Type II pneumocyte changes during hyperoxic lung injury and recovery.
Adult rabbits exposed to 100% O2 for 64 h and then returned to room air for up to 200 h, develop a lung injury characterized by decreased levels of alveolar surfactant followed by a rebound recovery. In the present study we isolated alveolar type II cells from rabbits at various times during hyperoxic exposure and recovery and measured rates of phosphatidylcholine (PC) synthesis, cellular lipid content, and the specific activity of glycerol 3-phosphate (G-3-P) acyltransferase, an enzyme that catalyzes one of the early reactions in phosphoglyceride biosynthesis. These biochemical parameters were compared with measurements of cell size and cell cycle phase by laser flow cytometry. Results showed that alterations in alveolar phospholipid levels in vivo correlated consistently with cellular lipid metabolic changes measured in isolated type II pneumocytes. In particular, alveolar pneumocytes isolated from lungs of rabbits exposed to 100% O2 for 64 h exhibited a 60% decrease in PC synthesis, cell lipid content, and G-3-P acyltransferase activity. All variables then followed a pattern of recovery to normal and ultimately supranormal levels beginning at approximately 3 days postexposure, at which point there was also a measured increase in the number of type II cells in S phase. These findings suggest that O2-induced changes in type II cell surfactant biosynthesis may account, at least in part, for observed changes in lung phospholipid levels in vivo.


Minireview: The adipocyte--at the crossroads of energy homeostasis, inflammation, and atherosclerosis.
Adipose tissue evolved to efficiently store energy for times of caloric restriction. The large caloric excess common in many Western diets has negated the need for this thrifty function, leaving adipose tissue ill-equipped to handle this increased load. An excess of adipose tissue increases risk for a number of conditions including coronary artery disease, hypertension, dyslipidemias, type 2 diabetes, and even cancer. Indeed, the ability of the adipocyte to function properly when engorged with lipid can lead to lipid accumulation in other tissues, reducing their ability to function and respond normally. The role of adipose tissue as an endocrine organ capable of secreting a number of adipose tissue-specific or enriched hormones, known as adipokines, is gaining appreciation. The normal balance of these adipose tissue secretory proteins is perturbed in obesity. Paradoxically, the lack of normal adipose tissue, as seen in cases of lipodystrophy and lipoatrophy, is also associated with pathologic sequelae similar to what is seen with obesity. The pathologic findings associated with lack of adipose tissue, largely due to inability to properly store lipids, may also be due to a lack of adipokines. In this review, we highlight the role of adipose tissue as an endocrine organ focusing on some of the recent advances in the identification and pharmacological characterization of adipokines as well as their regulation in the context of obesity and insulin-resistant states.


A systematic overview of the scientific literature on the association between Mediterranean Diet and the Stroke prevention.
Stroke is the most common cardiovascular disorder after heart disease and one of the major causes of death and disability. Mediterranean diet has proven to be an effective means to prevent cardiovascular diseases and may contribute to the prevention of stroke. This overview aims to analyze all reviews that examine the association between Mediterranean diet pattern and stroke. We conducted a literature search on PubMed and Scopus databases, using the keywords "Mediterranean diet" and "Stroke". All studies were selected evaluating the association between the Mediterranean diet and the prevention of stroke and only systematic reviews, meta-analysis and narrative reviews were included. 25 eligible articles were included (16 narrative reviews, 9 systematic reviews, 6 systematic reviews with meta-analyses). The authors stated that Mediterranean diet may be a useful means of preventing stroke, especially the 6 meta-analyses highlighted that high adherence to Mediterranean diet was protective against stroke, with a relative risk ranging from 0,64 (95% CI 0,48-0,88) to 0,90 (95% CI 0,87-0,93). Moderate adherence has not shown significant results. A high adherence to the Mediterranean diet is inversely associated with stroke risk, and can modify the costs of its management, therefore the prevention policies should implement adherence to this healthy diet.


Treatment of Hip Fractures in the Elderly.
Evidence-based information, in conjunction with the clinical expertise of physicians, was used to develop the Appropriate Use Criteria (AUC) document Treatment of Hip Fractures in the Elderly to improve patient care and obtain optimal outcomes while considering the subtleties and distinctions necessary in making clinical decisions. The AUC clinical patient scenarios were derived from indications typical of patients commonly presenting with hip fractures in clinical practice, as well as from current evidence-based clinical practice guidelines and supporting literature. The 30 patient scenarios and 6 treatments were developed by the Writing Panel, a group of clinicians who are specialists in this AUC topic. A separate, multidisciplinary Voting Panel made up of specialists and nonspecialists rated the appropriateness of treatment of each patient scenario using a 9-point scale to designate a treatment as Appropriate (median rating, 7 to 9), May Be Appropriate (median rating, 4 to 6), or Rarely Appropriate (median rating, 1 to 3).


Isoform-specific induction of a retinoid-responsive antigen after biolistic transfection of chimaeric retinoic acid/thyroid hormone receptors into a regenerating limb.
Retinoic acid (RA) induces secretory differentiation in the wound epidermis of a regenerating amphibian limb. We investigated the role of individual RA receptor (RAR) types in the newt wound epidermis by introducing chimaeric RA/thyroid hormone (T3) receptors (chi alpha 1 and chi delta 1) that can be activated by T3. A biolistic particle delivery system was employed to transfect cells in the wound epidermis of a regenerating limb and approximately 10% of the cells in targeted surface areas expressed marker genes. Both chi alpha 1 and chi delta 1 were comparable in their ability to stimulate transcription of a synthetic reporter construct through a RA response element after activation with T3 in situ. This activation was also comparable to that obtained by the endogenous complement of RARs in the RA-treated, transfected wound epidermis. The RA-inducible WE3 antigen, a marker for secretory differentiation, which distinguishes the wound epidermis from normal skin (Tassava, R. A., Johnson-Wint, B. and Gross, J. 1986, J. Exp. Zool. 239, 229-240), was used to assess the functional role of chi alpha 1 and chi delta 1. Chimaeric receptors were transfected with an alkaline phosphatase marker gene, activated with T3, and the expression of both the marker and WE3 was analyzed by double-label immunofluorescence. Newt limbs transfected with chi delta 1 showed many double-labelled cells dependent on the presence of T3, whereas contralateral limbs transfected with an alkaline phosphatase marker lacking chimaeric receptor sequences did not.(ABSTRACT TRUNCATED AT 250 WORDS)


Individual-level and group-level mediators of contact effects in Northern Ireland: the moderating role of social identification.
We tested a model which considered individual-level (intergroup anxiety) and group-level (perceived realistic and symbolic threats to the in-group) threats as simultaneous mediators in the relationship between the quantity and quality of cross-community contact and intergroup attitudes (Study 1, N=166) and trust (Study 2, N=163) in Northern Ireland. The studies tested the hypothesis that the strength of group-identification moderates the importance of individual- vs. group-level threats as predictors of attitudes and trust and as mediators of contact effects. Both anxiety and symbolic threat, but not realistic threat, emerged as predictors of the criterion variables and mediated contact effects. Our results provide support for the moderating role of identification and suggest that while symbolic threat predicts attitudes and trust for high, but not low identifiers, anxiety is a somewhat more important predictor for low than for high identifiers. We discuss these results against the background of current intergroup relations in Northern Ireland.


CMV Immunoglobulins for the Treatment of CMV Infections in Thoracic Transplant Recipients.
Intravenous ganciclovir and, increasingly, oral valganciclovir are now considered the mainstay of treatment for cytomegalovirus (CMV) infection or CMV disease. Under certain circumstances, CMV immunoglobulin (CMVIG) may be an appropriate addition or, indeed, alternative. Data on monotherapy with CMVIG are limited, but encouraging, for example in cases of ganciclovir intolerance. In cases of recurrent CMV in thoracic transplant patients after a disease- and drug-free period, adjunctive CMVIG can be considered in patients with hypogammaglobulinemia. Antiviral-resistant CMV, which is more common among thoracic organ recipients than in other types of transplant, can be an indication for introduction of CMVIG, particularly in view of the toxicity associated with other options, such as foscarnet. Due to a lack of controlled trials, decision-making is based on clinical experience. In the absence of a robust evidence base, it seems reasonable to consider the use of CMVIG to treat CMV in adult or pediatric thoracic transplant patients with ganciclovir-resistant infection, or in serious or complicated cases. The latter can potentially include (i) treatment of severe clinical manifestations, such as pneumonitis or eye complications; (ii) patients with a positive biopsy in end organs, such as the lung or stomach; (iii) symptomatic cases with rising polymerase chain reaction values (for example, higher than 5.0 log10) despite antiviral treatment; (iv) CMV disease or CMV infection or risk factors, such as CMV-IgG-negative serostatus; (vi) ganciclovir intolerance; (vii) patients with hypogammaglobulinemia.


Docking of tryptophanyl [corrected tryptophan] analogs to trytophanyl-tRNA synthetase: implications for non-canonical amino acid incorporations.
Non-canonical amino acids (NAA), as building blocks for peptides and proteins during ribosomal translation, represent a nearly infinite supply of novel functions. The specific selection, activation and tRNA-charging of amino acids by aminoacyl-tRNA synthetases (AARS) in the aminoacylation reaction are essential steps. In most cases, aminoacylation of N(AA) is a good indication that the related amino acid will participate in ribosomal translation as well. However, testing the translational capacity of amino acid analogs has technical limitations. Therefore, a rapid and reliable in silico test for NAA recognition by AARS would be advantageous in experimental design. We chose tryptophanyl-tRNA synthetase from Escherichia coli as a model system for docking studies with various tryptophan analogs using the FlexX-Pharm strategy. We were able to calculate relative binding energies for Trp analogs in TrpRS that correlate well with their translational activities in E. coli. In particular, FlexX-Pharm predicted the binding sites of fluoro-, amino-, hydroxyl- and aza-containing Trp analogs within 1.5 A of Trp in the homology model of E. coli TrpRS. Therefore, the use of ligand docking prior to NAA incorporation experiments might provide a straightforward means for determining NAA that can be efficiently incorporated into a protein.


Associations among albuminuria, C-reactive protein concentrations, survival predictor index scores, and survival in 78 critically ill dogs.
Microalbuminuria and C-reactive protein (CRP) are predictors of morbidity and survival in critically ill human patients. To evaluate results of microalbuminuria assays (untimed single-sample urine albumin concentration [U-ALB] and the urine albumin:creatinine ratio [UACR]), serum CRP, and survival predictor index (SPI2) scores as predictors of survival in critically ill dogs. Seventy-eight dogs admitted to intensive care units at University of Tennessee (UT) and Colorado State University (CSU). Prospective observational study. Critically ill dogs were eligible for enrollment, unless euthanized because of financial constraints. Samples were collected within 3 hours of admission. Spearman's rank-correlation coefficients were determined for U-ALB, UACR, CRP, and SPI2. U-ALB, UACR, CRP, and SPI2 were assessed for associations with 7- and 30-day survival by Mann-Whitney U-tests and receiver operating characteristic (ROC) curves. P-values < .0125 were considered significant. UT (n = 49) and CSU (n = 29) patients did not differ significantly. Forty percent (31/78) of dogs died. SPI2 was inversely correlated with U-ALB (r(s) = -0.39, P < .001) and UACR (r(s) = -0.41, P < .001). CRP was not correlated with SPI2 (P = .019), U-ALB (P > .1), or UACR (P > .1). U-ALB and UACR had very high correlation (r(s) = 0.95, P < .001). SPI2, U-ALB, and UACR differed significantly for survivors and nonsurvivors. SPI2, U-ALB, and UACR had areas under the ROC curve (AUC) from 0.68 to 0.74 for survival prediction. Albuminuria and SPI2, but not CRP, are associated with survival in critically ill dogs. Suboptimal AUCs limit the value of microalbuminuria testing for clinical risk assessment. Additional studies are necessary to determine the usefulness of microalbuminuria testing in patient risk stratification for prospective research.


The perception of three-dimensional cast-shadow structure is dependent on visual awareness.
In the present study we examined whether the perception of depth from cast shadows is dependent on visual awareness using continuous flash suppression (CFS). As a direct measure of how the visual system infers depth from cast shadows, we examined the cast-shadow motion illusion originally reported by Kersten, Knill, Mamassian, and Bulthoff (1996), in which a moving cast shadow induces illusory motion in depth in a physically stationary object. In Experiment 1, we used a disparity defined probe to determine the stereo motion speed required to match the cast-shadow motion illusion for different cast shadow speeds (0°/s-1.6°/s) and different lighting directions. We found that configurations implying light from above produce more compelling illusory effects. We also found that increasing shadow speed monotonically increased the stereo motion speed required to match the illusory motion, which suggests that quantitative depth can be derived from cast shadows when they are in motion. In Experiment 2, we used CFS to suppress the cast shadow from visual awareness. Visual suppression of the cast shadow from awareness greatly diminished the perception of illusory motion in depth. In Experiment 3 we confirmed that while CFS suppresses the cast-shadow motion from awareness, it continues to be processed by the visual system sufficient to generate a significant motion after effect. The results of the present study suggest that cast shadows can greatly contribute to the perception of scene depth structure, through a process that is dependent on the conscious awareness of the cast shadow.


Pilot testing a cognitive-behavioral protocol on psychosocial predictors of exercise, nutrition, weight, and body satisfaction changes in a college-level health-related fitness course.
Small-scale pilot testing of supplementing a required college health-related fitness course with a cognitive-behavioral exercise-support protocol (The Coach Approach). Three classes were randomly assigned to Usual processes (n = 32), Coach Approach-supplemented: Mid-size Groups (n = 32), and Coach Approach-supplemented: Small Groups (n = 34) conditions. Repeated-measures analyses of variance (ANOVAs) assessed overall and between-class changes in the behavioral/physiological factors of exercise, fruit/vegetable intake, and body mass index (BMI); and the psychosocial factors of self-regulation, exercise self-efficacy, mood, and body satisfaction. Dependent t tests evaluated within-class changes. Multiple regression analyses tested prediction of exercise by changes in self-regulation, self-efficacy, and mood. Significant improvements in self-regulation and fruit/vegetable intake were found in all classes. The Coach Approach-supplemented classes demonstrated significant increases in exercise. Significant improvements in BMI, self-efficacy, and body satisfaction were found in only The Coach Approach-supplemented: Small Groups class. Psychosocial changes predicted increased exercise. Self-regulation was the strongest contributor. Overall, results were positive and warrant more comprehensive testing.


Red leaf margins indicate increased polygodial content and function as visual signals to reduce herbivory in Pseudowintera colorata.
Red-pigmented leaf margins are common, but their functional significance is unknown. We hypothesized that red leaf margins reduce leaf herbivory by signalling to herbivorous insects the presence of increased chemical defences. Leaves were collected from a natural population of Pseudowintera colorata. Margin size, herbivory damage, anthocyanin content and concentrations of polygodial, a sesquiterpene dialdehyde with antifeedant properties, were quantified. Feeding trials involving larvae of Ctenopseustis obliquana, a generalist herbivore, were conducted on red- and green-margined P. colorata leaves in darkness, or under white, green or red light. Leaves with wider red margins contained higher concentrations of polygodial and anthocyanins, and incurred less natural herbivory. In trials under white light, C. obliquana consumed disproportionately more green- than red-margined leaf laminae. Larvae exhibited no feeding preference when light was manipulated such that leaf colour discrimination was impaired. Red leaf margins provide a reliable and effective visual signal of chemical defence in P. colorata. Ctenopseustis obliquana larvae perceive and respond to the colour of the leaf margins, rather than to olfactory signals. Our study provides direct experimental evidence for aposematic coloration in red leaves.


Prospects and challenges of graphene in biomedical applications.
Graphene materials have entered a phase of maturity in their development that is characterized by their explorative utilization in various types of applications and fields from electronics to biomedicine. Herein, we describe the recent advances made with graphene-related materials in the biomedical field and the challenges facing these exciting new tools both in terms of biological activity and toxicological profiling in vitro and in vivo. Graphene materials today have mainly been explored as components of biosensors and for construction of matrices in tissue engineering. Their antimicrobial activity and their capacity to act as drug delivery platforms have also been reported, however, not as coherently. This report will attempt to offer some perspective as to which areas of biomedical applications can expect graphene-related materials to constitute a tool offering improved functionality and previously unavailable options.


Treating intractable phantom limb pain with ambulatory continuous peripheral nerve blocks: a pilot study.
There is currently no reliable treatment for phantom limb pain (PLP). Chronic PLP and associated cortical abnormalities may be maintained from abnormal peripheral input, raising the possibility that a continuous peripheral nerve block (CPNB) of extended duration may permanently reorganize cortical pain mapping, thus providing lasting relief. Three men with below-the-knee (2) or -elbow (1) amputations and intractable PLP received femoral/sciatic or infraclavicular perineural catheter(s), respectively. Subjects were randomized in a double-masked fashion to receive perineural ropivacaine (0.5%) or normal saline for over 6 days as outpatients using portable electronic infusion pumps. Four months later, subjects returned for repeated perineural catheter insertion and received an ambulatory infusion with the alternate solution ("crossover"). Subjects were followed for up to 1 year. By chance, all three subjects received saline during their initial infusion and reported little change in their PLP. One subject did not receive crossover treatment, but the remaining two subjects reported complete resolution of their PLP during and immediately following treatment with ropivacaine. One subject experienced no PLP recurrence through the 52-week follow-up period and the other reported mild PLP occurring once each week of just a small fraction of his original pain (pretreatment: continuous PLP rated 10/10; posttreatment: no PLP at baseline with average of one PLP episode each week rated 2/10) for 12 weeks (lost to follow-up thereafter). A prolonged ambulatory CPNB may be a reliable treatment for intractable PLP. The results of this pilot study suggest that a large, randomized clinical trial is warranted.


Feasibility of Topical Applications of Natural High-Concentration Capsaicinoid Solutions in Patients with Peripheral Neuropathic Pain: A Retrospective Analysis.
Background. Capsaicin, one of several capsaicinoid compounds, is a potent TRPV1 agonist. Topical application at high concentration (high concentration, >1%) induces a reversible disappearance of epidermal free nerve endings and is used to treat peripheral neuropathic pain (PNP). While the benefit of low-concentration capsaicin remains controversial, the 8%-capsaicin patch (Qutenza®, 2010, Astellas, Netherlands) has shown its effectiveness. This patch is, however, costly and natural high-concentration capsaicinoid solutions may represent a cheaper alternative to pure capsaicin. Methods. In this retrospective study, 149 patients were screened, 132 were included with a diagnosis of neuropathic pain, and eighty-four were retained in the final analyses (median age: 57.5 years [IQR25-75: 44.7-67.1], male/female: 30/54) with PNP who were treated with topical applications of natural high-concentration capsaicinoid solutions (total number of applications: 137). Indications were postsurgical PNP (85.7%) and nonsurgical PNP (14.3%) (posttraumatic, HIV-related, postherpetic, and radicular PNP). Objectives. To assess the feasibility of topical applications of natural high-concentration capsaicinoid solutions for the treatment of PNP. Results. The median treated area was 250 cm2 [IQR25-75: 144-531]. The median amount of capsaicinoids was 55.1 mg [IQR25-75: 28.7-76.5] per plaster and the median concentration was 172.3 μg/cm2 [IQR25-75: 127.6-255.2]. Most patients had local adverse effects on the day of treatment, such as mild to moderate burning pain and erythema. 13.6-19.4% of the patients experienced severe pain or erythema. Following treatment, 62.5% of patients reported a lower pain intensity or a smaller pain surface, and 35% reported a sustained pain relief lasting for at least 4 weeks. Conclusion. Analgesic topical treatment with natural high-concentration capsaicinoid is feasible and may represent a low cost alternative to alleviate PNP in clinical practice.


Stereochemical restrictions on the occurrence of amino acid residues in the collagen structure.
The primary structure of collagen is characterized by the repeating tripeptide sequence (Gly-R2-R3)n. The results of theoretical studies, carried out using contact criteria to compute the stereochemically allowed orientations for various side chains at locations 2 and 3, are reported here. It is found that side chains with only gamma-atoms, as in valine, serine and threonine, or with only one delta-methyl group, as in isoleucine, can occur equally well at locations 2 and 3, as is actually the case in collagen. Side chains with two Cdelta-atoms, as in leucine and phenylalanine, can also be accommodated at both positions. However, if they occur as R3, their freedom of orientation is severely restricted in the presence of a proline residue as R2 in a neighbouring chain. If water molecules bound to the chains of the triple helix are assumed to be present, then location 3 is virtually impossible for leucine and phenylalanine residues. Location 2 is, however, unaffected, and their presence as R2 can help to shield the water molecules from disturbance by the solvent medium. This may be the reason for the preferential occurrence of Leu and Phe residues in location 2 in the collagen triplets, although the polypeptides (Gly-Pro-Leu)n and (Gly-Pro-Phe)n form collagen-like structures.


A multidisciplinary approach for assessing the toxicity of marine sediments: analysis of metal content and elutriate bioassays using metal bioavailability and genotoxicity biomarkers.
The goal of this article is to verify the applicability of two different biological assays for studying a coastal area that is subject to anthropogenic inputs. Phytochelatins in the marine diatom Thalassiosira weissflogii were used as a biomarker of metal bioavailability. The frequency of genetic damage in the sensitive D7 strain of the yeast Saccharomyces cerevisiae was used to estimate the mutagenic potential. Biological assays were carried out using sediment elutriates. Sediments were collected at three selected sites located in the Gulf of Follonica (Tuscany, Italy), during a 2-year sampling period: Cala Violina (reference site) and the mouths of the rivers Pecora and Cornia, named sites V, P and C, respectively. The chemical characterization of each site was determined in terms of metal concentrations (As, Cd, Cr, Cu, Ni, Pb), measured in 11 sediment samples for each site. The results showed that metal concentrations in sediments from sites C and P were 2-10 times higher than the reference values (site V, year 2004). In addition, we found generally higher metal concentrations in the 2007 sediments than in the 2008 ones, including those of site V, due to the occurrence of an unexpected pollution event. This enabled us to obtain a pollution gradient to validate the proposed bioassays. In fact, the bioassays showed a potential biological hazard in the 2007 elutriates. Significant mutagenic effects were found in samples exhibiting higher concentrations of Cd and Cr. The induction of phytochelatins in T. weissflogii correlated positively with the Cd concentration in the elutriates.


Tissue specific HPV expression and downregulation of local immune responses in condylomas from HIV seropositive individuals.
To study the effect of tissue specific human papillomavirus (HPV) expression and its effect on local immunity in condylomas from HIV positive individuals. Biopsy specimens of eight penile and eight perianal condylomas from HIV seropositive individuals were analysed. Expression of viral genes (HIV-tat and HPV E7 and L1) was determined by RT-PCR. The status of local immunity also was determined by RT-PCR by measuring CD4, CD8, CD16, CD1a, HLA-DR, and HLA-B7 mRNA levels in the tissues. Differentiation was determined by measuring involucrin, keratinocyte transglutaminase, as well as cytokeratins 10, 16, and 17. Proliferation markers such as PCNA and c-myc were also determined. The transcription pattern of HPV in perianal condylomas, which preferentially expressed the early (E7) gene, was different from that of penile condylomas, which primarily expressed the late (L1) gene. This transcription pattern is in good correlation with the keratinisation and differentiation patterns of the two epithelia: perianal biopsies preferentially expressed K16 and K17 while penile warts mainly expressed K10, markers of parakeratotic and orthokeratotic epithelia, respectively. Perianal biopsies also showed a higher degree of proliferation (PCNA and c-myc). Interestingly, transcription of HIV-tat was also higher in perianal than in penile biopsies. A high degree of local immunodeficiency was observed in perianal biopsies--that is, levels of CD4, CD16, and CD1a mRNAs were significantly lower. A negative correlation between CD1a (Langerhans cells) levels and HPV E7 levels was established. HPV E7 levels positively correlated with HIV-tat levels. Perianal tissues demonstrated more CD1a depression and tat associated HPV upregulation. HIV influences the expression of HPV genes resulting in local immunosuppression that might lead to an inappropriate immune surveillance of viral infection. Also, tissue type is an important factor in controlling viral transcription in a differentiation dependent manner. These findings may explain the higher rate of dysplasia and neoplasia in the perianal area.


Compatibility of aminophylline and verapamil in intravenous admixtures.
The chemical and visual compatibility of aminophylline and verapamil hydrochloride in intravenous admixtures was evaluated. Verapamil hydrochloride injection was added to a solution of aminophylline 1.0 mg/mL in 5% dextrose injection (D5W) to yield final verapamil hydrochloride concentrations of 0.1 and 0.4 mg/mL. Each solution type was prepared in triplicate. An aliquot from each of these solutions was assayed in duplicate for theophylline and verapamil by high-performance liquid chromatography at 0, 4, 8, 12, and 24 hours after mixing. All aliquots were filtered with a 0.22-micron filter immediately before assay. At each time interval, samples were assessed for pH and inspected visually and microscopically for evidence of incompatibility. Theophylline concentrations showed less than 10% change over 24 hours in the two-drug admixtures. Less than 1% of the original verapamil concentrations remained immediately after mixing with aminophylline injection in D5W. Turbidity was readily apparent in the admixture containing verapamil hydrochloride 0.4 mg/mL; however, microscopic evaluation revealed precipitate in both solutions. Solution pH was determined to be a primary cause of precipitation. The mean pH values for the verapamil hydrochloride 0.1 and 0.4 mg/mL control solutions were 4.09 and 4.36, respectively. The mean pH of the aminophylline 1.0 mg/mL control solution was 8.35. The mean pH of the aminophylline-verapamil admixtures at verapamil hydrochloride concentrations of 0.1 and 0.4 mg/mL was 8.14 and 8.06, respectively. Verapamil hydrochloride injection in final concentrations of 0.1 and 0.4 mg/mL is incompatible with aminophylline 1.0 mg/mL in D5W.


Translocation of silver nanoparticles in the ex vivo human placenta perfusion model characterized by single particle ICP-MS.
With the extensive use of silver nanoparticles (AgNPs) in various consumer products their potential toxicity is of great concern especially for highly sensitive population groups such as pregnant women and even the developing fetus. To understand if AgNPs are taken up and cross the human placenta, we studied their translocation and accumulation in the human ex vivo placenta perfusion model by single particle ICP-MS (spICP-MS). The impact of different surface modifications on placental transfer was assessed by AgNPs with two different modifications: polyethylene glycol (AgPEG NPs) and sodium carboxylate (AgCOONa NPs). AgNPs and ionic Ag were detected in the fetal circulation in low but not negligible amounts. Slightly higher Ag translocation across the placental barrier for perfusion with AgPEG NPs and higher AgNP accumulation in placental tissue for perfusion with AgCOONa NPs were observed. Since these AgNPs are soluble in water, we tried to distinguish between the translocation of dissolved and particulate Ag. Perfusion with AgNO3 revealed the formation of Ag containing NPs in both circulations over time, of which the amount and their size in the fetal circulation were comparable to those from perfusion experiments with both AgNP types. Although we were not able to clarify whether intact AgNPs and/or Ag precipitates from dissolved Ag cross the placental barrier, our study highlights that uptake of Ag ions and/or dissolution of AgNPs in the tissue followed by re-precipitation in the fetal circulation needs to be considered as an important pathway in studies of AgNP translocation across biological barriers.


Largely Unchanged Annual Incidence and Overall Survival of Pleural Mesothelioma in the USA.
Projections based on regulations curtailing asbestos use in the USA suggest that peak incidence of pleural mesothelioma would occur between 2000 and 2005 and then decline. We analyzed the National Cancer Database (NCDB) to assess current trends in disease incidence, patient demographics, cancer treatment, and survival. The NCDB was queried to identify patients diagnosed with pleural mesothelioma from 2004 through 2014. Clinical and pathologic characteristics, treatments, and survival were analyzed. Risk factors for death were identified by multivariable Cox regression. A total of 20,988 patients with pleural mesothelioma were reported to the NCDB. The number of cases per year increased from 1783 to 1961, accounting for roughly 0.3% of all reported cancers each year. The proportion of elderly patients increased from 75 to 80%, but distribution by sex remained constant (20% female). The proportion of patients undergoing treatment increased from 34 to 54%. One-year survival increased from 37 to 47% and 3-year survival from 9 to 15% (p < 0.001). Factors associated with improved survival included younger age, female sex, epithelioid histology, treatment in an academic center, health insurance, higher income, and multimodality therapy. The annual incidence of mesothelioma has not declined this century and remains stable. Reporting of histologic and clinical staging has improved. National trends suggest that survival is slowly increasing despite an aging cohort. Multimodal therapy and treatment at academic centers are modifiable risk factors associated with improved survival.


Comparison of cefotetan plus doxycycline with cefoxitin plus doxycycline in the inpatient treatment of acute salpingitis.
Pelvic inflammatory disease (PID), one of the major sequelae of the current epidemic of sexually transmitted diseases, has been shown to be a polymicrobial infection. This study compares the efficacy and safety of two broad-spectrum combination drug regimens, cefotetan with doxycycline and cefoxitin with doxycycline, in the treatment of PID. A total of 108 patients with acute salpingitis were hospitalized and randomized into two treatment groups: cefotetan/doxycycline (N = 54) and cefoxitin/doxycycline (N = 54). Before antibiotic administration, Chlamydia trachomatis was identified in 17 (16%) of the patients, Neisseria gonorrhoeae from 72 (67%), and anaerobic and aerobic bacteria were identified from the endometrial cultures of 86 (80%). There were seven tubo-ovarian abscesses (TOAs) that were diagnosed in the cefotetan group, and six in the cefoxitin group. Clinical cure was achieved in 51 of 54 (94%) patients in each group. Of the six patients whose treatment failed, all had positive cultures for N. gonorrhoeae and facultative/anaerobic bacteria, whereas none had C. trachomatis. Two patients from each study arm whose treatment failed were diagnosed with TOAs and responded subsequently to clindamycin plus an aminoglycoside. Cultures that were obtained after the completion of inpatient treatment showed the eradication of C. trachomatis and N. gonorrhoeae in all patients. Also, both regimens were effective in reducing aerobic and anaerobic pathogens. Finally, both regimens were well tolerated, with few side-effects.


On-chip integratable all-optical quantizer using strong cross-phase modulation in a silicon-organic hybrid slot waveguide.
High performance all-optical quantizer based on silicon waveguide is believed to have significant applications in photonic integratable optical communication links, optical interconnection networks, and real-time signal processing systems. In this paper, we propose an integratable all-optical quantizer for on-chip and low power consumption all-optical analog-to-digital converters. The quantization is realized by the strong cross-phase modulation and interference in a silicon-organic hybrid (SOH) slot waveguide based Mach-Zehnder interferometer. By carefully designing the dimension of the SOH waveguide, large nonlinear coefficients up to 16,000 and 18,069 W(-1)/m for the pump and probe signals can be obtained respectively, along with a low pulse walk-off parameter of 66.7 fs/mm, and all-normal dispersion in the wavelength regime considered. Simulation results show that the phase shift of the probe signal can reach 8π at a low pump pulse peak power of 206 mW and propagation length of 5 mm such that a 4-bit all-optical quantizer can be realized. The corresponding signal-to-noise ratio is 23.42 dB and effective number of bit is 3.89-bit.


The association between misperceptions around weight status and quality of life in adults in Australia.
Limited evidence supports a possible association between a person's perception of their weight status and their quality of life (QoL). This study evaluates whether misperception around weight status is associated with QoL and the impact of gender on this association. A cross-sectional survey of Australian adults (n = 1,905 analysed) collected self-reported height and weight (used to estimate BMI), gender and QoL (described using the AQoL-8D). Participants reported whether they perceived their weight status to be 'underweight', 'healthy weight', 'overweight' or 'obese'. Misperception around weight status was categorised based on perceived weight status and self-reported BMI. Ordinary least squares regression was used to test associations between self-reported overall, physical and psychosocial QoL, misperception of weight status, and gender, across different BMI categories, after controlling for income, education, relationship status and health conditions. Compared to accurate perception, underestimation of weight status was associated with higher overall QoL for obese males and females and for overweight males. Overestimation of weight status was associated with higher overall QoL for underweight females and lower overall QoL for healthy weight males and females. The same pattern was seen for psychosocial QoL. Physical QoL was less sensitive to misperception than psychosocial QoL. Self-reported misperception around weight status is associated with overall, psychosocial and to a lesser extent physical QoL in Australian adults, although its role depends on BMI category and gender. Generally misperception in the direction of "healthy weight" is associated with higher QoL and overestimation of weight status by those who are of healthy weight is associated with lower QoL. Findings should be confirmed in datasets that contain measured as opposed to self-report height and weight.


Principles to guide the development of population health incentives.
Improving population health is not simple. Many instruments are available for changing behavior and consequent outcomes. However, the following basic principles should guide development of any incentive arrangement: 1) identify the desired outcome, 2) identify the behavior change that will lead to this outcome, 3) determine the potential effectiveness of the incentive in achieving the behavior change, 4) link a financial incentive directly to this outcome or behavior, 5) identify the possible adverse effects of the incentive, and 6) evaluate and report changes in the behavior or outcome in response to the incentive. A wide range of financial and nonfinancial incentives is available to encourage efficient behaviors and discourage costly and unproductive ones. Evidence for the beneficial effects of incentive programs has been slow to emerge, partly because such evidence must show how behaviors have changed because of the incentive. Nevertheless, the potential for incentive programs in health care seems large, and research should support their design and assess their effect.


Very large magnetoresistance in graphene nanoribbons.
Graphene has unique electronic properties, and graphene nanoribbons are of particular interest because they exhibit a conduction bandgap that arises due to size confinement and edge effects. Theoretical studies have suggested that graphene nanoribbons could have interesting magneto-electronic properties, with a very large predicted magnetoresistance. Here, we report the experimental observation of a significant enhancement in the conductance of a graphene nanoribbon field-effect transistor by a perpendicular magnetic field. A negative magnetoresistance of nearly 100% was observed at low temperatures, with over 50% magnetoresistance remaining at room temperature. This magnetoresistance can be tuned by varying the gate or source-drain bias. We also find that the charge transport in the nanoribbons is not significantly modified by an in-plane magnetic field. The large observed values of magnetoresistance may be attributed to the reduction of quantum confinement through the formation of cyclotron orbits and the delocalization effect under the perpendicular magnetic field.


A SNP-centric database for the investigation of the human genome.
Single Nucleotide Polymorphisms (SNPs) are an increasingly important tool for genetic and biomedical research. Although current genomic databases contain information on several million SNPs and are growing at a very fast rate, the true value of a SNP in this context is a function of the quality of the annotations that characterize it. Retrieving and analyzing such data for a large number of SNPs often represents a major bottleneck in the design of large-scale association studies. SNPper is a web-based application designed to facilitate the retrieval and use of human SNPs for high-throughput research purposes. It provides a rich local database generated by combining SNP data with the Human Genome sequence and with several other data sources, and offers the user a variety of querying, visualization and data export tools. In this paper we describe the structure and organization of the SNPper database, we review the available data export and visualization options, and we describe how the architecture of SNPper and its specialized data structures support high-volume SNP analysis. The rich annotation database and the powerful data manipulation and presentation facilities it offers make SNPper a very useful online resource for SNP research. Its success proves the great need for integrated and interoperable resources in the field of computational biology, and shows how such systems may play a critical role in supporting the large-scale computational analysis of our genome.


A joint encryption/watermarking system for verifying the reliability of medical images.
In this paper, we propose a joint encryption/water-marking system for the purpose of protecting medical images. This system is based on an approach which combines a substitutive watermarking algorithm, the quantization index modulation, with an encryption algorithm: a stream cipher algorithm (e.g., the RC4) or a block cipher algorithm (e.g., the AES in cipher block chaining (CBC) mode of operation). Our objective is to give access to the outcomes of the image integrity and of its origin even though the image is stored encrypted. If watermarking and encryption are conducted jointly at the protection stage, watermark extraction and decryption can be applied independently. The security analysis of our scheme and experimental results achieved on 8-bit depth ultrasound images as well as on 16-bit encoded positron emission tomography images demonstrate the capability of our system to securely make available security attributes in both spatial and encrypted domains while minimizing image distortion. Furthermore, by making use of the AES block cipher in CBC mode, the proposed system is compliant with or transparent to the DICOM standard.


A di-iron protein recruited as an Fe[II] and oxygen sensor for bacterial chemotaxis functions by stabilizing an iron-peroxy species.
Many bacteria contain cytoplasmic chemoreceptors that lack sensor domains. Here, we demonstrate that such cytoplasmic receptors found in 8 different bacterial and archaeal phyla genetically couple to metalloproteins related to β-lactamases and nitric oxide reductases. We show that this oxygen-binding di-iron protein (ODP) acts as a sensor for chemotactic responses to both iron and oxygen in the human pathogen Treponema denticola (Td). The ODP di-iron site binds oxygen at high affinity to reversibly form an unusually stable μ-peroxo adduct. Crystal structures of ODP from Td and the thermophile Thermotoga maritima (Tm) in the Fe[III]2-O22-, Zn[II], and apo states display differences in subunit association, conformation, and metal coordination that indicate potential mechanisms for sensing. In reconstituted systems, iron-peroxo ODP destabilizes the phosphorylated form of the receptor-coupled histidine kinase CheA, thereby providing a biochemical link between oxygen sensing and chemotaxis in diverse prokaryotes, including anaerobes of ancient origin.


Do physicians always flee from HMOs? New results using dynamic panel estimation methods.
To assess the impact of changes in relative health maintenance organization (HMO) penetration on changes in the physician-to-population ratio in California counties when changes in the economic conditions in California counties relative to the U.S. average are taken into account. Data on physicians who practiced in California at any time from 1988 to 1998 were obtained from the AMA Masterfile. The analysis was restricted to active, patient care physicians, excluding medical residents. Data on other covariates in the model were obtained from the Bureau of Economic Analysis, InterStudy, the Area Resource File, and the California state government. Data were merged using county FIPS codes. Changes in the physician-to-population ratio in California counties include the effects of both intrastate migration and interstate migration. A reduced-form model was estimated using the Arellano-Bond dynamic panel estimator. Economic conditions in California relative to the U.S. were measured as the ratio of county-level real per capita income to national-level real per capita income. Relative HMO penetration in California was measured as the ratio of county-level HMO penetration to HMO penetration in the U.S. relative HMO penetration was instrumented using five identifying variables to address potential endogeneity. Omitted-variable bias was controlled for by first differencing the model. The model also incorporated eight other covariates that may be associated with the demand for physicians: the percentage of the population enrolled in Medicaid, beds in short-term hospitals per 100,000 population, the percentage of the population that is black, the percentage of the population that is Hispanic, the percentage of the population that is Asian, the percentage of the population that is below age 18, the percentage of the population that is aged 65 and older, and the percentage of the population that are new legal immigrants in a given year. All of the above variables were lagged one period. The lagged physician-to-population ratio was also included to control for the supply of physicians. Separate equations were estimated for primary care physicians and specialist physicians. Changes in lagged relative HMO penetration are negatively associated with changes in specialist physicians per 100,000 population. However, this effect of HMO penetration is attenuated and at times reversed in areas where the magnitude of the difference in relative economic conditions is sufficiently large. We did not find any statistically significant effects for primary care physicians. Consistent with prior studies, we find that changes in physician supply are associated with changes in relative HMO penetration. Relative economic conditions are an important moderator of the effect of changes in relative HMO penetration on physician migration.


Expression of chemokine receptors CCR1 and CCR5 reflects differential activation of mononuclear phagocytes in pattern II and pattern III multiple sclerosis lesions.
Multiple sclerosis (MS) is an inflammatory demyelinating disorder of the CNS. A recent study identified 4 patterns of demyelination in active MS lesions. The characteristics of pattern II lesions suggested a primary inflammatory mechanism of myelin injury, while pattern III lesions showed features consistent with dying-back oligodendrogliopathy. The recruitment, differentiation, and activation of mononuclear phagocytes are dependent on the expression of chemokine receptors. Using immunohistochemistry we quantified cellular expression of CCR1 and CCR5 in pattern II (n = 21) and pattern III (n = 17) lesion areas of differing demyelinating activity. Infiltrating monocytes in both lesion patterns co-expressed CCR1 and CCR5, suggesting conserved mechanisms of monocyte recruitment into the CNS. In pattern II lesions, the number of cells expressing CCR1 significantly decreased while CCR5 increased in late active compared with early active demyelinating regions. In striking contrast, numbers of cells expressing CCR1 and CCR5 were equal in all regions of pattern III lesions. As hypoxia-like mechanisms may play a role in pattern III lesions, we extended these studies to white matter infarcts (n = 7) in which the expression of CCR1 better resembled pattern III than pattern II lesions. As judged by mononuclear phagocyte chemokine receptor expression, there appear to be distinct tissue environments in pattern II and III MS lesions.


History of biological metal utilization inferred through phylogenomic analysis of protein structures.
The fundamental chemistry of trace elements dictates the molecular speciation and reactivity both within cells and the environment at large. Using protein structure and comparative genomics, we elucidate several major influences this chemistry has had upon biology. All of life exhibits the same proteome size-dependent scaling for the number of metal-binding proteins within a proteome. This fundamental evolutionary constant shows that the selection of one element occurs at the exclusion of another, with the eschewal of Fe for Zn and Ca being a defining feature of eukaryotic proteomes. Early life lacked both the structures required to control intracellular metal concentrations and the metal-binding proteins that catalyze electron transport and redox transformations. The development of protein structures for metal homeostasis coincided with the emergence of metal-specific structures, which predominantly bound metals abundant in the Archean ocean. Potentially, this promoted the diversification of emerging lineages of Archaea and Bacteria through the establishment of biogeochemical cycles. In contrast, structures binding Cu and Zn evolved much later, providing further evidence that environmental availability influenced the selection of the elements. The late evolving Zn-binding proteins are fundamental to eukaryotic cellular biology, and Zn bioavailability may have been a limiting factor in eukaryotic evolution. The results presented here provide an evolutionary timeline based on genomic characteristics, and key hypotheses can be tested by alternative geochemical methods.


e-ASPECTS software is non-inferior to neuroradiologists in applying the ASPECT score to computed tomography scans of acute ischemic stroke patients.
Background The Alberta Stroke Program Early Computed Tomography Score (ASPECTS) is an established 10-point quantitative topographic computed tomography scan score to assess early ischemic changes. We performed a non-inferiority trial between the e-ASPECTS software and neuroradiologists in scoring ASPECTS on non-contrast enhanced computed tomography images of acute ischemic stroke patients. Methods In this multicenter study, e-ASPECTS and three independent neuroradiologists retrospectively and blindly assessed baseline non-contrast enhanced computed tomography images of 132 patients with acute anterior circulation ischemic stroke. Follow-up scans served as ground truth to determine the definite area of infarction. Sensitivity, specificity, and accuracy for region- and score-based analysis, receiver-operating characteristic curves, Bland-Altman plots and Matthews correlation coefficients relative to the ground truth were calculated and comparisons were made between neuroradiologists and different pre-specified e-ASPECTS operating points. The non-inferiority margin was set to 10% for both sensitivity and specificity on region-based analysis. Results In total 2640 (132 patients × 20 regions per patient) ASPECTS regions were scored. Mean time from onset to baseline computed tomography was 146 ± 124 min and median NIH Stroke Scale (NIHSS) was 11 (6-17, interquartile range). Median ASPECTS for ground truth on follow-up imaging was 8 (6.5-9, interquartile range). In the region-based analysis, two e-ASPECTS operating points (sensitivity, specificity, and accuracy of 44%, 93%, 87% and 44%, 91%, 85%) were statistically non-inferior to all three neuroradiologists (all p-values <0.003). Both Matthews correlation coefficients for e-ASPECTS were higher (0.36 and 0.34) than those of all neuroradiologists (0.32, 0.31, and 0.3). Conclusions e-ASPECTS was non-inferior to three neuroradiologists in scoring ASPECTS on non-contrast enhanced computed tomography images of acute stroke patients.


Rupture of the device landing zone during transcatheter aortic valve implantation: a life-threatening but treatable complication.
Iatrogenic damage of different structures of the aortic root, in the region of the so-called "device landing zone," may occur during transcatheter aortic valve implantation (TAVI). It is mostly considered difficult to treat or even untreatable. We performed a retrospective analysis of the occurrence, clinical presentation, treatment, and outcome of iatrogenic rupture in the device landing zone in a series of 618 consecutive patients who underwent TAVI at our institution between April 2008 and October 2011. The incidence of rupture was 1% (6 patients). The correct diagnosis was established during TAVI procedures in 4 and postmortem in 2 patients. The major sign of the aortic rupture was apparent bleeding in 4 patients and failure of myocardial recovery after valve implantation in 1; it was asymptomatic in 1 patient. The iatrogenic rupture in the region of the device landing zone was treated surgically in 5 patients and only conservatively in the patient without symptoms. When the diagnosis was established correctly during TAVI, only 1 of 4 patients died (25%). The overall mortality rate was 50% (3 of 6 patients died). Rupture of different structures in the device landing zone during TAVI is a life-threatening complication that can be treated successfully if it is immediately recognized and adequately managed.


Prognostic impact of reduced connexin43 expression and gap junction coupling of neoplastic stromal cells in giant cell tumor of bone.
Missense mutations of the GJA1 gene encoding the gap junction channel protein connexin43 (Cx43) cause bone malformations resulting in oculodentodigital dysplasia (ODDD), while GJA1 null and ODDD mutant mice develop osteopenia. In this study we investigated Cx43 expression and channel functions in giant cell tumor of bone (GCTB), a locally aggressive osteolytic lesion with uncertain progression. Cx43 protein levels assessed by immunohistochemistry were correlated with GCTB cell types, clinico-radiological stages and progression free survival in tissue microarrays of 89 primary and 34 recurrent GCTB cases. Cx43 expression, phosphorylation, subcellular distribution and gap junction coupling was also investigated and compared between cultured neoplastic GCTB stromal cells and bone marow stromal cells or HDFa fibroblasts as a control. In GCTB tissues, most Cx43 was produced by CD163 negative neoplastic stromal cells and less by CD163 positive reactive monocytes/macrophages or by giant cells. Significantly less Cx43 was detected in α-smooth muscle actin positive than α-smooth muscle actin negative stromal cells and in osteoclast-rich tumor nests than in the adjacent reactive stroma. Progressively reduced Cx43 production in GCTB was significantly linked to advanced clinico-radiological stages and worse progression free survival. In neoplastic GCTB stromal cell cultures most Cx43 protein was localized in the paranuclear-Golgi region, while it was concentrated in the cell membranes both in bone marrow stromal cells and HDFa fibroblasts. In Western blots, alkaline phosphatase sensitive bands, linked to serine residues (Ser369, Ser372 or Ser373) detected in control cells, were missing in GCTB stromal cells. Defective cell membrane localization of Cx43 channels was in line with the significantly reduced transfer of the 622 Da fluorescing calcein dye between GCTB stromal cells. Our results show that significant downregulation of Cx43 expression and gap junction coupling in neoplastic stromal cells are associated with the clinical progression and worse prognosis in GCTB.


Serum Biomarkers of Myocardial Remodeling and Coronary Dysfunction in Early Stages of Hypertrophic Cardiomyopathy in the Young.
Hypertrophic cardiomyopathy (HCM) remains the leading cause of sudden cardiac death in the young. Early markers for HCM are important to identify individuals at risk. The aim of this study was to investigate novel serum biomarkers reflecting myocardial remodeling, microfibrosis, and vascular endotheliopathy in the early stages of familial HCM in young patients. Twenty-three HCM patients, 16 HCM-risk individuals, and 66 controls (median 15 years) underwent echocardiography and serum analysis for cathepsin S, endostatin, myostatin, type I collagen degradation marker (ICTP), matrix metalloproteinase (MMP)-9, vascular endothelial growth factor receptor (VEGFR)-1, and vascular and intercellular adhesion molecules (VCAM, ICAM). In a subset of the population, global myocardial perfusion was performed by magnetic resonance imaging. Cathepsin S (p = 0.0009), endostatin (p < 0.0001), MMP-9 (p = 0.008), and VCAM (p = 0.04) were increased in the HCM group and correlated to left ventricular mass index and mitral E/e' (p < 0.01). In the HCM-risk group, myostatin was decreased (p = 0.004), whereas ICAM was increased (p = 0.002). Global perfusion was decreased in the HCM group (p < 0.05) versus controls. Endostatin and mitral E/e' correlated inversely to myocardial perfusion (p ≤ 0.05). This is the first study demonstrating adverse changes in biomarkers reflecting myocardial matrix remodeling, microfibrosis, and vascular endotheliopathy in early stage of hypertrophic cardiomyopathy in the young.


Point spread function engineering for iris recognition system design.
Undersampling in the detector array degrades the performance of iris-recognition imaging systems. We find that an undersampling of 8 x 8 reduces the iris-recognition performance by nearly a factor of 4 (on CASIA iris database), as measured by the false rejection ratio (FRR) metric. We employ optical point spread function (PSF) engineering via a Zernike phase mask in conjunction with multiple subpixel shifted image measurements (frames) to mitigate the effect of undersampling. A task-specific optimization framework is used to engineer the optical PSF and optimize the postprocessing parameters to minimize the FRR. The optimized Zernike phase enhanced lens (ZPEL) imager design with one frame yields an improvement of nearly 33% relative to a thin observation module by bounded optics (TOMBO) imager with one frame. With four frames the optimized ZPEL imager achieves a FRR equal to that of the conventional imager without undersampling. Further, the ZPEL imager design using 16 frames yields a FRR that is actually 15% lower than that obtained with the conventional imager without undersampling.


Low-dose compared with standard-dose m-BACOD chemotherapy for non-Hodgkin's lymphoma associated with human immunodeficiency virus infection. National Institute of Allergy and Infectious Diseases AIDS Clinical Trials Group.
Reduced doses of cytotoxic chemotherapy or standard-dose therapy plus a myeloid colony-stimulating factor decreases hematologic toxicity and its complications in patients with non-Hodgkin's lymphoma associated with infection with the human immunodeficiency virus (HIV). However, the effect of reducing the doses of cytotoxic chemotherapeutic agents on clinical outcome is not known. We randomly assigned 198 HIV-seropositive patients with previously untreated, aggressive non-Hodgkin's lymphoma to receive standard-dose therapy with methotrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine, and dexamethasone (m-BACOD) along with granulocyte-macrophage colony-stimulating factor (GM-CSF; n=94) or reduced-dose m-BACOD with GM-CSF administered only as indicated (n=98). A complete response was achieved in 39 of the 94 assessable patients assigned to low-dose therapy (41 percent) and in 42 of the 81 assessable patients assigned to standard-dose therapy (52 percent, P= 0.56). There were no significant differences in overall or disease-free survival; median survival times were 35 weeks for patients receiving low-dose therapy and 31 weeks for those receiving standard-dose therapy (risk ratio for death in the standard-dose group=1.17; 95 percent confidence interval, 0.84 to 1.63; P=0.25). Toxic effects of chemotherapy rated grade 3 or higher occurred in 66 of 94 patients assigned to standard-dose therapy (70 percent) and 50 of 98 patients assigned to low-dose treatment (51 percent, P=0.008). Hematologic toxicity accounted for the difference. As compared with treatment with standard doses of cytotoxic chemotherapy (m-BACOD), reduced doses caused significantly fewer hematologic toxic effects yet had similar efficacy in patients with HIV-related lymphoma. Dose-modified chemotherapy should be considered for most HIV-infected patients with lymphoma.


Prospective analysis of factors predicting feasibility & success of longitudinal intussusception vasoepididymostomy in men with idiopathic obstructive azoospermia.
: Microsurgical reconstruction for idiopathic obstructive azoospermia is a challenging procedure, and selection of appropriate patients is important for successful outcomes. This prospective study was done to evaluate the ability of scrotal ultrasound measurements to predict the surgical feasibility and determine factors that could predict a patent anastomosis following vaso-epididymal anastomosis (VE) in men with idiopathic obstructive azoospermia. : In this prospective study, men diagnosed with idiopathic obstructive azoospermia, scheduled for a longitudinal intussusception VE, underwent a scrotal ultrasound measurement of testicular and epididymal dimensions. During surgery, site and type of anastomosis, presence of sperms in the epididymal fluid and technical satisfaction with the anastomosis were recorded. All men where VE could be performed were followed up for appearance of sperms in the ejaculate. Ultrasound parameters were compared between men who had a VE versus those with negative exploration. Predictive factors were compared between men with or without a patent anastomosis. : Thirty four patients were included in the study conducted between September 2014 and August 2016 and a VE was possible in only 19 (55%) patients. Of these 19 patients, six had a patent anastomosis with one pregnancy. Preoperative ultrasound measurements could not identify patients where a VE could not be performed. Motile sperm in the epididymal fluid was the only significant predictor of a successful anastomosis. : Forty five per cent of men planned for a VE for idiopathic obstructive azoospermia could not undergo a reconstruction. Ultrasound assessment of testicular and epididymal dimensions could not predict the feasibility of performing a VE. The presence of motile sperms in the epididymal fluid was the only significant predictor of a patent VE in our study.


Evolutionary rate and genetic drift of hepatitis C virus are not correlated with the host immune response: studies of infected donor-recipient clusters.
Six donor-recipient clusters of hepatitis C virus (HCV)-infected individuals were studied. For five clusters the period of infection of the donor could be estimated, and for all six clusters the time of infection of the recipients from the donor via blood transfusion was also precisely known. Detailed phylogenetic analyses were carried out to investigate the genomic evolution of the viral quasispecies within infected individuals in each cluster. The molecular clock analysis showed that HCV quasispecies within a patient are evolving at the same rate and that donors that have been infected for longer time tend to have a lower evolutionary rate. Phylogenetic analysis based on the split decomposition method revealed different evolutionary patterns in different donor-recipient clusters. Reactivity of antibody against the first hypervariable region (HVR1) of HCV in donor and recipient sera was evaluated and correlated to the calculated evolutionary rate. Results indicate that anti-HVR1 reactivity was related more to the overall level of humoral immune response of the host than to the HVR1 sequence itself, suggesting that the particular sequence of the HVR1 peptides is not the determinant of reactivity. Moreover, no correlation was found between the evolutionary rate or the heterogeneity of the viral quasispecies in the patients and the strength of the immune response to HVR1 epitopes. Rather, the results seem to imply that genetic drift is less dependent on immune pressure than on the rate of evolution and that the genetic drift of HCV is independent of the host immune pressure.


Phase I study of 131I-chimeric(ch) TNT-1/B monoclonal antibody for the treatment of advanced colon cancer.
The primary aim of this study was to evaluate the biodistribution and toxicity of 131I-chimeric(ch) TNT-1/B monoclonal antibody (MAB), which binds to intracellular antigens of necrotic regions within tumors, in patients with advanced colon or colorectal cancer. The rationale for targeting areas of tumor necrosis is the observation that necrotic lesions are more abundant in cancer lesions than in surrounding tissues. Cohorts of patients with advanced colon or colorectal cancer were administered a one-time 30-60-minute intravenous (i.v.) infusion of 131I-chTNT-1/B at doses ranging from 12.95 to 66.23 MBq/kg (0.35-1.79 mCi/kg). The dose-limiting toxicity, experienced at 66.23 MBq/kg (1.79 mCi/kg) 131I-chTNT-1/B MAB, was myelosuppression. Two (2) patients at the 66.23-MBq/kg (1.79 mCi/kg) dose level had both grade 3 thrombocytopenia and grade 3 neutropenia that persisted for at least 2 weeks but were reversible. The maximum tolerated dose was 58.09 MBq/kg (1.57 mCi/kg) 131I-chTNT-1/B MAB. Of the 21 patients, one developed a moderate human antichimeric antibody (HACA) response and 6 developed low HACA responses. The infusion of 131I-chTNT-1/B MAB was well tolerated, without significant nonhematological toxicity. No patient obtained a complete or partial response, based on tumor cross-product response criteria. Tumor localization was seen in patients with dose levels at, and exceeding, 50.23 MBq/kg (1.36 mCi/kg) 131I-chTNT-1/B MAB.


Negative Consequences of Pressure on Marksmanship May be Offset by Early Training Exposure to Contextually Relevant Threat Training: A Systematic Review and Meta-Analysis.
The purpose of this meta-analytic review is to examine the relationship between increased psychological pressure and Use of Force (UOF) behaviours, identifying current training methodologies and effectiveness of transfer of training interventions in high threat-simulated scenarios. Data from UOF performance within Law Enforcement indicates a low transfer of marksmanship training into real-world UOF, resulting in unnecessary damage to property, personal injury and increased risk to loss of life. This meta-analysis examines both the impact of increased pressure and current training interventions. A meta-analysis was conducted across a wide range of published research to answer the primary research questions. Increased levels of perceived pressure demonstrated an average decrease in marksmanship accuracy of 14.8%, together with a small increase in incorrect Decision Making (DM) and faster reaction Times (RT). Experience demonstrated a mitigating effect for pressure for marksmanship with a 1.1% increase for every one year of service but no effect on DM or RT. Training interventions utilizing a variety of early contextually relevant exposures to increased pressure improved performance over traditional training on average by 10.6%. The outcomes illustrate the negative effect of pressure on marksmanship and UOF behaviours, and that early exposure to contextually relevant pressure may increase the transfer of training to real-world performance. Occupational experience is an important component in reducing the impact of pressure on UOF performance, and transfer of training may be enhanced through training methodologies that combine early exposure to contextually relevant pressure, that may replicate the benefits of experience.


Conventional versus hypofractionated high-dose intensity-modulated radiotherapy for prostate cancer: 5-year outcomes of the randomised, non-inferiority, phase 3 CHHiP trial.
Prostate cancer might have high radiation-fraction sensitivity that would give a therapeutic advantage to hypofractionated treatment. We present a pre-planned analysis of the efficacy and side-effects of a randomised trial comparing conventional and hypofractionated radiotherapy after 5 years follow-up. CHHiP is a randomised, phase 3, non-inferiority trial that recruited men with localised prostate cancer (pT1b-T3aN0M0). Patients were randomly assigned (1:1:1) to conventional (74 Gy delivered in 37 fractions over 7·4 weeks) or one of two hypofractionated schedules (60 Gy in 20 fractions over 4 weeks or 57 Gy in 19 fractions over 3·8 weeks) all delivered with intensity-modulated techniques. Most patients were given radiotherapy with 3-6 months of neoadjuvant and concurrent androgen suppression. Randomisation was by computer-generated random permuted blocks, stratified by National Comprehensive Cancer Network (NCCN) risk group and radiotherapy treatment centre, and treatment allocation was not masked. The primary endpoint was time to biochemical or clinical failure; the critical hazard ratio (HR) for non-inferiority was 1·208. Analysis was by intention to treat. Long-term follow-up continues. The CHHiP trial is registered as an International Standard Randomised Controlled Trial, number ISRCTN97182923. Between Oct 18, 2002, and June 17, 2011, 3216 men were enrolled from 71 centres and randomly assigned (74 Gy group, 1065 patients; 60 Gy group, 1074 patients; 57 Gy group, 1077 patients). Median follow-up was 62·4 months (IQR 53·9-77·0). The proportion of patients who were biochemical or clinical failure free at 5 years was 88·3% (95% CI 86·0-90·2) in the 74 Gy group, 90·6% (88·5-92·3) in the 60 Gy group, and 85·9% (83·4-88·0) in the 57 Gy group. 60 Gy was non-inferior to 74 Gy (HR 0·84 [90% CI 0·68-1·03], pNI=0·0018) but non-inferiority could not be claimed for 57 Gy compared with 74 Gy (HR 1·20 [0·99-1·46], pNI=0·48). Long-term side-effects were similar in the hypofractionated groups compared with the conventional group. There were no significant differences in either the proportion or cumulative incidence of side-effects 5 years after treatment using three clinician-reported as well as patient-reported outcome measures. The estimated cumulative 5 year incidence of Radiation Therapy Oncology Group (RTOG) grade 2 or worse bowel and bladder adverse events was 13·7% (111 events) and 9·1% (66 events) in the 74 Gy group, 11·9% (105 events) and 11·7% (88 events) in the 60 Gy group, 11·3% (95 events) and 6·6% (57 events) in the 57 Gy group, respectively. No treatment-related deaths were reported. Hypofractionated radiotherapy using 60 Gy in 20 fractions is non-inferior to conventional fractionation using 74 Gy in 37 fractions and is recommended as a new standard of care for external-beam radiotherapy of localised prostate cancer. Cancer Research UK, Department of Health, and the National Institute for Health Research Cancer Research Network.


Society for Obstetric Anesthesia and Perinatology Consensus Statement: Monitoring Recommendations for Prevention and Detection of Respiratory Depression Associated With Administration of Neuraxial Morphine for Cesarean Delivery Analgesia.
The majority of women undergoing cesarean delivery in the United States receive neuraxial morphine, the most effective form of postoperative analgesia for this surgery. Current American Society of Anesthesiologists (ASA) and American Society of Regional Anesthesia and Pain Medicine (ASRA) recommend respiratory monitoring standards following neuraxial morphine administration in the general surgical population that may be too frequent and intensive when applied to the healthy obstetric population receiving a single dose of neuraxial morphine at the time of surgery. There is limited evidence to support or guide the optimal modality, frequency, and duration of respiratory monitoring in the postoperative cesarean delivery patient receiving a single dose of neuraxial morphine. Consistent with the mission of the Society for Obstetric Anesthesia and Perinatology (SOAP) to improve outcomes in pregnancy for women and neonates, the purpose of this consensus statement is to encourage the use of this highly effective analgesic technique while promoting safe practice and patient-centered care. The document aims to reduce unnecessary interruptions from respiratory monitoring in healthy mothers while focusing vigilance on monitoring in those women at highest risk for respiratory depression following neuraxial morphine administration. This consensus statement promotes the use of low-dose neuraxial morphine and multimodal analgesia after cesarean delivery, gives perspective on the safety of this analgesic technique in healthy women, and promotes patient risk stratification and perioperative risk assessment to determine and adjust the intensity, frequency, and duration of respiratory monitoring.


Lifestyle chemistries from phones for individual profiling.
Imagine a scenario where personal belongings such as pens, keys, phones, or handbags are found at an investigative site. It is often valuable to the investigative team that is trying to trace back the belongings to an individual to understand their personal habits, even when DNA evidence is also available. Here, we develop an approach to translate chemistries recovered from personal objects such as phones into a lifestyle sketch of the owner, using mass spectrometry and informatics approaches. Our results show that phones' chemistries reflect a personalized lifestyle profile. The collective repertoire of molecules found on these objects provides a sketch of the lifestyle of an individual by highlighting the type of hygiene/beauty products the person uses, diet, medical status, and even the location where this person may have been. These findings introduce an additional form of trace evidence from skin-associated lifestyle chemicals found on personal belongings. Such information could help a criminal investigator narrowing down the owner of an object found at a crime scene, such as a suspect or missing person.


Mutations in coenzyme Q10 biosynthetic genes.
Although it was first described in 1989, our understanding of coenzyme Q10 (CoQ10) deficiency is only now coming of age with the recent first description of the underlying molecular defects. The diverse clinical presentations, classifiable into four major syndromes, raise the question as to whether the deficiencies are primary or secondary. Recent studies, including the one by Mollet, Rötig, and colleagues reported in this issue of the JCI, document molecular defects in three of the nine genes required for CoQ10 biosynthesis, all of which are associated with early and severe clinical presentations (see the related article beginning on page 765). It is anticipated that defects in the other six genes will cause similar early-onset encephalomyopathies. Awareness of CoQ10 deficiency is important because individuals with primary or secondary variants may benefit from oral CoQ10 supplementation.


Disclosure of Sexual Orientation by Gay and Bisexual Men in Government-Administered Probability Surveys.
Researchers are increasingly using national population surveys (NPS) to understand the health of gay and bisexual men (GBM). However, valid inference from these surveys depends on accurate identification of GBM. We asked 8126 GBM in an anonymous, online, community-recruited survey about their willingness to reveal their sexual orientation in NPS. Overall, 30% indicated that they would not reveal their sexual orientation; however, there were differences in frequencies according to sexual orientation, relationship status, age, HIV status, living environment, education, income, and ethnicity. NPS might not be fully representative of GBM due to misclassification errors stemming from unwillingness to disclose.


Maternal smoking during pregnancy and postnatal exposure to environmental tobacco smoke as predisposition factors to acute respiratory infections.
This study compared susceptibility to respiratory morbidity in a cohort of 9-year-old children exposed congenitally and postnatally to environmental tobacco smoke (ETS) to susceptibility in a cohort of unexposed children. The epidemiologic study included 1129 children: 594 boys and 535 girls attending the second grade of grammar schools in Kraków, Poland. We found strong evidence that children exposed to ETS in their homes were more susceptible to acute respiratory tract illnesses than unexposed children. A dose-response relationship between degree of exposure [for lower ETS exposure, odds ratio (OR) = 1.32; for higher ETS exposure, OR = 1.74] supports a causal explanation for the association observed. The significant trend of increased risk of respiratory infections due to ETS level in nonatopic children whose mothers did not smoke cigarettes during pregnancy suggests a direct effect of ETS exposure on the child's respiratory health. ETS combined with allergy nearly tripled the risk of acute respiratory tract illness (OR = 3.39; 95% CI, 1.93-5.93), and maternal smoking during pregnancy had a modifying effect on the risk of respiratory illnesses due to ETS after accounting for atopy. The stronger effect of ETS in atopic children and in those whose mothers smoked during pregnancy may be result of biologic interaction of endogenous and environmental factors. The results of this study are of relevance to public health policy, as children with higher risk of respiratory infections may be more susceptible to environmental hazards later in adolescence or in adulthood. Respiratory infections also increase demands for medical interventions in terms of outpatient services and hospital administrations. In addition, respiratory illnesses cause missed school days, and caring for a sick child may lead to absenteeism from work.


Characterization of the B cell epitopes associated with a truncated form of Pseudomonas exotoxin (PE38) used to make immunotoxins for the treatment of cancer patients.
Recombinant immunotoxins composed of an Ab Fv fragment joined to a truncated portion of Pseudomonas exotoxin A (termed PE38) have been evaluated in clinical trials for the treatment of various human cancers. Immunotoxin therapy is very effective in hairy cell leukemia and also has activity in other hemological malignancies; however, a neutralizing Ab response to PE38 in patients with solid tumors prevents repeated treatments to maximize the benefit. In this study, we analyze the murine Ab response as a model to study the B cell epitopes associated with PE38. Sixty distinct mAbs to PE38 were characterized. Mutual competitive binding of the mAbs indicated the presence of 7 major epitope groups and 13 subgroups. The competition pattern indicated that the epitopes are discrete and could not be reproduced using a computer simulation program that created epitopes out of random surface residues on PE38. Using sera from immunotoxin-treated patients, the formation of human Abs to each of the topographical epitopes was demonstrated. One epitope subgroup, E1a, was identified as the principal neutralizing epitope. The location of each epitope on PE38 was determined by preparing 41 mutants of PE38 in which bulky surface residues were mutated to either alanine or glycine. All 7 major epitope groups and 9 of 13 epitope subgroups were identified by 14 different mutants and these retained high cytotoxic activity. Our results indicate that a relatively small number of discrete immunogenic sites are associated with PE38, most of which can be eliminated by point mutations.


Compressive sensing of sparse radio frequency signals using optical mixing.
We demonstrate an optical mixing system for measuring properties of sparse radio frequency (RF) signals using compressive sensing (CS). Two types of sparse RF signals are investigated: (1) a signal that consists of a few 0.4 ns pulses in a 26.8 ns window and (2) a signal that consists of a few sinusoids at different frequencies. The RF is modulated onto the intensity of a repetitively pulsed, wavelength-chirped optical field, and time-wavelength-space mapping is used to map the optical field onto a 118-pixel, one-dimensional spatial light modulator (SLM). The SLM pixels are programmed with a pseudo-random bit sequence (PRBS) to form one row of the CS measurement matrix, and the optical throughput is integrated with a photodiode to obtain one value of the CS measurement vector. Then the PRBS is changed to form the second row of the mixing matrix and a second value of the measurement vector is obtained. This process is performed 118 times so that we can vary the dimensions of the CS measurement matrix from 1×118 to 118×118 (square). We use the penalized ℓ(1) norm method with stopping parameter λ (also called basis pursuit denoising) to recover pulsed or sinusoidal RF signals as a function of the small dimension of the measurement matrix and stopping parameter. For a square matrix, we also find that penalized ℓ(1) norm recovery performs better than conventional recovery using matrix inversion.


Oral rapamycin reduces tumour burden and vascularization in Lkb1(+/-) mice.
Patients with Peutz-Jeghers syndrome (PJS) are affected by hamartomatous intestinal polyposis and increased risk of cancers in multiple organs caused by germline mutations in the tumour suppressor gene LKB1. Murine models that recapitulate aspects of PJS have been created. Here we examine the therapeutic effect of rapamycin, a macrolide with anti-tumourigenic and anti-angiogenic properties, in reducing tumour incidence in a large cohort of Lkb1(+/-) mice. To study the influence of early intervention, the animals were dosed with rapamycin from the age of 8 weeks, well before the onset of polyposis. These mice continued to receive the drug, which was well tolerated, throughout their lives. At sacrifice, we observed a reduction in gastric tumour burden in the rapamycin-treated mice (p = 0.0001) compared with age- and sex-matched controls. Treated animals also have a lower number of polyps per mouse than controls. In the polyps from the treated mice, phosphorylation of ribosomal p70 S6 kinase was maintained, while the phosphorylation of AKT at serine-473 was elevated, suggesting that mTORC1 function is maintained at this dosage. Despite this, a significant reduction in microvessel density was seen in polyps from the rapamycin-treated mice compared to those from the control mice (p = 5 x 10(-5)), suggesting that the anti-angiogenic effect of rapamycin played a role in polyp reduction. Overall, we demonstrated that prolonged oral administration of rapamycin from an early age is effective in lowering tumour burden in the Lkb1(+/-) mice without evident side effects.


Evaluation of saline for i.v. locks in children.
A practice change to saline for peripheral IV maintenance was evaluated in a large teaching hospital in the Midwest. Subjects (N = 126) were children over 28 days of age, with peripherally placed IVs. Group I (n = 68) were children randomly selected to receive saline flush in an experimental study. Group II (n = 58) consisted of children receiving the saline flush after the change in practice was made. There was no significant difference between groups for either of two measures of IV duration. The mean duration of the IV from first flush was 35.38 hours for Group I and 44.09 hours for Group II; the time from insertion to discontinuation was 60.86 and 60.03 hours respectively. Patient age, site location, number of flushes, number of irritating medications, and site complications did not differ significantly between groups. The results of this clinical evaluation support previous findings that saline is efficacious for maintaining the patency of peripheral IVs in children over 28 days of age.


A novel behavioral intervention in adolescents with type 1 diabetes mellitus improves glycemic control: preliminary results from a pilot randomized control trial.
The purpose of this study was to develop and pilot-test an innovative behavioral intervention in adolescents with type 1 diabetes mellitus (T1DM) incorporating structured care of a pet to improve glycemic control. Twenty-eight adolescents with A1C > 8.5% (69 mmol/mol) were randomly assigned to either the intervention group (care of a Betta splendens pet fish) or the control group (usual care). Adolescents in the intervention group were given instructions to associate daily and weekly fish care duties with diabetes self-management tasks, including blood glucose testing and parent-adolescent communication. After 3 months, the participants in the intervention group exhibited a statistically significant decrease in A1C level (-0.5%) compared with their peers in the control group, who had an increase in A1C level (0.8%) (P = .04). The younger adolescents (10-13 years of age) demonstrated a greater response to the intervention, which was statistically significant (-1.5% vs 0.6%, P = .04), compared with the older adolescents (14-17 years of age). Structured care of a pet fish can improve glycemic control in adolescents with T1DM, likely by providing cues to perform diabetes self-management behaviors.


The identification of a third fragile site, FRAXF, in Xq27--q28 distal to both FRAXA and FRAXE.
FRAXA is unique amongst fragile sites in that it is intimately involved with a specific clinical phenotype, the fragile X syndrome. Whilst the majority of fragile X individuals have been found to have a characteristic mutation in the FMR1 gene, a small proportion of individuals exhibiting fragility have no such mutation. Investigation of the site of chromosome fragility in these FMR1 mutation negative, fragile X site positive individuals, has identified a second site of fragility, FRAXE. However, the presence of FRAXE has not explained all such cases. Here we describe a fragile X site positive, FMR1 mutation negative family, in which chromosome fragility is not due to the FRAXA or FRAXE but is due to a third site designated FRAXF. Using fluorescent in situ hybridisation (FISH) this site is shown to lie over 1Mb distal to FRAXA. The identification of a third fragile site in this small region of the X chromosome provides an opportunity to extend our studies of the molecular nature of chromosome fragility.


Stimulation of the brain with radiofrequency electromagnetic field pulses affects sleep-dependent performance improvement.
Sleep-dependent performance improvements seem to be closely related to sleep spindles (12-15 Hz) and sleep slow-wave activity (SWA, 0.75-4.5 Hz). Pulse-modulated radiofrequency electromagnetic fields (RF EMF, carrier frequency 900 MHz) are capable to modulate these electroencephalographic (EEG) characteristics of sleep. The aim of our study was to explore possible mechanisms how RF EMF affect cortical activity during sleep and to test whether such effects on cortical activity during sleep interact with sleep-dependent performance changes. Sixteen male subjects underwent 2 experimental nights, one of them with all-night 0.25-0.8 Hz pulsed RF EMF exposure. All-night EEG was recorded. To investigate RF EMF induced changes in overnight performance improvement, subjects were trained for both nights on a motor task in the evening and the morning. We obtained good sleep quality in all subjects under both conditions (mean sleep efficiency > 90%). After pulsed RF EMF we found increased SWA during exposure to pulse-modulated RF EMF compared to sham exposure (P < 0.05) toward the end of the sleep period. Spindle activity was not affected. Moreover, subjects showed an increased RF EMF burst-related response in the SWA range, indicated by an increase in event-related EEG spectral power and phase changes in the SWA range. Notably, during exposure, sleep-dependent performance improvement in the motor sequence task was reduced compared to the sham condition (-20.1%, P = 0.03). The changes in the time course of SWA during the exposure night may reflect an interaction of RF EMF with the renormalization of cortical excitability during sleep, with a negative impact on sleep-dependent performance improvement.


Correcting BLAST e-values for low-complexity segments.
The statistical estimates of BLAST and PSI-BLAST are of extreme importance to determine the biological relevance of sequence matches. While being very effective in evaluating most matches, these estimates usually overestimate the significance of matches in the presence of low complexity segments. In this paper, we present a model, based on divergence measures and statistics of the alignment structure, that corrects BLAST e-values for low complexity sequences without filtering or excluding them and generates scores that are more effective in distinguishing true similarities from chance similarities. We evaluate our method and compare it to other known methods using the Gene Ontology (GO) knowledge resource as a benchmark. Various performance measures, including ROC analysis, indicate that the new model improves upon the state of the art. The program is available at biozon.org/ftp/ and www.cs.technion.ac.il/ approximately itaish/lowcomp/.


Synthetic Cathinone and Cannabinoid Designer Drugs Pose a Major Risk for Public Health.
As part of an increasing worldwide use of designer drugs, recent use of compounds containing cathinones and synthetic cannabinoids is especially prevalent. Here, we reviewed current literature on the prevalence, epidemiology, bio-behavioral effects, and detection of these compounds. Gender differences and clinical effects will also be examined. Chronic use of synthetic cathinone compounds can have major effects on the central nervous system and can induce acute psychosis, hypomania, paranoid ideation, and delusions, similar to the effects of other better-known amphetamine-type stimulants. Synthetic cannabinoid products have effects that are somewhat similar to those of natural cannabis but more potent and long-lasting than THC. Some of these compounds are potent and dangerous, having been linked to psychosis, mania, and suicidal ideation. Novel compounds are developed rapidly and new screening techniques are needed to detect them as well as a rigorous regulation and legislation reinforcement to prevent their distribution and use. Given the rapid increase in the use of synthetic cathinones and cannabinoid designer drugs, their potential for dependence and abuse, and harmful medical and psychiatric effects, there is a need for research and education in the areas of prevention and treatment.


Prevention of Firearm Injuries Among Children and Adolescents: Consensus-Driven Research Agenda from the Firearm Safety Among Children and Teens (FACTS) Consortium.
Firearm injuries are the second leading cause of death among US children and adolescents. Because of the lack of resources allocated to firearm injury prevention during the past 25 years, research has lagged behind other areas of injury prevention. Identifying timely and important research questions regarding firearm injury prevention is a critical step for reducing pediatric mortality. The Firearm Safety Among Children and Teens (FACTS) Consortium, a National Institute for Child Health and Human Development-funded group of scientists and stakeholders, was formed in 2017 to develop research resources for the field, including a pediatric-specific research agenda for firearm injury prevention to assist future researchers and funders, as well as to inform cross-disciplinary evidence-based research on this critical injury prevention topic. A nominal group technique process was used, including 4 key steps (idea generation, round-robin, clarification, and voting and consensus). During idea generation, stakeholders and workgroups generated initial research agenda topics after conducting scoping reviews of the literature to identify existing gaps in knowledge. Agenda topics were refined through 6 rounds of discussion and survey feedback (ie, round-robin, and clarification steps). Final voting (using a 5-point Likert scale) was conducted to achieve consensus (≥70% of consortium ranking items at 4 or 5 priority for inclusion) around key research priorities for the next 5 years of research in this field. Final agenda questions were reviewed by both the stakeholder group and an external panel of research experts not affiliated with the FACTS Consortium. Feedback was integrated and the final set of agenda items was ratified by the entire FACTS Consortium. Overall, 26 priority agenda items with examples of specific research questions were identified across 5 major thematic areas, including epidemiology and risk and protective factors, primary prevention, secondary prevention and sequelae, cross-cutting prevention factors, policy, and data enhancement. These priority agenda items, when taken together, define a comprehensive pediatric-specific firearm injury prevention research agenda that will guide research resource allocation within this field during the next 5 years.


Autoregulation of RCO by Low-Affinity Binding Modulates Cytokinin Action and Shapes Leaf Diversity.
Mechanisms through which the evolution of gene regulation causes morphological diversity are largely unclear. The tremendous shape variation among plant leaves offers attractive opportunities to address this question. In cruciferous plants, the REDUCED COMPLEXITY (RCO) homeodomain protein evolved via gene duplication and acquired a novel expression domain that contributed to leaf shape diversity. However, the molecular pathways through which RCO regulates leaf growth are unknown. A key question is to identify genome-wide transcriptional targets of RCO and the DNA sequences to which RCO binds. We investigate this question using Cardamine hirsuta, which has complex leaves, and its relative Arabidopsis thaliana, which evolved simple leaves through loss of RCO. We demonstrate that RCO directly regulates genes controlling homeostasis of the hormone cytokinin to repress growth at the leaf base. Elevating cytokinin signaling in the RCO expression domain is sufficient to both transform A. thaliana simple leaves into complex ones and partially bypass the requirement for RCO in C. hirsuta complex leaf development. We also identify RCO as its own target gene. RCO directly represses its own transcription via an array of low-affinity binding sites, which evolved after RCO duplicated from its progenitor sequence. This autorepression is required to limit RCO expression. Thus, evolution of low-affinity binding sites created a negative autoregulatory loop that facilitated leaf shape evolution by defining RCO expression and fine-tuning cytokinin activity. In summary, we identify a transcriptional mechanism through which conflicts between novelty and pleiotropy are resolved during evolution and lead to morphological differences between species.


Analysis of the presence or absence of atrophy of the subgenual and subcallosal cingulate cortices using voxel-based morphometry on MRI is useful to select prescriptions for patients with depressive symptoms.
We objectively evaluated the presence or absence of atrophy of the subgenual anterior cingulate cortex (sgACC) and the subcallosal anterior cingulate cortex (scACC), using new voxel-based morphometry (VBM) software employing Statistical Parametric Mapping software v8 and diffeomorphic anatomic registration through an exponentiated lie algebra. We prepared a database covering young-mature adulthood and investigated the clinical usefulness of the evaluation. One hundred seven patients with major depressive disorder (MDD), 74 patients with bipolar disorder (BD), and 240 healthy control subjects underwent 1.5T magnetic resonance imaging scanning. Using new VBM software and databases covering young-mature adults and the elderly, target volumes of interest were set in the sgACC and scACC, four indicators (severity, extent, ratio, and whole-brain extent) were determined, and the presence or absence of atrophy of the sgACC and scACC was evaluated on the basis of the indicators. In addition, the relationships between the presence or absence of atrophy of the sgACC and scACC and performance of diagnosing MDD and BD and therapeutic drugs were investigated. It was clarified that the disease is likely to be MDD when atrophy is detected in the sgACC, and likely to be BD when no atrophy is detected in the sgACC but is detected in the scACC. Regarding the relationship with therapeutic drugs, it was clarified that, when atrophy is detected in both the sgACC and the scACC, concomitant administration of mood stabilizers and atypical antipsychotics acting as dopamine-system stabilizers is necessary in many cases. VBM on magnetic resonance imaging enabled automatic analysis of atrophy in the sgACC and scACC, and findings obtained by this procedure are useful not only for differentiation of MDD and BD patients but also for selection of prescriptions.


Smooth muscle tumour of uncertain malignant potential (SMTUMP) in the nasal cavity: an incidental finding.
Sino-nasal smooth muscle tumours of uncertain malignant potential (SMTUMP) are very rare neoplasms of mesenchymal origin with features in between a benign leiomyoma and a leiomyosarcoma. We report a rare case of SMTUMP in a 44-year-old woman, who presented with vague symptoms of pharyngitis. Nasal endoscopy revealed a smooth mass in left nasal cavity. Contrast-enhanced CT and MRI scans showed features likely to be inverted papilloma or olfactory neuroblastoma or meningioma. Excision was planned and intraoperatively, frozen section revealed a probable spindle cell lesion. Final histopathological report following immunohistochemistry (IHC) & immunofluoresence (IF) confirmed it to be a SMTUMP. This patient underwent complete resection via endoscopic KTP laser assisted, anterior skull base surgery with no recurrence on follow-up.