sustained viral response, 94.3%; 115/122) and safety have been achieved. Preliminary evidence on the combined treatment of sofosbuvir (NS5B inhibitor) and simeprevir (NS3/4A inhibitor) has given a viral response of 89%, but the size of the study group (n = 38 patients with end-stage renal disease) was small. Some phase 2 and 3 clinical trials based on other antiviral combinations (3D regimen, sofosbuvir/ledipasvir, or other sofosbuvir-containing approaches) are ongoing. Thus, the antiviral regimens based on direct-acting antivirals promise to play a pivotal role in the eradication of hepatitis C among kidney disease patients. Direct-acting antivirals are very expensive; in an era of cost containment this is a crucial point either in developed and developing countries. Adverse drug reactions resulting from concomitantly administered medications are another ongoing concern for patients undergoing HCV treatment, particularly for chronic kidney disease patients who have a heavy burden of comorbidities.


An ethnobotanical survey on hormozgan province, Iran.
The present study is based on an ethnobotanical research project conducted in Hormozgan province that is located in south of Iran, bordering waters of the Persian Gulf and Oman Sea. This survey was carried out in order to recover the ethnobotanical and ethnomedicinal knowledge of the residents of this province. They are using medicinal and functional plants for treating or preventing several diseases. Ethnobotanical data sheets were run with the native inhabitants and people of the province by arranging frequent field trips to different parts of the province and direct interviews with them especially those who were more familiar with the plants and their usage. A total of 150 plant species belonging to 53 families were recorded for their ethnobotanical and ethnomedicinal uses among the people of province. The records were developed by scientific names, family names, local names, medicinal parts used, different ways of their application, and traditional uses of the plants. There was high compliance in the use of plants in painful disorders, gastrointestinal, and dermatological diseases. This study revealed that the people of Hormozgan province have a rich knowledge of natural resources. The use and consumption of medicinal plants are still important parts of their life. Rational use of native medicinal plants may benefit and improve their living standards and quality of life. The results of this study can be used as a basis for selecting herbs for further pharmacological, phytochemical, and pharmacognostical studies.


Lack of effect of salt intake on urinary uric acid excretion.
Although it has been established that acute expansion of the extracellular fluid volume results in enhanced uric acid clearance, the effect of chronic volume expansion by a high salt diet on urinary uric acid excretion has not been examined. Eleven normal subjects were placed on a constant diet containing 10 mEq. sodium per day for 10 days, followed by 240 mEq. sodium daily for another 10 days. Measurements were performed on the final 3 days of each phase. Urinary sodium increased from 9 plus or minus 3 standard error to 221 plus or minus 9 mEq. per day (p less than 0.001), and uric acid clearance increased from 5.9 plus or minus 0.4 to 7.1 plus or minus 0.6 ml. per minute (p less than 0.01). However, serum uric acid decreased from 6.4 plus or minus 0.4 to 5.5 plus or minus 0.3 mg./dl. (p less than 0.001). Total urinary excretion of uric acid did not change (533 plus or minus 24 to 535 plus or minus 26 mg. per day). A high salt diet does not result in sustained hyperuricosuria, although it may predispose to kidney stone formation in other ways.


Measuring multiple minority stress: the LGBT People of Color Microaggressions Scale.
Lesbian, gay, and bisexual individuals who are also racial/ethnic minorities (LGBT-POC) are a multiply marginalized population subject to microaggressions associated with both racism and heterosexism. To date, research on this population has been hampered by the lack of a measurement tool to assess the unique experiences associated with the intersection of these oppressions. To address this gap in the literature, we conducted a three-phase, mixed method empirical study to assess microaggressions among LGBT-POC. The LGBT People of Color Microaggressions Scale is an 18-item self-report scale assessing the unique types of microaggressions experienced by ethnic minority LGBT adults. The measure includes three subscales: (a) Racism in LGBT communities, (b) Heterosexism in Racial/Ethnic Minority Communities, and (c) Racism in Dating and Close Relationships, that are theoretically consistent with prior literature on racial/ethnic minority LGBTs and have strong psychometric properties including internal consistency and construct validity in terms of correlations with measures of psychological distress and LGBT-identity variables. Men scored higher on the LGBT-PCMS than women, lesbians and gay men scored higher than bisexual women and men, and Asian Americans scored higher than African Americans and Latina/os.


Performances of hill-type and neural network muscle models-toward a myosignal-based exoskeleton.
Muscle models are the essential components of any musculoskeletal simulation. In addition, muscle models which are incorporated in neural-based prosthetic and orthotic devices may significantly improve their performance. The aim of the study was to compare the performances of two types of muscle models in terms of predicting the moments developed at the human elbow joint complex based on joint kinematics and neuromuscular activity. The performance evaluation of the muscle models was required to implement them in a powered myosignal-driven exoskeleton (orthotic device). The experimental setup included a passive exoskeleton capable of measuring the joint kinematics and dynamics in addition to the muscle myosignal activity (EMG). Two types of models were developed and analyzed: (i) a Hill-based model and (ii) a neural network. The task, which was selected for evaluating the muscle models performance, was the flexion-extension movement of the forearm with a hand-held weight. For this task the muscle model inputs were the normalized neural activation levels of the four main flexor-extensor muscles of the elbow joint, and the elbow joint angle and angular velocity. Using this inputs, the muscle model predicted the moment applied on the elbow joint during the movement. Results indicated a good performance of the Hill model, although the neural network predictions appeared to be superior. Relative advantages and shortcomings of both approaches were presented and discussed.


Reducing random variation in reported rates of pressure ulcer development.
The authors evaluated methods of reporting on rates of pressure ulcer development in long-term care to identify approaches that lead to more stable estimates of actual performance. Performance measures for facilities that adequately adjust for both random variation and casemix should be relatively stable from one time period to the next. The authors calculated facility rates of pressure ulcer development over eight consecutive time periods and correlated measures over time using different reporting methods including z-scores, combining rates from several time periods, and limiting analyses to large facilities. Results were compared with a Monte Carlo simulation. Observed facility rates of pressure ulcer development varied considerably over time. The average correlation coefficient across seven time comparisons for observed rates was 0.17. Reporting performance as a z-score or limiting the analyses to large facilities increased the correlation. Combining two time periods was effective only when used with one of these other approaches. The correlation coefficient based on a simulation using only large facilities was 0.51. Random variation affects reported rates of pressure ulcer development. Using only large facilities and combining two time periods limits the effects of random variation and results in more stable estimates of performance. When describing performance, management must consider tradeoffs between having more accurate data, the frequency with which data are provided, and whether it is given to all providers.


Sexual maturation and fertility of mice exposed to triphenyltin during prepubertal and pubertal periods.
This study investigated the effects of pre- and peripubertal exposure (PND 15-45) to triphenyltin hydroxide (TPT: 0, 1.875, 3.75, 7.5 and 15 mg/kg bw/d po) on mouse sexual maturation and fertility. Half of the mice were euthanized on PND 46 and the remaining mice were submitted to fertility tests on PND 65-75. TPT caused a transient decrease of weight gain at 3.75 mg/kg bw/d, and deaths and body weight deficits at higher doses. Delays of testes descent (TD), vaginal opening (VO) and first estrus (FE) occurred at doses ≥3.75 (TD) and ≥7.5 mg/kg bw/d (VO, FE), respectively. Body weight on the days of TD, VO and FE did not differ among groups. TPT at doses ≥3.75 mg/kg decreased sperm and spermatid counts at the end of treatment (PND 46) but no alteration was noted later on PND 75. Testicular histopathology (PND 46) showed a dose-dependent reduction of seminiferous tubules diameter, a greater degree of vacuolation in Sertoli cells and germ cell degeneration and necrosis in TPT-treated mice. TPT did not affect the outcome of fertility tests. Study-derived NOAEL was 1.875 mg TPT/kg bw/d for males and 3.75 mg TPT/kg bw/d for females. The detrimental effects of TPT on spermatogenesis were reversed after treatment discontinuation.


Functional analysis of the U5 snRNA loop 1 in the second catalytic step of yeast pre-mRNA splicing.
The U5 snRNA loop 1 interacts with the 5' exon before the first step of pre-mRNA splicing and with the 5' and 3' exons following the first step. These U5-exon interactions are proposed to hold the exons in the correct orientation for the second step of splicing. Reconstitution of U5 snRNPs in vitro indicated that U5 loop 1-5' exon interactions are not necessary for the first catalytic step of splicing but are critical for the second step in yeast spliceosomes. We systematically made deletion and insertion mutations in loop 1 then monitored splicing activity and loop-exon interactions by cross-linking. Single nucleotide deletions or insertions in loop 1 permitted both steps of splicing. Larger insertions or deletions allowed the first step but progressively inhibited the second step. Analysis of selected loop 1 insertions and deletions by cross-linking revealed that inhibition of the second catalytic step resulted from misalignment of the 5' and 3' exons. These data indicate that the size of loop 1 is critical for proper alignment of the exons for the second catalytic step of splicing and that the 3' exon is positioned on loop 1 independently of the 5' exon.


Streptococcus mitis. A cause of serious infection in adults.
Twenty strains of Streptococcus mitis were isolated from blood or body fluids at the Cleveland Veterans Administration Medical Center from Jan 1, 1981, to April 30, 1984. Fifteen (75%) isolates were considered contaminants. Five (25%) were clinically important and associated with a serious infection of the oropharynx or gastrointestinal tract (three of five), endovascular system (one of five), or a prosthetic hip. Four of five patients required surgical intervention for treatment. Two of five died; one death was directly attributable to S mitis infection. Eighteen strains were available for detailed bacteriologic study. Three strains had a minimum inhibitory concentration of greater than 0.1 micrograms/mL of penicillin and six other strains were tolerant to penicillin. This review suggests that S mitis can be an important pathogen in adults and may cause infections other than endocarditis.


Intermittent supplementation with fisetin improves arterial function in old mice by decreasing cellular senescence.
Cellular senescence and the senescence-associated secretory phenotype (SASP) contribute to age-related arterial dysfunction, in part, by promoting oxidative stress and inflammation, which reduce the bioavailability of the vasodilatory molecule nitric oxide (NO). In the present study, we assessed the efficacy of fisetin, a natural compound, as a senolytic to reduce vascular cell senescence and SASP factors and improve arterial function in old mice. We found that fisetin decreased cellular senescence in human endothelial cell culture. In old mice, vascular cell senescence and SASP-related inflammation were lower 1 week after the final dose of oral intermittent (1 week on-2 weeks off-1 weeks on dosing) fisetin supplementation. Old fisetin-supplemented mice had higher endothelial function. Leveraging old p16-3MR mice, a transgenic model allowing genetic clearance of p16INK4A -positive senescent cells, we found that ex vivo removal of senescent cells from arteries isolated from vehicle- but not fisetin-treated mice increased endothelium-dependent dilation, demonstrating that fisetin improved endothelial function through senolysis. Enhanced endothelial function with fisetin was mediated by increased NO bioavailability and reduced cellular- and mitochondrial-related oxidative stress. Arterial stiffness was lower in fisetin-treated mice. Ex vivo genetic senolysis in aorta rings from p16-3MR mice did not further reduce mechanical wall stiffness in fisetin-treated mice, demonstrating lower arterial stiffness after fisetin was due to senolysis. Lower arterial stiffness with fisetin was accompanied by favorable arterial wall remodeling. The findings from this study identify fisetin as promising therapy for clinical translation to target excess cell senescence to treat age-related arterial dysfunction.


Viscoelastic-Sorting Integrated Deformability Cytometer for High-Throughput Sorting and High-Precision Mechanical Phenotyping of Tumor Cells.
The counts and phenotypes of circulating tumor cells (CTCs) in whole blood are useful for disease monitoring and prognostic assessment of cancer. However, phenotyping CTCs in the blood is difficult due to the presence of a large number of background blood cells, especially some blood cells with features similar to those of tumor cells. Herein, we presented a viscoelastic-sorting integrated deformability cytometer (VSDC) for high-throughput label-free sorting and high-precision mechanical phenotyping of tumor cells. A sorting chip for removing large background blood cells and a detection chip for detecting multiple cellular mechanical properties were integrated into our VSDC. Our VSDC has a sorting efficiency and a purity of over 95% and over 81% for tumor cells, respectively. Furthermore, multiple mechanical parameters were used to distinguish tumor cells from white blood cells using machine learning. An accuracy of over 97% for identifying tumor cells was successfully achieved with the highest identification accuracy of 99.4% for MCF-7 cells. It is envisioned that our VSDC will open up new avenues for high-throughput and label-free single-cell analysis in various biomedical applications.


Sustained Attentional States Require Distinct Temporal Involvement of the Dorsal and Ventral Medial Prefrontal Cortex.
Attending the sensory environment for cue detection is a cognitive operation that occurs on a time scale of seconds. The dorsal and ventral medial prefrontal cortex (mPFC) contribute to separate aspects of attentional processing. Pyramidal neurons in different parts of the mPFC are active during cognitive behavior, yet whether this activity is causally underlying attentional processing is not known. We aimed to determine the precise temporal requirements for activation of the mPFC subregions during the seconds prior to cue detection. To test this, we used optogenetic silencing of dorsal or ventral mPFC pyramidal neurons at defined time windows during a sustained attentional state. We find that the requirement of ventral mPFC pyramidal neuron activity is strictly time-locked to stimulus detection. Inhibiting the ventral mPFC 2 s before or during cue presentation reduces response accuracy and hampers behavioral inhibition. The requirement for dorsal mPFC activity on the other hand is temporally more loosely related to a preparatory attentional state, and short lapses in pyramidal neuron activity in dorsal mPFC do not affect performance. This only occurs when the dorsal mPFC is inhibited during the entire preparatory period. Together, our results reveal that a dissociable temporal recruitment of ventral and dorsal mPFC is required during attentional processing.


Digital pathology and artificial intelligence in non-alcoholic steatohepatitis: current status and future directions.
Non-alcoholic steatohepatitis (NASH) prevalence is increasing worldwide, causing a significant medical burden, but no approved therapeutics are currently available. NASH drug development requires histological analysis of liver biopsies by expert pathologists for trial enrollment and efficacy assessment, which can be hindered by multiple issues including sample heterogeneity, inter-reader and intra-reader variability, and ordinal scoring systems. Consequently, there is a high unmet need for accurate, reproducible, quantitative, and automated methods to assist pathologists with histological analysis to improve the precision around treatment and efficacy assessment. Digital pathology (DP) workflows in combination with artificial intelligence (AI) have been established in other areas of medicine and are being actively investigated in NASH to assist pathologists in the evaluation and scoring of NASH histology. DP/AI models can be used to automatically detect, localize, quantify, and score histological parameters and have the potential to reduce the impact of scoring variability in NASH clinical trials. This narrative review provides an overview of DP/AI tools in development for NASH, highlights key regulatory considerations, and discusses how these advances may impact the future of NASH clinical management and drug development. This should be a high priority in the NASH field, particularly to improve the development of safe and effective therapeutics.


The role of vascular smooth muscle cell integrins in the compaction and mechanical strengthening of a tissue-engineered blood vessel.
Vascular smooth muscle cells (VSMC) influence vessel structure and function during normal development, and in disease states. VSMC interactions with extracellular matrix, via cell surface integrins, play an important role in these processes. A greater understanding of the molecular basis of these interactions is also critical to advances in the field of cardiovascular tissue engineering. This study examined the role of VSMC integrins in the spontaneous compaction and eventual strengthening of a rudimentary tissue-engineered blood vessel (TEBV) consisting of a fibrillar type I collagen network populated by human aortic smooth muscle cells. Using integrin subunit-specific antibodies, we demonstrated that anti-beta1 (Mab13 and P4C10) and anti-alpha2 (P1E6) antibodies that inhibit aortic smooth muscle cell (AoSMC) adhesion to collagen, also significantly inhibit TEBV compaction during the 24-hour period following TEBV construction. However, no difference in the tensile stress of antibody-treated and control TEBVs was observed at this time point. In contrast, 72 hours after construction, the inhibitory effect of anti-integrin antibodies on compaction had been overcome but tensile stress was decreased in TEBVs treated with anti-alpha2/anti-beta1 antibodies when compared to controls. These data provide evidence linking VSMC integrins, specifically the alpha2beta1 integrin, with the initial compaction, as well as, the postcompaction strengthening of the TEBV.


[Rare tumours: a new heading in Bulletin du cancer].
Rare cancers are defined by an incidence less than 5/100,000, which means in France less than 3,000 new cases a year. They are difficult to diagnose, their physiopathology has led to new knowledge in cancer medicine. There is no large experience for their management, and they are not generally the subject of randomized trials to establish treatment strategy. Therefore they are often managed by suboptimal cares. Even individually rare cancers do not concern large populations, the number of patients suffering of rare cancer is important. This is the reason why the "Bulletin du cancer" will open a new section on rare cancers. This article aims to draw the context of such a decision, based on an effort to allow these patients to receive optimal management.


Characterization and expression analysis of seven lipid metabolism-related genes in yellow catfish Pelteobagrus fulvidraco fed high fat and bile acid diet.
SREBPs, such as SREBP1 and SREBP2, were the key transcriptional factors regulating lipid metabolism. The processing of SREBPs involved many genes, such as scap, s1p, s2p, cideb. Here, we deciphered the full-length cDNA sequences of scap, srebp1, srebp2, s1p, s2p, cideb and cidec from yellow catfish Pelteobagrus fulvidraco. Their full-length cDNA sequences ranged from 1587 to 3884 bp, and their ORF length from 1191 to 2979 bp, encoding 396-992 amino acids. Some conservative domains were predicted, including the multiple transmembrane domains in SCAP, the bHLH-ZIP domain in SREBP1 and SREBP2, the ApoB binding region, ER targeting region and LD targeting region in CIDEb, the LD targeting region in the CIDEc, the conserved catalytic site and processing site in S1P, and the transmembrane helix domain in S2P. Their mRNA expression could be observed in the heart, spleen, liver, kidney, brain, muscle, intestine and adipose, but varied with tissues. The changes of their mRNA expression in responses to high-fat (HFD) and bile acid (BA) diets were also investigated in the brain, heart, intestine, kidney and spleen tissues. In the brain, HFD significantly increased the mRNA expression of seven genes (scap, srebp1, srebp2, s1p, s2p, cideb and cidec), and the BA attenuated the increase of scap, srebp1, srebp2, s1p, s2p, cideb and cidec mRNA expression induced by HFD. In the heart, HFD significantly increased the mRNA abundances of six genes (srebp1, srebp2, scap, s2p, cideb and cidec), and BA attenuated the increase of their mRNA abundances induced by HFD. In the intestine, HFD increased the cideb, s1p and s2p mRNA abundances, and BA attenuated the HFD-induced increment of their mRNA abundances. In the kidney, HFD significantly increased the scap, cidec and s1p mRNA expression, and BA diet attenuated the increment of their mRNA expression. In the spleen, HFD treatment increased the scap, srebp2, s1p and s2p mRNA expression, and BA diet attenuated HFD-induced increment of their mRNA expression. Taken together, our study elucidated the characterization, expression profiles and transcriptional response of seven lipid metabolic genes, which would serve as the good basis for the further exploration into their function and regulatory mechanism in fish.


Optimal determination of particle orientation, absolute hand, and contrast loss in single-particle electron cryomicroscopy.
A computational procedure is described for assigning the absolute hand of the structure of a protein or assembly determined by single-particle electron microscopy. The procedure requires a pair of micrographs of the same particle field recorded at two tilt angles of a single tilt-axis specimen holder together with the three-dimensional map whose hand is being determined. For orientations determined from particles on one micrograph using the map, the agreement (average phase residual) between particle images on the second micrograph and map projections is determined for all possible choices of tilt angle and axis. Whether the agreement is better at the known tilt angle and axis of the microscope or its inverse indicates whether the map is of correct or incorrect hand. An increased discrimination of correct from incorrect hand (free hand difference), as well as accurate identification of the known values for the tilt angle and axis, can be used as targets for rapidly optimizing the search or refinement procedures used to determine particle orientations. Optimized refinement reduces the tendency for the model to match noise in a single image, thus improving the accuracy of the orientation determination and therefore the quality of the resulting map. The hand determination and refinement optimization procedure is applied to image pairs of the dihydrolipoyl acetyltransferase (E2) catalytic core of the pyruvate dehydrogenase complex from Bacillus stearothermophilus taken by low-dose electron cryomicroscopy. Structure factor amplitudes of a three-dimensional map of the E2 catalytic core obtained by averaging untilted images of 3667 icosahedral particles are compared to a scattering reference using a Guinier plot. A noise-dependent structure factor weight is derived and used in conjunction with a temperature factor (B=-1000A(2)) to restore high-resolution contrast without amplifying noise and to visualize molecular features to 8.7A resolution, according to a new objective criterion for resolution assessment proposed here.


Fertility preservation for genetic diseases leading to premature ovarian insufficiency (POI).
The current review aims to summarize the data available concerning the applicability of fertility preservation techniques to genetic conditions at risk of premature ovarian insufficiency (POI). A literature review through the PubMed Database was carried out. About 10% of cases of POI is related to genetic diseases. The most frequent conditions associated with POI are Turner syndrome and fragile X pre-mutation; mutation of BRCA 1-2 genes and several other mutations and genetic syndromes have recently been highlighted, although they rarely occur. If a diagnosis is issued before POI onset, counseling on currently available fertility preservation techniques is advisable. In case of spontaneous menarche (this can occur variably depending on the mutation) established techniques like embryo or oocyte cryopreservation can be proposed, even if, in some cases, their effectiveness may be reduced by ovarian alterations connected to the mutation. Ovarian tissue cryopreservation has recently been defined as an established medical procedure for fertility preservation in young cancer patients and may be an option for prepubertal patients. However, it is still experimental in special populations with genetic diseases causing POI. New innovative experimental techniques, like in vitro maturation of immature oocytes (IVM) and vitro activation (IVA) of immature follicles on ovarian tissue, have shown limited but encouraging data and they will be probably available in the near future. For a correct risk-benefit evaluation, the following aspects should be considered: actual knowledge about the pathology-specific efficacy of the various techniques, the average age of onset of POI, the possible risks associated with the procedure in relation to the underlying pathology, the probability of spontaneous conception, as well as the health implications of a possible future pregnancy.. Fertility preservation techniques represent a crucial opportunity for patients with genetic risk of POI. Early diagnosis increases the chances to apply these techniques. No specific recommendations concerning fertility preservation for each genetic pathology are available, and clinicians should first counsel the patient and her relatives about known risks and benefits of the available techniques, both those established and those considered as experimental.


Analysis of the dbpBA upstream regulatory region controlled by RpoS in Borrelia burgdorferi.
Decorin-binding proteins B and A (DbpB and DbpA) are thought to play important roles in Borrelia burgdorferi pathogenesis by serving as adhesins for the extracellular matrix. It has been established that the expression of DbpBA is governed by the Rrp2-RpoN-RpoS regulatory pathway. However, the precise mechanism underlying the control of DbpBA expression has been unclear. In particular, it has been unknown whether RpoS influences DbpBA expression directly or indirectly (through an additional regulatory molecule[s]). Here, employing a wild-type B. burgdorferi strain and a dbpBA-deficient mutant, we analyzed the 5' genetic elements of the dbpBA operon using deletion analysis, coupled with luciferase reporter assays, quantitative reverse transcription PCR, and immunoblot analyses. A minimal promoter, encompassed within 70 bp upstream of the ATG start codon of dbpBA, was identified and found to be necessary and sufficient to initiate dbpBA transcription. The minimal dbpBA promoter was responsive to environmental stimuli such as temperature, pH, and whole blood. Two in silico-identified inverted repeat elements were not involved in the response of dbpBA expression to in vitro stimulation by environmental factors. The expression of dbpBA from the minimal promoter was abolished when rpoS was inactivated. In addition, the targeted mutagenesis of a C at position -14 within the extended -10 region of dbpBA, which has been postulated to be strategic for Esigma(S) binding in Escherichia coli, abolished dbpBA expression in B. burgdorferi. These combined data suggest that the Rrp2-RpoN-RpoS pathway controls dbpBA expression by the direct binding of RpoS to an RpoS-dependent promoter. However, given that there remains a distinct difference between the expression of DbpBA and other genes under the direct control of RpoS (e.g., OspC), our findings do not preclude the existence of another layer of gene regulation that may contribute to the modulation of DbpBA expression via an as-yet unknown mechanism.


A good daddy.
This personal narrative presents the imagined inner dialogue of my father, when caring for me as a young sickly child. It is a compassionate exercise in attempting to understand the remote inner emotional world of my father, a Holocaust survivor, as he contended with my ongoing medical challenges that perhaps triggered his traumatic memories from the war. I am the daughter who eventually grew up to be a physician herself. (PsycINFO Database Record


Effects of 6 Single-File Systems on Dentinal Crack Formation.
The purpose of this study was to compare the formation of microcracks after canal preparation performed with different single-file systems as One Shape (Micro-Mega, Besancon, Cedex, France), F6 SkyTaper (Komet Italia Srl, Milan, Italy), HyFlex EDM (Coltene/Whaledent AG, Altstatten, Switzerland), WaveOne (Dentsply Maillefer, Ballaigues, Switzerland), Reciproc (VDW, Munich, Germany), and WaveOne Gold (Dentsply Maillefer). Eighty-four human extracted mandibular central incisors (40-60 y) were selected and divided into 6 experimental groups (n = 12 teeth) and a control group (unprepared teeth): One Shape (group 1), F6 SkyTaper (group 2), HyFlex EDM (group 3), WaveOne (group 4), Reciproc (group 5), and WaveOne Gold (group 6). Roots were then sectioned at 3, 6, and 9 mm from the apex, and the surface was observed under a stereomicroscope. Data were analyzed using logistic regression (P < .05). No cracks were observed in the control group. All the systems tested caused cracks, mainly in the apical section (3 mm). HyFlex EDM (33.3%) and WaveOne Gold (58.3%) showed fewer microcracks than other experimental groups (P < .01); however, no significant difference was found between them in crack formation (P > .05). There was no difference among the other experimental groups (P > .05). All the instruments tested created dentinal cracks. Within the limitations of this study, the flexibility of nickel-titanium instruments because of heat treatment seems to have a significant influence on dentinal crack formation. HyFlex EDM and WaveOne Gold caused less microcracks than the other instruments tested.


Gait instability and estimated core temperature predict exertional heat stroke.
Exertional heat stroke (EHS), characterised by a high core body temperature (Tcr) and central nervous system (CNS) dysfunction, is a concern for athletes, workers and military personnel who must train and perform in hot environments. The objective of this study was to determine whether algorithms that estimate Tcr from heart rate and gait instability from a trunk-worn sensor system can forward predict EHS onset. Heart rate and three-axis accelerometry data were collected from chest-worn sensors from 1806 US military personnel participating in timed 4/5-mile runs, and loaded marches of 7 and 12 miles; in total, 3422 high EHS-risk training datasets were available for analysis. Six soldiers were diagnosed with heat stroke and all had rectal temperatures of >41°C when first measured and were exhibiting CNS dysfunction. Estimated core temperature (ECTemp) was computed from sequential measures of heart rate. Gait instability was computed from three-axis accelerometry using features of pattern dispersion and autocorrelation. The six soldiers who experienced heat stroke were among the hottest compared with the other soldiers in the respective training events with ECTemps ranging from 39.2°C to 40.8°C. Combining ECTemp and gait instability measures successfully identified all six EHS casualties at least 3.5 min in advance of collapse while falsely identifying 6.1% (209 total false positives) examples where exertional heat illness symptoms were neither observed nor reported. No false-negative cases were noted. The combination of two algorithms that estimate Tcr and ataxic gate appears promising for real-time alerting of impending EHS.


Aβ promotes VDAC1 channel dephosphorylation in neuronal lipid rafts. Relevance to the mechanisms of neurotoxicity in Alzheimer's disease.
Voltage-dependent anion channel (VDAC) is a mitochondrial protein abundantly found in neuronal lipid rafts. In these membrane domains, VDAC is associated with a complex of signaling proteins that trigger neuroprotective responses. Loss of lipid raft integrity may result in disruption of multicomplex association and alteration of signaling responses that may ultimately promote VDAC activation. Some data have demonstrated that VDAC at the neuronal membrane may be involved in the mechanisms of amyloid beta (Aβ)-induced neurotoxicity, through yet unknown mechanisms. Aβ is generated from amyloid precursor protein (APP), and is released to the extracellular space where it may undergo self-aggregation. Aβ aggregate deposition in the form of senile plaques may lead to Alzheimer's disease (AD) neuropathology, although other pathological hallmarks (such as hyper-phosphorylated Tau deposition) also participate in this neurodegenerative process. The present study demonstrates that VDAC1 associates with APP and Aβ in lipid rafts of neurons. Interaction of VDAC1 with APP was observed in lipid rafts from the frontal and entorhinal cortex of human brains affected by AD at early stages (I-IV/0-B of Braak and Braak). Furthermore, Aβ exposure enhanced the dephosphorylation of VDAC1 that correlated with cell death. Both effects were reverted in the presence of tyrosine phosphatase inhibitors. VDAC1 dephosphorylation was corroborated in lipid rafts of AD brains. These results demonstrate that Aβ is involved in alterations of the phosphorylation state of VDAC in neuronal lipid rafts. Modulation of this channel may contribute to the development and progression of AD pathology.


NeuroLOG: a community-driven middleware design.
The NeuroLOG project designs an ambitious neurosciences middleware, gaining from many existing components and learning from past project experiences. It is targeting a focused application area and adopting a user-centric perspective to meet the neuroscientists expectations. It aims at fostering the adoption of HealthGrids in a pre-clinical community. This paper details the project's design study and methodology which were proposed to achieve the integration of heterogeneous site data schemas and the definition of a site-centric policy. The NeuroLOG middleware will bridge HealthGrid and local resources to match user desires to control their resources and provide a transitional model towards HealthGrids.


An improved algorithm for satellite-derived UV radiations.
The improved algorithm surface irradiance derived from a range of satellite-based sensors (SIDES) is presented in this article. It calculates various types of surface UV intensities, such as biologically weighted or unweighted UV spectra, integrated doses or irradiance at specific wavelengths, using data from satellite instruments. These surface UV data are mainly useful for environmental impact or process studies where high accuracy or a high temporal resolution is required. In contrast to several previous studies, SIDES has been validated with spectral measurements. By this method an averaging of positive or negative deviations over the complete wavelength range is avoided. This is especially important for UV wavelengths around 300 nm where biological effectiveness is highest. The results of SIDES deviate less than 7% from ground-based observations for wavelengths between 295 and 400 nm. In contrast, the corresponding deviations of the joint research center algorithm escalate for shorter wavelengths, reaching 35% at 295 nm. This large deviation is due to an inaccurate interpolation procedure that has been detected by spectral analysis. Thus, spectral validation is demonstrated to be an appropriate tool to detect weaknesses in such an algorithm and provides information essential for improvement.


Mastocytosis and the Fig Wasp (Blastophaga psenes).
Mastocytosis involves the abnormal proliferation of mast cells and clinical variability. In the case of anaphylaxis, the triggering antigen, often associated with Hymenoptera allergens, must be identified. The common fig (Ficus carica) requires the fig wasp (Blastophaga psenes) for pollination. We evaluated the ingestion of B. psenes as a trigger of anaphylaxis in patients with mastocytosis. Skin prick tests (SPTs) and specific immunoglobulin E to the possible involved allergens were carried out in the patient and in 4 controls allergic to Hymenoptera and fig. Given the possibility of hidden allergens, we studied the source (figs of various origins) and possible hypersensitivity to Hymenoptera allergens, including the fig wasp (B. psenes). In all subjects, the SPT resulted in a wheal (larger than with histamine) with the extract of the inferior part of the female fig but not with the male extract (lower pole and stem). Immune detection was made with the stem and inferior part of figs and venom of Polistes and Vespula. Recognition bands were observed at 25 kDa with female fig extracts that were also recognized by the patient with anaphylaxis to Hymenoptera venom. We cannot exclude the possibility that the ingestion of fig with Blastophaga antigens may have triggered anaphylaxis in our patient.


[Angio-CT: an improvement in the diagnosis of malignant liver diseases].
Dynamic contrast studies of the liver make it possible to evaluate the vascularity of liver metastases. Up to the present, the examination has only been carried out in single planes, whereas studies of the whole of the liver during one examination have not yet been published. This can be obtained by performing sequential CT (angio-CT), using special software. A clinical study of the value of the procedure has been undertaken on 64 patients with suspected liver metastases. In addition to the plain scans, the examination was repeated during the early phase of a bolus injection and subsequently ten minutes after injection (enhancement). The various structures which can be seen are described and the changes in density patterns have been interpreted according to contrast kinetics derived from nephrographic examinations. The advantages of angio-CT as compared with plain films and with scans after normal contrast infusions are described. The improved sensitivity and specificity obtained by using the three modes of examination, as compared with a single examination, is stressed.


Longitudinal growth changes of the cranial base from puberty to adulthood. A comparison of different superimposition methods.
To investigate the stability of cranial reference landmarks from puberty through adulthood and to compare the displacement of these landmarks among the superimposition methods of Björk, Ricketts, Steiner, and the proposed tuberculum sella-wing (T-W) reference line. The sample consisted of serial lateral cephalometric radiographs of 30 Class II division 1 patients taken at the pretreatment (T1; mean age, 11.98 years), posttreatment (T2; mean age, 15.32 years) and postretention (T3; mean age, 32.12 years) periods. All cephalometric radiographs were superimposed at the cranial base according to the overall superimposition methods of Björk, Ricketts, Steiner, and the T-W method. The horizontal and vertical displacements of cranial landmarks (nasion, wing, tuberculum sella, sella, basion, and pterygomaxillare) were assessed by paired t-test according to Björk's structural method. One-way analysis of variance (ANOVA) was used for comparison of the displacement of cranial landmarks among the superimposition methods. The tuberculum sella and wing were the most stable cranial landmarks of the cranial base. The stability of sella and pterygomaxillare points were somewhat questionable. Nasion and basion were highly variable. The displacements of all cranial landmarks were similar between the Björk and T-W methods in all study periods. Most of the cranial landmarks displaced similarly in the horizontal direction among the methods. Vertically, the behaviors of the cranial landmarks were frequently different. T-W is the most similar superimposition method to Björk's structural method; thus, it is a reliable method for examining overall facial changes.


Precise mapping of a locus affecting grain protein content in durum wheat.
Grain protein content (GPC) is an important factor in pasta and breadmaking quality, and in human nutrition. It is also an important trait for wheat growers because premium prices are frequently paid for wheat with high GPC. A promising source for alleles to increase GPC was detected on chromosome 6B of Triticum turgidum var. dicoccoides accession FA-15-3 (DIC). Two previous quantitative trait locus (QTL) studies found that the positive effect of DIC-6B was associated to a single locus located between the centromere and the Nor-B2 locus on the short arm of chromosome 6B. Microsatellite markers Xgwm508 and Xgwm193 flanking the QTL region were used in this study to develop 20 new homozygous recombinant substitution lines (RSLs) with crossovers between these markers. These 20 RSLs, plus nine RSLs developed in previous studies were characterized with four new RFLP markers located within this chromosome segment. Grain protein content was determined in three field experiments organized as randomized complete block designs with ten replications each. The QTL peaks for protein content were located in the central region of a 2.7-cM interval between RFLP markers Xcdo365 and Xucw67 in the three experiments. Statistical analyses showed that almost all lines could be classified unequivocally within low- and high- protein groups, facilitating the mapping of this trait as a single Mendelian locus designated Gpc-6B1. The Gpc-6B1 locus was mapped 1.5-cM proximal to Xcdo365 and 1.2-cM distal to Xucw67. These new markers can be used to reduce the size of the DIC chromosome segment selected in marker-assisted selection programs. Markers Nor-B2 and Xucw66 flanking the previous two markers can be used to select against the DIC segment and reduce the linkage drag during the transfer of Gpc-6B1 into commercial bread and pasta wheat varieties. The precise mapping of the high GPC gene, the high frequency of recombinants recovered in the targeted region, and the recent development of a tetraploid BAC library including the Gpc-6B1 DIC allele are the first steps towards the map-based cloning of this gene.


Tumor-infiltrating lymphocytes genetically engineered with an inducible gene encoding interleukin-12 for the immunotherapy of metastatic melanoma.
Infusion of interleukin-12 (IL12) can mediate antitumor immunity in animal models, yet its systemic administration to patients with cancer results in minimal efficacy and severe toxicity. Here, we evaluated the antitumor activity of adoptively transferred human tumor-infiltrating lymphocytes (TILs) genetically engineered to secrete single-chain IL12 selectively at the tumor site. Thirty-three patients with metastatic melanoma were treated in a cell dose-escalation trial of autologous TILs transduced with a gene encoding a single-chain IL12 driven by a nuclear factor of the activated T cells promoter (NFAT.IL12). No IL2 was administered. The administration of 0.001 to 0.1 × 10(9) NFAT.IL12-transduced TILs to 17 patients resulted in a single, objective response (5.9%). However, at doses between 0.3 and 3 × 10(9) cells, 10 of 16 patients (63%) exhibited objective clinical responses. The responses tended to be short, and the administered IL12-producing cells rarely persisted at 1 month. Increasing cell doses were associated with high serum levels of IL12 and IFNγ as well as clinical toxicities, including liver dysfunction, high fevers, and sporadic life-threatening hemodynamic instability. In this first-in-man trial, administration of TILs transduced with an inducible IL12 gene mediated tumor responses in the absence of IL2 administration using cell doses 10- to 100-fold lower than conventional TILs. However, due to toxicities, likely attributable to the secreted IL12, further refinement will be necessary before this approach can be safely used in the treatment of cancer patients.


To Purge or Not to Purge.
To remove gaseous microemboli (GME) using an oxygenator with an integrated arterial filter, it is recommended by some manufacturers to purge the oxygenator as an additional safety feature while on bypass. In this in vitro study, we evaluated whether purging of oxygenators with an integrated arterial filter is efficient in reducing GME. Five different types of commercially available contemporary oxygenators with an integrated arterial filter based on progressive filter filtration (1), cascade filtration (1), screen filtration (2), or self-venting (1) were tested for their efficiency in removing GME while keeping the purge line open or closed. A bubble counter was used for pre- and post-oxygenator GME signaling, from which the filter efficiency was computed. Freshly drawn heparinized porcine blood was used at blood flow rates of 3 and 5 L/min. Three units of each oxygenator were tested with its specific reservoir at a fixed volume level of 1,500 mL. GME load was introduced into the venous line at 1,000 mL air/min. Measurements started as soon as GME were detected by the pre-oxygenator probe and then continued for 1 minute. There was no statistically significant difference in filter efficiency between the purged and non-purged groups for specific oxygenators. At a blood flow of 3 L/min, the average filter efficiency stayed approximately invariable when comparing the non-purged and purged groups, where 89.1-88.2% indicated the largest difference between the groups. At a blood flow rate of 5 L/min, the filter efficiency changed in one screen filter group from an average of 55.7% in the non-purged group to 42.4% in the purged group. Other filter efficiencies at the blood flow rate of 5 L/min for non-purged compared with purged groups were, respectively, 98.0 vs. 98.0% (screen filtration), 88.6 vs. 85.8% (self-venting filtration), 82.8 vs. 75.5% (progressive filter filtration), and 65.4 vs. 65.1% (cascade filtration). Based on these results, purging while confronted with continuous GME challenge did not result in an increased filter efficiency.


Predicting treatment outcome in nocturnal enuresis.
A presenting sample of 127 consecutive referrals to a community based enuresis clinic were evaluated after treatment with baseline behavioural recording and the enuresis alarm. Almost one in five became dry after baseline recording only while 81 of 96 (84%) enuretics who used the alarm achieved the initial dryness criterion. Successful outcome was associated with the absence of adverse environmental factors and psychiatric disorders in the child. A logistic regression procedure enabled a risk score to be created so that successful outcome could be predicted. Psychiatric disorder in the child, family stress, and the degree of concern shown by the child emerged as the most important prognostic factors in the treatment of enuresis. The favourable success rates with baseline recording and the enuresis alarm confirm the role of conditioning treatment at the forefront of management of enuresis and the risk score allows outcome to be predicted for the first time.


Assessing and documenting dark skin tones in stoma care.
The stoma care nurse (SCN) assesses peristomal skin during each patient intervention. Living in a diverse multicultural society, the SCN needs to consider dark skin tones and how these are documented. This article looks at how the literature on peristomal skin assessment and available tools discuss skin colour, and compare this with the tissue viability literature. Stoma care and peristomal skin literature features very little about skin colour. Registered nurses are often unaware of the differences when assessing light skin tones versus dark skin tones. The article discusses how to assess for, identify and document problems around peristomal skin with patients who have dark skin tones. The differences in skin breakdown between light skin tones and dark skin tones are highlighted. There needs to be further research and development of tools to assist clinicians in identification and documentation relating to skin tone, thus providing consistency in assessment.


Suprajugular extension of the retrosigmoid approach: microsurgical anatomy.
Jugular foramen tumors often extend intra- and extracranially. The gross-total removal of tumors located both intracranially and intraforaminally is technically challenging and often requires a combined skull base approach. This study presents a suprajugular extension of the retrosigmoid approach directed through the osseous roof of the jugular foramen that allows the removal of tumors located in the cerebellopontine angle with extension into the upper part of the foramen, with demonstration of an illustrative case. The cerebellopontine angles and jugular foramina were examined in dry skulls and cadaveric heads to clarify the microsurgical anatomy around the jugular foramen and to define the steps of the suprajugular exposure. The area drilled in the suprajugular approach is inferior to the acoustic meatus, medial to the endolymphatic depression and surrounding the superior half of the glossopharyngeal dural fold. Opening this area exposed the upper part of the jugular foramen and extended the exposure along the glossopharyngeal nerve below the roof of the jugular foramen. In the illustrative case, a schwannoma originating from the glossopharyngeal nerve in the cerebellopontine angle and extending below the roof of the jugular foramen and above the jugular bulb was totally removed without any postoperative complications. The suprajugular extension of the retrosigmoid approach will permit removal of tumors located predominantly in the cerebellopontine angle but also extending into the upper part of the jugular foramen without any additional skull base approaches.


Effect of long-term music therapy intervention on autonomic function in anthracycline-treated breast cancer patients.
Anthracyclines are potent antineoplastic agents associated with cardiotoxicity, which may lead to congestive heart failure, causing impairment of autonomic cardiovascular function as assessed by heart rate variability (HRV). This decreases survival rates. This study aimed to determine whether music therapy intervention improves autonomic function in anthracycline-treated breast cancer patients, and if so, whether such improvements persist after cessation of the intervention. Participants were 12 women with breast cancer who had undergone mastectomy or breast-conserving treatment and adjuvant chemotherapy; they attended 8 weekly music therapy sessions, each lasting 2 hours. Electrocardiogram traces (5 minutes) for HRV analysis were recorded 4 times: prior to the first music session, T1; after the fourth music session, T2; after the eighth music session, T3; and 4 weeks after the completion of music therapy, T4. HRV parameters were subjected to a nonparametric Friedman test on the differences between T1 and T2, T3, and T4. The standard deviation of normal intervals and the total power of HRV parameters, related to global autonomic function, were significantly higher at T3 than at T1. The root-mean-square differences of successive normal R-R intervals and high-frequency (HF) HRV parameters, related to parasympathetic activity, were significantly increased, but no change was seen in the LF/HF ratio of HRV parameters (which is related to sympathetic activity) during the music therapy. Global autonomic function and parasympathetic activity had not changed significantly at T4 relative to T1. The authors provide preliminary evidence of the benefits of music therapy for anthracycline-treated breast cancer survivors.


Sorting particles with nanoscale thermophoretic devices: how efficient is it?
We investigate particle separation driven by thermal gradients across solid state nanopores using a combined molecular dynamics simulation, non-equilibrium thermodynamics theory and a kinetic model approach. The thermophoretic device, a thermal nanopump, exploits thermal gradients to sort particles of different mass, which accumulate preferentially in hot or cold reservoirs. We show that the large amount of energy dissipated by the thermal nanopump during the transport process leads in general to very low efficiencies, 0.01-0.15%. We find that the nanopump thermal conductivity and structure plays a crucial role in determining the efficiency and a route to enhance it. Doubling the pore radius, from 0.5-1 nm radius, leads to a large increase in the mass diffusion and to a 20 fold increase in the efficiency. Addition of nanoscale defects, without modification of the nanopore structure, leads to a large reduction of the nanopump thermal conductivity and to a large enhancement of the thermodynamic efficiency. We find that nanopumps with nanoscale defects are >3 times more efficient than those without defects. Finally, we identify the microscopic variables responsible for the enhancement of thermally induced transport across nanopores and discuss strategies to tune these variable in order to regulate transport efficiency.


[The use of a heparin ointment in combination with dimexide in treating psoriasis].
Thirty-five male patients with psoriasis en plaques, persisting for 2-5 years, resistant to routine therapy, were treated with official heparin ointment with 15% dimexide under an occlusion dressing. Positive results were achieved in 41.2 +/- 5.9 days of the ointment application. Complete resolution of the rash was observed in 19 (54.3%) patients, partial regression in 14 (40%), no effect in 2 (5.7%) patients. This ointment is recommended for active therapy of patients with local psoriatic plaques with a stable course of the condition, torpid to routine antipsoriatic therapy.


Postoperative hemorrhage with nonsteroidal anti-inflammatory drug use after tonsillectomy: a meta-analysis.
To use standard meta-analysis techniques to determine the risk of postoperative hemorrhage associated with the use of nonsteroidal anti-inflammatory drugs (NSAIDs) after tonsillectomy. The MEDLINE database (1966-2001) restricted to the English language was searched using the keywords tonsillectomy, hemorrhage, analgesics, and NSAID in various combinations. Additionally, published articles were cross-referenced. To ensure completeness, the search was rerun using the Science Citation Index database. Of the 110 articles identified, 7 were selected. Selected studies were prospective trials comparing the effects of an NSAID and a control drug on posttonsillectomy pain and hemorrhage in pediatric and/or adult patients. In all cases, the NSAID or control was administered through an enteric route in the postoperative period. Patients were monitored for early and delayed hemorrhage. Data were extracted independently by 2 investigators. A random effects model was used to compute a pooled odds ratio. For the 1368 patients included in analysis, the pooled odds ratio of posttonsillectomy hemorrhage with NSAIDs compared with controls was 1.29 and was not statistically significant (95% confidence interval, 0.85-1.73; P>/=.05). A subgroup analysis revealed an odds ratio of 0.93 (95% confidence interval, 0.44 -1.95; P>/=.05) for the nonaspirin NSAID group, while the aspirin group had a statistically significant odds ratio of 1.94 (95% confidence interval, 1.09-3.42; P =.02). There is an increased risk of posttonsillectomy hemorrhage with the use of aspirin after tonsillectomy; however, there appears to be no significant increased risk of bleeding for nonaspirin NSAIDs in this meta-analysis.


In vitro activity of tigecycline and comparators against Gram-positive and Gram-negative isolates collected from the Middle East and Africa between 2004 and 2011.
The Tigecycline Evaluation and Surveillance Trial (T.E.S.T.) was established in 2004 to monitor longitudinal changes in bacterial susceptibility to numerous antimicrobial agents, specifically tigecycline. In this study, susceptibility among Gram-positive and Gram-negative isolates between 2004 and 2011 from the Middle East and Africa was examined. Antimicrobial susceptibilities were determined using Clinical and Laboratory Standards Institute (CLSI) interpretive criteria, and minimum inhibitory concentrations (MICs) were determined by broth microdilution methods. US Food and Drug Administration (FDA)-approved breakpoints were used for tigecycline. In total, 2967 Gram-positive and 6322 Gram-negative isolates were examined from 33 participating centres. All Staphylococcus aureus isolates, including meticillin-resistant S. aureus, were susceptible to tigecycline, linezolid and vancomycin. Vancomycin, linezolid, tigecycline and levofloxacin were highly active (>97.6% susceptibility) against Streptococcus pneumoniae, including penicillin-non-susceptible strains. All Enterococcus faecium isolates were susceptible to tigecycline and linezolid, including 32 vancomycin-resistant isolates. Extended-spectrum β-lactamases were produced by 16.6% of Escherichia coli and 32.9% of Klebsiella pneumoniae. More than 95% of E. coli and Enterobacter spp. were susceptible to amikacin, tigecycline, imipenem and meropenem. The most active agents against Pseudomonas aeruginosa and Acinetobacter baumannii were amikacin (88.0% susceptible) and minocycline (64.2% susceptible), respectively; the MIC90 (MIC required to inhibit 90% of the isolates) of tigecycline against A. baumannii was low at 2mg/L. Tigecycline and carbapenem agents were highly active against most Gram-negative pathogens. Tigecycline, linezolid and vancomycin showed good activity against most Gram-positive pathogens from the Middle East and Africa.


Single-Center 20-Year Experience in Surgical Treatment of Malignant Pleural Mesothelioma.
Objectives: We examined a series of malignant pleural mesothelioma (MPM) patients who consecutively underwent surgery in our institution during the last 20 years. Across this period, we changed our surgical approach to MPM, adopting extended pleurectomy and decortication (eP/D) instead of extrapleural pneumonectomy (EPP). In this study, we compare the perioperative outcomes and long-term survival of patients who underwent EPP vs. eP/D. Methods: A retrospective analysis was carried out of all the MPM patients identified from our departmental database who underwent EPP or P/D from 2000 to 2021. Clavien−Dindo criteria was adopted to score postoperative complications, while Kaplan−Meier methods and a Cox multivariable analysis were used to perform the survival analysis. Results: Of 163 patients, 78 (48%) underwent EPP and 85 (52%) eP/D. Induction chemotherapy was significantly administrated more often in the eP/D group (88% vs. 51%). Complete trimodality treatment including induction chemotherapy, radical surgery, and adjuvant radiotherapy was administered in 74% of the eP/D group versus 32% of the EPP group (p < 0.001). The postoperative morbidity rate was higher in the eP/D group (54%) compared to the EPP group (36%) (p = 0.02); no statistically significant differences were identified concerning major complications (EPP 43% vs. eP/D 24%, p = 0.08). No statistical differences were identified in 30-day mortality, 90-day mortality, median disease-free, and overall survival statistics between the two groups. The Cox multivariable analysis confirmed no induction chemotherapy (HR, 0.5; p = 0.002), RDW (HR, 1.08; p = 0.02), and the presence of pathological nodal disease (HR, 1.99; p = 0.001) as factors associated with worse survival in the entire series. Conclusions: Our data support that eP/D is a well-tolerated procedure allowing the implementation of a trimodality strategy (induction chemotherapy, surgery, and radiotherapy) in most MPM patients. When eP/D is offered in this setting, the oncological results are comparable to EPP. To obtain the best oncological results, the goal of surgical resection should be macroscopic complete resection (R0) in carefully selected patients (clinical N0).


Selectfluor: mechanistic insight and applications.
The replacement of hydrogen atoms with fluorine substituents in organic substrates is of great interest in synthetic chemistry because of the strong electronegativity of fluorine and relatively small steric footprint of fluorine atoms. Many sources of nucleophilic fluorine are available for the derivatization of organic molecules under acidic, basic, and neutral conditions. However, electrophilic fluorination has historically required molecular fluorine, whose notorious toxicity and explosive tendencies limit its application in research. The necessity for an electrophilic fluorination reagent that is safe, stable, highly reactive, and amenable to industrial production as an alternative to very hazardous molecular fluorine was the inspiration for the discovery of selectfluor. This reagent is not only one of the most reactive electrophilic fluorinating reagents available, but it is also safe, nontoxic, and easy to handle. In this Review we document the many applications of selectfluor and discuss possible mechanistic pathways for its reaction.


Insufficiency of BUBR1, a mitotic spindle checkpoint regulator, causes impaired ciliogenesis in vertebrates.
Budding uninhibited by benzimidazole-related 1 (BUBR1) is a central molecule of the spindle assembly checkpoint. Germline mutations in the budding uninhibited by benzimidazoles 1 homolog beta gene encoding BUBR1 cause premature chromatid separation (mosaic variegated aneuploidy) [PCS (MVA)] syndrome, which is characterized by constitutional aneuploidy and a high risk of childhood cancer. Patients with the syndrome often develop Dandy-Walker complex and polycystic kidneys; implying a critical role of BUBR1 in morphogenesis. However, little is known about the function of BUBR1 other than mitotic control. Here, we report that BUBR1 is essential for the primary cilium formation, and that the PCS (MVA) syndrome is thus a novel ciliopathy. Morpholino knockdown of bubr1 in medaka fish also caused ciliary dysfunction characterized by defects in cerebellar development and perturbed left-right asymmetry of the embryo. Biochemical analyses demonstrated that BUBR1 is required for ubiquitin-mediated proteasomal degradation of cell division cycle protein 20 in the G0 phase and maintains anaphase-promoting complex/cyclosome-CDC20 homolog 1 activity that regulates the optimal level of dishevelled for ciliogenesis.


Determinants of cigarette smoking initiation in Jordanian schoolchildren: longitudinal analysis.
To identify determinants of cigarette smoking initiation, by gender, among schoolchildren in Irbid, Jordan. Between 2008 and 2011, data were collected annually using self-reported questionnaires over 4-years in a prospective cohort of 1,781 students recruited from all 7th grade classes in 19 secondary schools, selected out of a total 60, using probability-proportionate-to-size method. Independent predictors of smoking initiation were identified among the cigarette naïve participants (N = 1,454) with mixed-effect multivariable logistic regression. Participants were 12.6 years of age on average at baseline. 29.8% of the 1,454 students (37.2% of boys and 23.7% of girls) initiated cigarette smoking by 10th grade. Of those who initiated (n = 498), 47.2% of boys and 37.2% of girls initiated smoking in the 8th grade. Determinants of cigarette smoking initiation included ever smoking a waterpipe, low cigarette refusal self-efficacy, intention to start smoking cigarettes, and having friends who smoked. For girls, familial smoking was also predictive of cigarette initiation. This study shows that many Jordanian youth have an intention to initiate cigarette smoking and are susceptible to cigarette smoking modeled by peers and that girls are influenced as well by familial cigarette smoking. Prevention efforts should be tailored to address culturally relevant gender norms, help strengthen adolescents' self-efficacy to refuse cigarettes, and foster strong non-smoking social norms.


The aetiology of Type I diabetes.
The aetiology of Type I diabetes involves both genetic and environmental factors. The genes implicated are 'susceptibility genes', which modify risk. Individual susceptibility genes may not be required and are not sufficient for disease development. The strongest genetic risk component is encoded within the major histocompatibility complex (MHC) and is designated IDDM I. The HLA-DQ genes contribute to the risk, but so may other MHC-encoded genes. The susceptibility encoded by IDDM2 refers to a variable number of tandem repeats in the insulin gene region. Many other genomic regions have been designated as susceptibility intervals potentially containing candidate genes. Environmental factors appear to be important in disease expression in either a causative or a protective role. Epidemiological data indicate that such factors operate from early in life. Viral infection(s) may have a disease-initiating and/ or accelerating effect. A potential diabetogenic role for cows' milk protein remains unconfirmed. Further research is necessary to elucidate fully the aetiological factors involved and how they interact.


Critical Role of Monoclinic Polarization Rotation in High-Performance Perovskite Piezoelectric Materials.
High-performance piezoelectric materials constantly attract interest for both technological applications and fundamental research. The understanding of the origin of the high-performance piezoelectric property remains a challenge mainly due to the lack of direct experimental evidence. We perform in situ high-energy x-ray diffraction combined with 2D geometry scattering technology to reveal the underlying mechanism for the perovskite-type lead-based high-performance piezoelectric materials. The direct structural evidence reveals that the electric-field-driven continuous polarization rotation within the monoclinic plane plays a critical role to achieve the giant piezoelectric response. An intrinsic relationship between the crystal structure and piezoelectric performance in perovskite ferroelectrics has been established: A strong tendency of electric-field-driven polarization rotation generates peak piezoelectric performance and vice versa. Furthermore, the monoclinic M_{A} structure is the key feature to superior piezoelectric properties as compared to other structures such as monoclinic M_{B}, rhombohedral, and tetragonal. A high piezoelectric response originates from intrinsic lattice strain, but little from extrinsic domain switching. The present results will facilitate designing high-performance perovskite piezoelectric materials by enhancing the intrinsic lattice contribution with easy and continuous polarization rotation.


Long-term quality of life, work limitation, physical activity, economic cost and disease burden following ACL and meniscal injury: a systematic review and meta-analysis for the OPTIKNEE consensus.
Determine the long-term health-related quality-of-life (HRQoL), work limitation, physical activity, health/economic cost and disease burden of traumatic ACL and/or meniscal injury. Findings will inform OPTIKNEE evidence-based consensus recommendations. Random-effects meta-analysis evaluated HRQoL (SF-36/SF-12/VR-12 Physical Component Scores (PCS) and Mental Component Scores (MCS), EuroQol-5D (EQ-5D)) stratified by time postinjury, and pooled mean differences (95% CI) between ACL-injured and uninjured controls. Other outcomes were synthesised descriptively. Risk-of-bias (RoB) and certainty of evidence (Grading of Recommendations Assessment, Development and Evaluation) were assessed. MEDLINE, EMBASE, CENTRAL, SPORTDiscus, CINAHL searched inception: 22 November 2021. Studies reporting HRQoL, work limitations, physical activity levels, health/economic costs or disease burden, ≥2 years post-ACL and/or meniscal injury. Fifty studies were included (10 high-RoB, 28 susceptible-to-some-bias and 12 low-RoB). Meta-analysis (27 studies, very low certainty of evidence) estimated a pooled mean (95% CI) PCS of 52.4 (51.4 to 53.4) and MCS of 54.0 (53.0 to 55.0) 2-14 years post-ACL injury. Pooled PCS scores were worse >10 years (50.8 (48.7 to 52.9)) compared with 2-5 years (53.9 (53.1 to 54.7)) postinjury. Excluding high-RoB studies, PCS scores were worse in ACL-injured compared with uninjured controls (-1.5 (-2.9 to -0.1)). Six studies (low certainty of evidence) informed a pooled EQ-5D score of 0.83 (0.81 to 0.84). Some individuals experienced prolonged work absenteeism and modified activities ≥2 years post-ACL injury. ACL injury was associated with significant direct and indirect costs, and early ACL reconstruction may be less cost-effective than rehabilitation. Only three studies evaluated meniscal injury outcomes (all evaluated HRQoL). There is a very-low certainty of evidence that PCS scores ≥2 years post-ACL injury are worse than uninjured controls and decline over time, whereas MCS scores remain high. ACL injury can result in prolonged work absenteeism and high health/economic costs. Further studies are needed to determine the long-term burden of traumatic meniscal injury.


[Choriocarcinoma with pulmonary metastasis: diagnosis and treatment].
Choriocarcinoma is a rare tumour which results from the anarchic proliferation of a gonadic or extra gonadic germinal cell. A 45 year old pre menopausal woman of African origin presented with a persistent cough and deterioration of general status. The chest X-ray revealed a cavitated mass of the right upper lobe. Other lesions were associated (liver, kidney and scalp). Choriocarcinoma, suspected in the presence of an elevated ssHCG without a gravid uterus, was confirmed by biopsy excision of a haemorrhagic cutaneous lesion of the scalp. Despite the poor prognosis methotrexate based chemotherapy resulted in control of the disease and a good remission.


Calcium and strontium contractile activation properties of single skinned skeletal muscle fibres from elderly women 66-90 years of age.
The single freshly skinned muscle fibre technique was used to investigate Ca2+- and Sr2+-activation properties of skeletal muscle fibres from elderly women (66-90 years). Muscle biopsies were obtained from the vastus lateralis muscle. Three populations of muscle fibres were identified according to their specific Sr2+-activation properties: slow-twitch (type I), fast-twitch (type II) and hybrid (type I/II) fibres. All three fibre types were sampled from the biopsies of 66 to 72 years old women, but the muscle biopsies of women older than 80 years yielded only slow-twitch (type I) fibres. The proportion of hybrid fibres in the vastus lateralis muscle of women of circa 70 years of age (24%) was several-fold greater than in the same muscle of adults (< 10%), suggesting that muscle remodelling occurs around this age. There were no differences between the Ca2+- and Sr2+-activation properties of slow-twitch fibres from the two groups of elderly women, but there were differences compared with muscle fibres from young adults with respect to sensitivity to Ca2+, steepness of the activation curves, and characteristics of the fibre-type dependent phenomenon of spontaneous oscillatory contractions (SPOC) (or force oscillations) occurring at submaximal levels of activation. The maximal Ca2+ activated specific force from all the fibres collected from the seven old women use in the present study was significantly lower by 20% than in the same muscle of adults. Taken together these results show there are qualitative and quantitative changes in the activation properties of the contractile apparatus of muscle fibres from the vastus lateralis muscle of women with advancing age, and that these changes need to be considered when explaining observed changes in women's mobility with aging.


Deletions in epidermal keratins leading to alterations in filament organization in vivo and in intermediate filament assembly in vitro.
To investigate the sequences important for assembly of keratins into 10-nm filaments, we used a combined approach of (a) transfection of mutant keratin cDNAs into epithelial cells in vivo, and (b) in vitro assembly of mutant and wild-type keratins. Keratin K14 mutants missing the nonhelical carboxy- and amino-terminal domains not only integrated without perturbation into endogenous keratin filament networks in vivo, but they also formed 10-nm filaments with K5 in vitro. Surprisingly, keratin mutants missing the highly conserved L L E G E sequence, common to all intermediate filament proteins and found at the carboxy end of the alpha-helical rod domain, also assembled into filaments with only a somewhat reduced efficiency. Even a carboxy K14 mutant missing approximately 10% of the rod assembled into filaments, although in this case filaments aggregated significantly. Despite the ability of these mutants to form filaments in vitro, they often perturbed keratin filament organization in vivo. In contrast, small truncations in the amino-terminal end of the rod domain more severely disrupted the filament assembly process in vitro as well as in vivo, and in particular restricted elongation. For both carboxy and amino rod deletions, the more extensive the deletion, the more severe the phenotype. Surprisingly, while elongation could be almost quantitatively blocked with large mutations, tetramer formation and higher ordered lateral interactions still occurred. Collectively, our in vitro data (a) provide a molecular basis for the dominance of our mutants in vivo, (b) offer new insights as to why different mutants may generate different phenotypes in vivo, and (c) delineate the limit sequences necessary for K14 to both incorporate properly into a preexisting keratin filament network in vivo and assemble efficiently into 10-nm keratin filaments in vitro.


'That is a Ministry of Health thing': Article 5.3 implementation in Uganda and the challenge of whole-of-government accountability.
While Uganda has made legislative progress towards implementing Article 5.3 of the WHO Framework Convention on Tobacco Control (FCTC), ongoing challenges in minimising tobacco industry interference have not been adequately explored. This analysis focuses on understanding difficulties in managing industry engagement across government ministries and in developing effective whole-of-government accountability for tobacco control. Interviews with Uganda government officials within the health sector and beyond, including in Ministries of Trade, Agriculture and Revenue. The findings indicate substantial variations in awareness of Article 5.3, its norm and practices across government sectors. The data suggest ambiguity and uncertainty about accountability for Article 5.3 implementation, with policy makers in departments beyond health often uncertain about obligations under the FCTC. Second, we highlight how responsibility for Article 5.3 implementation and the obligations incurred are widely seen as restricted to the Ministry of Health. Third, competing mandates and perceived difficulties in reconciling health goals with economic growth are shown to impact on accountability for tobacco control. Yet, importantly, the data also demonstrate enthusiasm in some unexpected parts of government for actively engaging with Article 5.3 and for promoting greater intersectoral coordination. This paper demonstrates the intrinsic challenges of developing whole-of-government approaches, highlighting considerable uncertainty and ambiguity among decision makers in Uganda about tobacco control governance. The analysis points to the potential for Uganda's national coordinating mechanism to help reconcile competing expectations and demonstrate the importance of Article 5.3 beyond health actors.


Morning surge in blood pressure is associated with reactivity of the sympathetic nervous system.
An exaggerated morning surge in blood pressure (BP) closely relates to target organ damage and cardiovascular risk, but whether the causative mechanism involves greater reactivity of the sympathetic nervous system (SNS) is unknown. We determined whether the response of the SNS to a cold pressor test predicted the BP morning surge. Ambulatory BP recordings were obtained from 14 men and 19 women (age = 41±4 years), and the amplitude (day-night difference), rate of rise (RoR), rate by amplitude product (BPPower), and morning BP surge (MBPS; post-awake minus pre-awake) of morning mean arterial pressure (MAP) were determined. The reactivity of the SNS to CPT was assessed by recording of muscle sympathetic nerve activity (MSNA). CPT induced a marked increase in MAP and all parameters of MSNA, including burst amplitude. Log-normalized BPPower positively correlated with the overall average CPT-induced increases in total MSNA (r = 0.38; P = 0.04) and burst amplitude (r = 0.43; P = 0.02) but was not related to the increase in MSNA frequency. Furthermore, a strong positive linear trend in the CPT-induced changes in burst amplitude across tertiles of BPPower and RoR was observed. BPPower and RoR were not related to CPT-induced hemodynamic changes. The MBPS did not correlate with any of the CPT-induced changes in vascular or MSNA variables. These results suggest that the central nervous system mechanisms influencing the increase in MSNA burst amplitude during arousal may also be fundamental in determining the rate and power of BP rise during the morning period.


Metabolomics revealed disruptions in amino acid and antioxidant biochemistry in Daphnia magna exposed to industrial effluents associated with plastic and polymer production.
Industrial wastewater effluents are a major source of chemicals in aquatic environments, and many of these chemicals may negatively impact aquatic life. In this study, the crustacean Daphnia magna, a common model organism in ecotoxicity studies, was exposed for 48 h to nine different industrial effluent samples from manufacturing facilities associated with the production of plastics, polymers, and coating products at a range of dilutions: 10, 25, 50, 100% (undiluted). A targeted metabolomic-based approach using liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to quantify polar metabolites from individual daphnids that survived the 48 h exposure. Multivariate analyses and metabolite changes revealed metabolic perturbations across all effluent samples studied, with non-monotonic responses and both up and downregulation relative to the unexposed control. Pathway analyses indicated the disruption of similar and distinct pathways, mostly connected to protein synthesis, amino acid metabolism, and antioxidant processes. Overall, we observed disruptions in Daphnia biochemistry that were similar across the effluent samples, but with unique features for each effluent sample. Additionally, non-monotonic heightened responses suggested additive and/or synergistic interactions between the chemicals within the industrial effluents. These findings demonstrate that targeted metabolomic approaches are a powerful tool for the biomonitoring of aquatic ecosystems in the context of complex mixtures, such as industrial wastewater effluents.


Toward correlating structure and mechanics of platelets.
The primary physiological function of blood platelets is to seal vascular lesions after injury and form hemostatic thrombi in order to prevent blood loss. This task relies on the formation of strong cellular-extracellular matrix interactions in the subendothelial lesions. The cytoskeleton of a platelet is key to all of its functions: its ability to spread, adhere and contract. Despite the medical significance of platelets, there is still no high-resolution structural information of their cytoskeleton. Here, we discuss and present 3-dimensional (3D) structural analysis of intact platelets by using cryo-electron tomography (cryo-ET) and atomic force microscopy (AFM). Cryo-ET provides in situ structural analysis and AFM gives stiffness maps of the platelets. In the future, combining high-resolution structural and mechanical techniques will bring new understanding of how structural changes modulate platelet stiffness during activation and adhesion.


Compound analysis via graph kernels incorporating chirality.
High accuracy is paramount when predicting biochemical characteristics using Quantitative Structural-Property Relationships (QSPRs). Although existing graph-theoretic kernel methods combined with machine learning techniques are efficient for QSPR model construction, they cannot distinguish topologically identical chiral compounds which often exhibit different biological characteristics. In this paper, we propose a new method that extends the recently developed tree pattern graph kernel to accommodate stereoisomers. We show that Support Vector Regression (SVR) with a chiral graph kernel is useful for target property prediction by demonstrating its application to a set of human vitamin D receptor ligands currently under consideration for their potential anti-cancer effects.


Bedfellows: mycobacteria and rheumatoid arthritis in the era of biologic therapy.
In modern times a relationship between tuberculosis (TB) and rheumatoid arthritis (RA) has been firmly recognized, and is primarily attributable to the immunosuppressive therapies used to treat RA. Whereas TB can complicate the successful management of RA, nontuberculous mycobacteria have now perhaps become as important as (if not more so than) TB in the setting of RA, and can represent an even greater challenge to the rheumatologist wishing to use immunosuppressive therapies. This article reviews our most recent understanding of the epidemiological and clinical aspects of mycobacterial disease as it relates to RA, and the existing and emerging immunosuppressive therapies used to treat this disease.


Coexistance of giant tunneling electroresistance and magnetoresistance in an all-oxide composite magnetic tunnel junction.
We propose, by performing advanced ab initio electron transport calculations, an all-oxide composite magnetic tunnel junction, within which both large tunneling magnetoresistance (TMR) and tunneling electroresistance (TER) effects can coexist. The TMR originates from the symmetry-driven spin filtering provided by an insulating BaTiO(3) barrier to the electrons injected from the SrRuO(3) electrodes. Following recent theoretical suggestions, the TER effect is achieved by intercalating a thin insulating layer, here SrTiO(3), at one of the SrRuO(3)/BaTiO(3) interfaces. As the complex band structure of SrTiO(3) has the same symmetry as that of BaTiO(3), the inclusion of such an intercalated layer does not negatively alter the TMR and in fact increases it. Crucially, the magnitude of the TER also scales with the thickness of the SrTiO(3) layer. The SrTiO(3) thickness becomes then a single control parameter for both the TMR and the TER effect. This protocol offers a practical way to the fabrication of four-state memory cells.


In Vitro-In Vivo Dose Response of Ursolic Acid, Sulforaphane, PEITC, and Curcumin in Cancer Prevention.
According to the National Center of Health Statistics, cancer was the culprit of nearly 600,000 deaths in 2016 in the USA. It is by far one of the most heterogeneous diseases to treat. Treatment for metastasized cancers remains a challenge despite modern diagnostics and treatment regimens. For this reason, alternative approaches are needed. Chemoprevention using dietary phytochemicals such as triterpenoids, isothiocyanates, and curcumin in the prevention of initiation and/or progression of cancer poses a promising alternative strategy. However, significant challenges exist in the extrapolation of in vitro cell culture data to in vivo efficacy in animal models and to humans. In this review, the dose at which these phytochemicals elicit a response in vitro and in vivo of a multitude of cellular signaling pathways will be reviewed highlighting Nrf2-mediated antioxidative stress, anti-inflammation, epigenetics, cytoprotection, differentiation, and growth inhibition. The in vitro-in vivo dose response of phytochemicals can vary due, in part, to the cell line/animal model used, the assay system of the biomarker used for the readout, chemical structure of the functional analog of the phytochemical, and the source of compounds used for the treatment study. While the dose response varies across different experimental designs, the chemopreventive efficacy appears to remain and demonstrate the therapeutic potential of triterpenoids, isothiocyanates, and curcumin in cancer prevention and in health in general.


Electrochemical detection of DNA binding by tumor suppressor p53 protein using osmium-labeled oligonucleotide probes and catalytic hydrogen evolution at the mercury electrode.
In this paper, we present an electrochemical DNA-protein interaction assay based on a combination of protein-specific immunoprecipitation at magnetic beads (MBIP) with application of oligonucleotide (ON) probes labeled with an electroactive oxoosmium complex (Os,bipy). We show that double-stranded ONs bearing a dT20 tail labeled with Os,bipy are specifically recognized by the tumor suppressor p53 protein according to the presence or absence of a specific binding site (p53CON) in the double-stranded segment. We demonstrate the applicability of the Os,bipy-labeled probes in titration as well as competition MBIP assays to evaluate p53 relative affinity to various sequence-specific or structurally distinct unlabeled DNA substrates upon modulation of the p53-DNA binding by monoclonal antibodies used for the immunoprecipitation. To detect the p53-bound osmium-labeled probes, we took advantage of a catalytic peak yielded by Os,bipy-modified DNA at the mercury-based electrodes, allowing facile determination of subnanogram quantities of the labeled oligonucleotides. Versatility of the electrochemical MBIP technique and its general applicability in studies of any DNA-binding protein is discussed.


Frequency of severe hypoglycemia requiring emergency treatment in type 1 and type 2 diabetes: a population-based study of health service resource use.
To determine the incidence, predisposing factors, and costs of emergency treatment of severe hypoglycemia in people with type 1 and type 2 diabetes. Over a 12-month period, routinely collected datasets were analyzed in a population of 367,051 people, including 8,655 people with diabetes, to measure the incidence of severe hypoglycemia that required emergency assistance from Ninewells Hospital and Medical School (NHS) personnel including those in primary care, ambulance services, hospital accident and emergency departments, and inpatient care. Associated costs with these episodes were calculated. A total of 244 episodes of severe hypoglycemia were recorded in 160 patients, comprising 69 (7.1%) people with type 1 diabetes, 66 (7.3%) with type 2 diabetes treated with insulin, and 23 (0.8%) with type 2 diabetes treated with sulfonylurea tablets. Incidence rates were 11.5 and 11.8 events per 100 patient-years for type 1 and type 2 patients treated with insulin, respectively. Age, duration, and socioeconomic status were identified as risk factors for severe hypoglycemia. One in three cases were treated solely by the ambulance service with no other contact from health care professionals. The total estimated cost of emergency treatment of severe hypoglycemia was </= pound 92,078 in one year. Hypoglycemia requiring emergency assistance from health service personnel is as common in people with type 2 diabetes treated with insulin as in people with type 1 diabetes. It is associated with considerable NHS resource use that has a significant economic and personal cost.


Breathing shifts visuo-spatial attention.
Considering recent findings that breathing influences cognitive processes, two experiments explored the relationship between breathing and visuo-spatial attention. In Experiment 1, a lateralized probe detection task was inserted into the breathing cycles of 21 healthy adults to probe effects of breathing on the distribution of spatial attention. In Experiment 2 (N = 26), the Posner cueing task measured breathing-contingent detection speed for lateralized probes after endogenous or exogenous cueing. We consistently found faster responses for left probes after exhalation and for right probes after inhalation in both experiments. Breathing also affected the speed of re-alignment of spatial attention after invalid cueing in Experiment 2. This novel breathing bias shows that our ability to encode visuo-spatial information systematically fluctuates during breathing.


Sensory protection of rat muscle spindles following peripheral nerve injury and reinnervation.
Skeletal muscle structure and function are dependent on intact innervation. Prolonged muscle denervation results in irreversible muscle fiber atrophy, connective tissue hyperplasia, and deterioration of muscle spindles, specialized sensory receptors necessary for proper skeletal muscle function. The protective effect of temporary sensory innervation on denervated muscle, before motor nerve repair, has been shown in the rat. Sensory-protected muscles exhibit less fiber atrophy and connective tissue hyperplasia and maintain greater functional capacity than denervated muscles. The purpose of this study was to determine whether temporary sensory innervation also protects muscle spindles from degeneration. Rat tibial nerve was transected and repaired with either the saphenous or the original transected nerve. Negative controls remained denervated. After 3 to 6 months, the electrophysiologic response of the nerve to stretch in the rat gastrocnemius muscle was measured (n = 3 per group). After the animals were euthanized, the gastrocnemius muscle was removed, sectioned, stained, and examined for spindle number (n = 3 per group) and morphology (one rat per group). Immunohistochemical assessment of muscle spindle innervation was examined in four additional animals. Significant deterioration of muscle spindles was seen in denervated muscle, whereas in muscle reinnervated with the tibial or the saphenous nerve, spindle number and morphology were improved. Histologic and functional evidence of spindle reinnervation by the sensory nerve was obtained. These findings add to the known means by which motor or sensory nerves exert protective effects on denervated muscle, and further promote the use of sensory protection for improving the outcome after peripheral nerve injury.


Structure, tissue distribution, and chromosomal localization of the prepronociceptin gene.
Nociceptin (orphanin FQ), the newly discovered natural agonist of opioid receptor-like (ORL1) receptor, is a neuropeptide that is endowed with pronociceptive activity in vivo. Nociceptin is derived from a larger precursor, prepronociceptin (PPNOC), whose human, mouse, and rat genes we have now isolated. The PPNOC gene is highly conserved in the three species and displays organizational features that are strikingly similar to those of the genes of preproenkephalin, preprodynorphin, and preproopiomelanocortin, the precursors to endogenous opioid peptides, suggesting the four genes belong to the same family-i.e., have a common evolutionary origin. The PPNOC gene encodes a single copy of nociceptin as well as of other peptides whose sequence is strictly conserved across murine and human species; hence it is likely to be neurophysiologically significant. Northern blot analysis shows that the PPNOC gene is predominantly transcribed in the central nervous system (brain and spinal cord) and, albeit weakly, in the ovary, the sole peripheral organ expressing the gene. By using a radiation hybrid cell line panel, the PPNOC gene was mapped to the short arm of human chromosome 8 (8p21), between sequence-tagged site markers WI-5833 and WI-1172, in close proximity of the locus encoding the neurofilament light chain NEFL. Analysis of yeast artificial chromosome clones belonging to the WC8.4 contig covering the 8p21 region did not allow to detect the presence of the gene on these yeast artificial chromosomes, suggesting a gap in the coverage within this contig.