Unintentional injuries in the home in the United States Part II: morbidity.
Homes are an important setting for nonfatal unintentional injuries. The purpose of this study was to quantify and describe nonfatal, unintentional injuries in the United States, in which the injury took place at home. Data derived from the National Health Interview Survey, National Ambulatory Medical Care Survey, and National Hospital Ambulatory Medical Care Surveys for Outpatient and Emergency Departments. The nonfatal unintentional home injury rate and 95% confidence interval were computed for the United States overall (1998-1999), as well as by type of injury, gender, and age group. Weights were applied for each data set as designated by the National Center for Health Statistics. In 1998, there were more than 12 million unintentional home injuries requiring some form of medical attention. Falls were the most common injury among all age groups, followed by cutting/piercing injuries, and injuries associated with being struck by or against an object or person. Injury rates were highest among the oldest and youngest age groups. There was inconsistency across data sets with regard to the presence of location information and definitions of the home environment, inclusion criteria, and the presence of external cause of injury and poisoning codes (E-codes). Depending on the data set, information was missing for 8% and 41% of cases on the location of injury, making it impossible to determine whether the injuries occurred in the home environment. Falls are a significant problem, particularly among older adults. Additionally, data collection systems need to be improved so that location of injury data are routinely collected using consistent definitions so as to allow comparisons across data sets and over time.


Patched1 interacts with cyclin B1 to regulate cell cycle progression.
The initiation of mitosis requires the activation of M-phase promoting factor (MPF). MPF activation and its subcellular localization are dependent on the phosphorylation state of its components, cdc2 and cyclin B1. In a two-hybrid screen using a bait protein to mimic phosphorylated cyclin B1, we identified a novel interaction between cyclin B1 and patched1 (ptc1), a tumor suppressor associated with basal cell carcinoma (BCC). Ptc1 interacted specifically with constitutively phosphorylated cyclin B1 derivatives and was able to alter their normal subcellular localization. Furthermore, addition of the ptc1 ligand, sonic hedgehog (shh), disrupts this interaction and allows cyclin B1 to localize to the nucleus. Expression of ptc1 in 293T cells was inhibitory to cell proliferation; this inhibition could be relieved by coexpression of a cyclin B1 derivative that constitutively localizes to the nucleus and that could not interact with ptc1 due to phosphorylation-site mutations to ALA: In addition, we demonstrate that endogenous ptc1 and endogenous cyclin B1 interact in vivo. The findings reported here demonstrate that ptc1 participates in determining the subcellular localization of cyclin B1 and suggest a link between the tumor suppressor activity of ptc1 and the regulation of cell division. Thus, we propose that ptc1 participates in a G(2)/M checkpoint by regulating the localization of MPF.


Cannabidiol as a Potential New Type of an Antipsychotic. A Critical Review of the Evidence.
There is urgent need for the development of mechanistically different and less side-effect prone antipsychotic compounds. The endocannabinoid system has been suggested to represent a potential new target in this indication. While the chronic use of cannabis itself has been considered a risk factor contributing to the development of schizophrenia, triggered by the phytocannabinoid delta-9-tetrahydrocannabinol (Δ9-THC), cannabidiol, the second most important phytocannabinoid, appears to have no psychotomimetic potential. Although, results from animal studies are inconsistent to a certain extent and seem to depend on behavioral paradigms, treatment duration and experimental conditions applied, cannabidiol has shown antipsychotic properties in both rodents and rhesus monkeys. After some individual treatment attempts, the first randomized, double-blind controlled clinical trial demonstrated that in acute schizophrenia cannabidiol exerts antipsychotic properties comparable to the antipsychotic drug amisulpride while being accompanied by a superior, placebo-like side effect profile. As the clinical improvement by cannabidiol was significantly associated with elevated anandamide levels, it appears likely that its antipsychotic action is based on mechanisms associated with increased anandamide concentrations. Although, a plethora of mechanisms of action has been suggested, their potential relevance for the antipsychotic effects of cannabidiol still needs to be investigated. The clarification of these mechanisms as well as the establishment of cannabidiol's antipsychotic efficacy and its hopefully benign side-effect profile remains the subject of a number of previously started clinical trials.


[Cost utility of renal transplant vs. hemodialysis in the treatment of end stage chronic kidney failure in a Peruvian hospital].
To assess and compare the cost utility of the cadaveric donor renal transplant (CDRT) at the Hospital Nacional Guillermo Almenara Irigoyen between 2000 to 2001, against haemodialysis (HD), 5 years after treatment initiation. A cost utility study design was used, which evaluated every patient continuing treatment after 5 years of having the CDRT done, and 2 controls consisting in patients having received HD for 5 years, matched by age, sex and disease duration. The costs of each procedure and their Quality-adjusted life years (QALY´s) were evaluated using the questionnaire of quality of life SF-36v2(TM), finally calculating the cost utility (CU) and incremental cost utility (ICU) ratios. Fifty-eight CDRT were performed between 2000-1. Five years later, 17 (29%) patients died and only 27 (47%) continued the treatment after CDRT. Out of the 31 patients (53%) having treatment failures, 26% rejected the transplant, 55% presented a complication and 19% were irregular. The mean SF-36v2(TM) scores obtained by the CDRT and HD patients were 95±12 and 87±18 points, respectively. The QALYs obtained by the CDRT and HD groups were 251 and 229 points, respectively; the CU ratios for the CDRT and HD were USD 11,984 and USD 9,243; and the ICU ratio for the period was USD 40,669. CDRTs performed during the years 2000-1 at the HNGAI, were 5 years later surprisingly less cost effective than the HD and CDRT´s performed at year 2000 had a lower incremental cost utility ratio that those performed the 2001, probably because of the highest rate of irregular treatment.


Incidence of displacement after nondisplaced distal radial fractures in adults.
It is standard practice to closely monitor distal radial fractures treated nonoperatively to ensure that there is no fracture displacement. Patients are often asked to initially return weekly for radiographs. To our knowledge, nondisplaced distal radial fractures in adults have not been specifically evaluated to determine if this level of vigilance is required. If this subset of fractures is unlikely to displace, the cost, radiation exposure, and inconvenience of weekly office visits could be spared. Using our billing database, we identified 642 closed distal radial fractures among the patients who presented to our institution during the four-year period from the beginning of 2006 to the end of 2009. Radiographs of the injuries were reviewed to identify fractures for which radiographic measurements were within predefined radiographic norms. Only those fractures that were believed to be nondisplaced by all reviewers were classified as nondisplaced for the purposes of this study. Radiographic measurements were made at the time of injury and at the time of fracture union to evaluate for displacement over time. The total number of clinic visits and radiographs that were received were calculated from the longitudinal medical record for each patient. Eighty-two fractures were identified as nondisplaced. None displaced or required operative intervention. The largest measured difference from injury to fracture union for radial inclination was 3.6° (average 0.8°); for radial height, 2.1 mm (average 0.5 mm); and for palmar tilt, 3.1° (average 1.0°). These numbers are all within the error of measurement. Nondisplaced distal radial fractures in adults appear to be inherently stable, and it may be appropriate to treat this subset of distal radial fractures with cast immobilization (when swelling allows) and a single follow-up visit with radiographs to document union at the time of cast removal. Prognostic level III. See Instructions for authors for a complete description of levels of evidence.


Body image satisfaction, dieting beliefs, and weight loss behaviors in adolescent girls and boys.
Body image and weight loss beliefs and behaviors were assessed in 341 female and 221 male high school students. Estimates of body dissatisfaction varied depending on the measurement strategy used. Despite having similar weight distributions around the expected norm, girls were significantly more dissatisfied with their bodies than boys. Body Mass Index was positively related to body dissatisfaction in girls and boys, while higher exercise levels were related to higher body satisfaction in boys. Nearly two-thirds of girls and boys believed being thinner would have an impact on their lives, but the majority of girls believed this would be positive while the majority of boys believed this would be negative. Thirteen percent of female subjects reported using one or more extreme weight loss behavior at least weekly. Beliefs regarding the effectiveness of different weight loss measures were assessed. Weight loss behaviors in this Australian sample appear similar to comparable U.S. samples.


Wireless, soft electronics for rapid, multisensor measurements of hydration levels in healthy and diseased skin.
Precise, quantitative measurements of the hydration status of skin can yield important insights into dermatological health and skin structure and function, with additional relevance to essential processes of thermoregulation and other features of basic physiology. Existing tools for determining skin water content exploit surrogate electrical assessments performed with bulky, rigid, and expensive instruments that are difficult to use in a repeatable manner. Recent alternatives exploit thermal measurements using soft wireless devices that adhere gently and noninvasively to the surface of the skin, but with limited operating range (∼1 cm) and high sensitivity to subtle environmental fluctuations. This paper introduces a set of ideas and technologies that overcome these drawbacks to enable high-speed, robust, long-range automated measurements of thermal transport properties via a miniaturized, multisensor module controlled by a long-range (∼10 m) Bluetooth Low Energy system on a chip, with a graphical user interface to standard smartphones. Soft contact to the surface of the skin, with almost zero user burden, yields recordings that can be quantitatively connected to hydration levels of both the epidermis and dermis, using computational modeling techniques, with high levels of repeatability and insensitivity to ambient fluctuations in temperature. Systematic studies of polymers in layered configurations similar to those of human skin, of porcine skin with known levels of hydration, and of human subjects with benchmarks against clinical devices validate the measurement approach and associated sensor hardware. The results support capabilities in characterizing skin barrier function, assessing severity of skin diseases, and evaluating cosmetic and medication efficacy, for use in the clinic or in the home.


Multiple-system atrophy with cerebellar predominance presenting as respiratory insufficiency and vocal cords paralysis.
Background. MSA (Multiple System Atrophy) may be associated either with Parkinsonism or with cerebellar ataxia (MSA-c subtype). It is considered a rare disease, but many patients are misdiagnosed as suffering from idiopathic Parkinson's disease. In this paper, we report a case of a patient admitted with respiratory failure and vocal cords paralysis due to MSA-c. Case Report. A 79-year-old Caucasian woman was admitted in March 2010 with dyspnea, asthenia, stridor, and respiratory failure needing noninvasive ventilation. She had orthostatic blood pressure decline, constipation, insomnia, daytime sleepiness, and snoring. The neurologic examination revealed cerebellar ataxia. A laryngoscopy revealed vocal cord paralysis in midline position and tracheostomy was performed. The Brain Magnetic Resonance Imaging revealed atrophy of middle cerebellar peduncles and pons with the "hot cross bun sign." Conclusion. Although Multiple-system atrophy is a rare disease, unexplained respiratory failure, bilateral vocal cord paralysis, or stridor should lead to consider MSA as diagnosis.


COVID-19 Infection Among Healthcare Workers: Serological Findings Supporting Routine Testing.
A growing body of evidence demonstrates that asymptomatic and pre-symptomatic transmission of SARS-CoV-2 is a major contributor to the COVID-19 pandemic. Frontline healthcare workers in COVID-19 hotspots have faced numerous challenges, including shortages of personal protective equipment (PPE) and difficulties acquiring clinical testing. The magnitude of the exposure of healthcare workers and the potential for asymptomatic transmission makes it critical to understand the incidence of infection in this population. To determine the prevalence of asymptomatic SARS-CoV-2 infection amongst healthcare workers, we studied frontline staff working in the Montefiore Health System in New York City. All participants were asymptomatic at the time of testing and were tested by RT-qPCR and for anti-SARS-CoV-2 antibodies. The medical, occupational, and COVID-19 exposure histories of participants were recorded via questionnaires. Of the 98 asymptomatic healthcare workers tested, 19 (19.4%) tested positive by RT-qPCR and/or ELISA. Within this group, four (4.1%) were RT-qPCR positive, and four (4.1%) were PCR and IgG positive. Notably, an additional 11 (11.2%) individuals were IgG positive without a positive PCR. Two PCR positive individuals subsequently developed COVID-19 symptoms, while all others remained asymptomatic at 2-week follow-up. These results indicate that there is considerable asymptomatic infection with SARS-CoV-2 within the healthcare workforce, despite current mitigation policies. Furthermore, presuming that asymptomatic staff are not carrying SARS-CoV-2 is inconsistent with our results, and this could result in amplified transmission within healthcare settings. Consequently, aggressive testing regiments, such as testing frontline healthcare workers on a regular, multi-modal basis, may be required to prevent further spread within the workforce and to patients.


The strength of two indicators of social position on oral health among persons over the age of 80 years.
The objective of the present study is to analyze how two dimensions of social position, education and social class, are associated with oral health among generally healthy, community-dwelling persons over the age of 80 years. The present investigation is based on a sample of 157 community-dwelling individuals from The Kungsholmen Elders Oral Health Study (KEOHS) and included data from interviews and oral examinations. Social position was measured by education and social class. Oral health was measured by active coronal caries, active root caries, edentulism and use of dental services. The primary findings of the adjusted multivariate logistic regression analysis were that, compared to persons who had been in higher positions, persons who had been blue-collar/ white-collar workers had significantly greater odds of having coronal caries and high, but nonsignificant odds of being edentulous. Further, persons with elementary/ medium education tended to forego regular dental services more than persons with high education. The study identified social inequalities in oral health even in a population of independently living, generally healthy very old Swedes and in a country where the public health policies have tried to minimize these inequalities.


3D-QSAR studies of latrunculin-based actin polymerization inhibitors using CoMFA and CoMSIA approaches.
The marine-derived macrolide latrunculins A and B, from the Red Sea sponge Negombata magnifica, are known to reversibly bind actin monomers, forming 1:1 complex with G-actin, disrupting its polymerization. Latrunculins have remarkable physiological properties and widely used as biochemical markers. Nevertheless, no QSAR studies have been developed for any kind of actin disruptors. In the present study, Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Indices Analysis (CoMSIA) implemented in the SYBYL software packages were used to develop predictive 3D-QSAR models. Two alignment strategies were used to fit analyzed molecules to a suitable conformational template. By means of the SYBYL multifit alignment function, the best CoMFA and CoMSIA results presented cross-validated correlation coefficient values (q(2)) of 0.621 and 0.659, and non-cross-validated values (r(2)) of 0.938 and 0.965, respectively. Comparable to multifit-derived models, CoMFA and CoMSIA 3D-QSAR models were also derived using a molecular alignment obtained by docking latrunculin derivatives into the ATP active site of actin. In addition to q(2), the predictive ability was validated using external test set of five compounds. The results of this study suggest that the established model has a strong predictive ability and can be prospectively used in the molecular design and action mechanism analysis of this kind of cytotoxic compounds.


Mobility restriction in vivo of the heavy ribosomal subunit in a secretory cell.
Analysis in insect (Chironomus tentans) salivary gland cells of labeled RNA as a function of time after precursor injection and its distance to the nuclear membrane, cytoplasmic zone analysis, could previously be used to demonstrate the presence of short-lasting gradients in newly labeled ribosomal RNA. Since the gradients were sensitive to puromycin, they are likely to be a result of diffusion restriction due to an engagement of the subunits into polysomes. In the present paper the possibility was explored of recording gradients that were caused by labeled subunits in puromycin-resistant associations, which, in all probability, involve the endoplasmic reticulum. It was found that labeled 28 S and 5 S RNA but not 18 S RNA were present in radioactivity gradients lasting for at least 2 days but less than 6 days. The gradients also remained during inhibition of RNA synthesis by actinomycin, and they were completely resistant to puromycin whether given in vivo or in vitro. The semipermanent gradients formed fhere offer a unique parameter for the in vivo study of conditions for formation and maintenance of heavy subunits in puromycin-resistant bonds. An explanation for these and previous results is that the light subunit, although restricted in movement by engagement to polysomes, is nevertheless free to exchange and spread between rounds of translation, whereas at least part of the heavy subunit population is bound to the endoplasmic reticulum and less free to spread. These results offer a good in vivo correlate to previous results on in vitro exchangeability of subunits.


A Novel Millet-Based Probiotic Fermented Food for the Developing World.
Probiotic yogurt, comprised of a Fiti sachet containing Lactobacillus rhamnosus GR-1 and Streptococcus thermophilus C106, has been used in the developing world, notably Africa, to alleviate malnutrition and disease. In sub-Saharan African countries, fermentation of cereals such as millet, is culturally significant. The aim of this study was to investigate the fermentation capability of millet when one gram of the Fiti sachet consortium was added. An increase of 1.8 and 1.4 log CFU/mL was observed for S. thermophilus C106 and L. rhamnosus GR-1 when grown in 8% millet in water. Single cultures of L. rhamnosus GR-1 showed the highest μmax when grown in the presence of dextrose, galactose and fructose. Single cultures of S. thermophilus C106 showed the highest μmax when grown in the presence of sucrose and lactose. All tested recipes reached viable counts of the probiotic bacteria, with counts greater than 10⁶ colony-forming units (CFU)/mL. Notably, a number of organic acids were quantified, in particular phytic acid, which was shown to decrease when fermentation time increased, thereby improving the bioavailability of specific micronutrients. Millet fermented in milk proved to be the most favorable, according to a sensory evaluation. In conclusion, this study has shown that sachets being provided to African communities to produce fermented milk, can also be used to produce fermented millet. This provides an option for when milk supplies are short, or if communities wish to utilize the nutrient-rich qualities of locally-grown millet.


Association of small intestinal diverticulosis with chronic pancreatitis leading to severe malabsorption. Report of three cases.
Three cases of chronic pancreatitis occurring in patients with small intestinal diverticulosis and bacterial overgrowth are reported. In two of the cases, pancreatic supplements were therapeutically beneficial (the third being unable to tolerate them). Two of the patients also developed diverticular perforation. The possible nature of the association between small intestinal diverticulosis and chronic pancreatitis is discussed.


[Evaluation of public policies to promote food security and the fight against hunger, 1995-2002. 3--the Brazilian National Program to Control Vitamin A Deficiency].
Vitamin A supplements have been distributed during National Immunization Days since 1983, and Brazil has been a pioneer in this kind of strategy. The current study evaluated the National Program from 1995 to 2002, from a structure-process-results perspective. The methodology involved document research, interviews with health services managers, and a case study in 44 municipalities in Bahia State, resulting in 1,344 household interviews. In relation to structure, from 1998 on the program operated without a normative instrument due to the extinction of the National Institute of Nutrition. Improvements in the processes of vitamin supply procurement and distribution had a positive impact on coverage, reaching 3.5 million capsules in 2002 (72% coverage). For the 2,546 children studied in Bahia, vitamin A distribution was irregular, with annual coverage varying from 8% to 26%. Program managers reported time constraints and insufficient human resources, consistent with the hypothesis that this type of strategy does not help inform the population about the importance of vitamin A. These findings point to the need for systematic linkage between different levels of government in order to fully implement and monitor the program.


CCK-5: sequence analysis of a small cholecystokinin from canine brain and intestine.
The purpose of this study is to purify and to characterize chemically cholecystokinin (CCK)-like peptides present in brain and gut extracts that elute from gel filtration after the octapeptide. Canine small intestinal mucosa and brain were boiled in water and then extracted in cold trifluoroacetic acid, and cholecystokinin-like immunoreactivity was determined by carboxyl-terminal specific radioimmunoassay. Gel permeation chromatography on Sephadex G-50 revealed a form of CCK apparently smaller than CCK-8. This peptide was purified by immunoaffinity chromatography and three successive reverse phase high-performance liquid chromatography steps. Microsequence analysis showed that the amino terminal primary sequence of this small CCK was Gly-Trp-Met-Asp. Immunochemical and chromatographic analysis indicated that the carboxyl-terminal residue was Phe-NH2 and thus the full sequence is Gly-Trp-Met-Asp-Phe-NH2. An antibody that recognizes synthetic CCK-8, CCK-5, and CCK-4 equally did not reveal the presence of significant amounts of CCK-4. These results indicate that CCK-5 is the major CCK form smaller than the octapeptide present in brain (19% of total CCK immunoreactivity) and small intestine (7% of total). This finding, coupled with the demonstration by others that CCK-5 interacts with high-affinity brain CCK receptors, indicates that CCK-5 may play a physiological role in brain function.


The role of adenosine in CBF increases during hypoxia in young vs aged rats.
The role of adenosine in the regional cerebral blood flow (rCBF) response to hypoxia was evaluated in young (6 month) and aged (26-28 month) F344 rats using theophylline, an adenosine antagonist. Regional CBF was measured with radioactive microspheres under control anesthetized conditions (70% N2O, 30% O2) and at two levels of hypoxia (CaO2 = 8.7-9.0 ml . 100ml-1 and 3.2-3.7 ml . 100ml-1). Without theophylline infusion, CBF increases were similar between young and aged rats during moderate hypoxia but were increased more in young during severe hypoxia. Intracerebrovascular theophylline infusion significantly attenuated the increase in CBF during both moderate and severe hypoxia and decreased the difference between young and aged rats. Theophylline infusion produced no significant effect on the increase in CBF produced by hypercapnia, indicating the specificity of the treatment for hypoxic induced CBF changes and adenosine release. Intracerebrovascular infusion of adenosine had no effect on CBF, presumably due to the presence of the blood brain barrier. The results suggest that adenosine plays a major role in CBF increases during both moderate and severe hypoxia and in the difference in response to hypoxia between young and aged rats.


Epidemiology of bronchioloalveolar carcinoma.
Descriptive features of bronchioloalveolar carcinoma (BAC) are presented using Surveillance, Epidemiology and End Results Program population-based incidence data from 1973 through 1987, along with risk factors from histologically confirmed cases of BAC identified in a hospital-based case-control study conducted in Louisiana between 1979 and 1982. Compared to the rising incidence of lung cancer overall, BAC rates have remained relatively constant, accounting for less than 3% of all lung cancer. BAC incidence rates were higher in males, yet it explained proportionately more of the total lung cancer incidence in females. In the case-control study, 21 of the 33 cases originally ascertained from hospital pathology records were histologically confirmed as BAC. Most cases smoked cigarettes, with a 4-fold risk for ever smoking. Risks tended to increase with smoking intensity (reaching 10-fold for more than 1.5 packs/day) and duration (reaching 5-fold for more than 45 years of smoking). Following 10 or more years of employment, there was a 4-fold risk associated with motor freight occupations, along with nonsignificant excesses among construction workers, petroleum manufacturers, and sugar cane farmers. Cases were more likely than controls to have had emphysema or to have had a close family member with lung cancer. Although based on small numbers, this study suggests that BAC shares many of the epidemiological characteristics of lung adenocarcinoma.


Association between anxiety and severe quality-of-life impairment in postmenopausal women: analysis of a multicenter Latin American cross-sectional study.
To evaluate associations between anxiety and severe impairment of quality of life (QoL) in Latin American postmenopausal women. This was a secondary analysis of a multicenter cross-sectional study among postmenopausal women aged 40 to 59 from 11 Latin American countries. We evaluated anxiety (The Goldberg Depression and Anxiety Scale), and QoL (Menopause Rating Scale [MRS]), and included sociodemographic, clinical, lifestyle, and anthropometric variables in the analysis. Poisson family generalized linear models with robust standard errors were used to estimate prevalence ratios (PRs) and 95% CIs. There were two adjusted models: a statistical model that included variables associated with the outcomes in bivariate analyses, and an epidemiologic model that included potentially confounding variables from literature review. Data from 3,503 women were included; 61.9% had anxiety (Goldberg). Severe QoL impairment (total MRS score ≥17) was present in 13.7% of women, as well as severe symptoms (MRS subscales): urogenital (25.5%), psychological (18.5%), and somatic (4.5%). Anxiety was independently associated with severe QoL impairment and severe symptoms in the epidemiological (MRS total score: PR 3.6, 95% CI, 2.6-5.0; somatic: 5.1, 95% CI, 2.6-10.1; psychological: 2.8, 95% CI, 2.2-3.6; and urogenital: 1.4, 95% CI, 1.2-1.6) and the statistical model (MRS total score: PR 3.5, 95% CI, 2.6-4.9; somatic: 5.0, 95% CI, 2.5-9.9; psychological: 2.9, 95% CI, 2.2-3.7; and urogenital: 1.4; 95% CI, 1.2-1.6). In this postmenopausal Latin American sample, anxiety was independently associated with severe QoL impairment. Hence, screening for anxiety in this population is important.


Characterization of the Aspergillus fumigatus detoxification systems for reactive nitrogen intermediates and their impact on virulence.
Aspergillus fumigatus is a saprophytic mold that can cause life-threatening infections in immunocompromised patients. In the lung, inhaled conidia are confronted with immune effector cells that attack the fungus by various mechanisms such as phagocytosis, production of antimicrobial proteins or generation of reactive oxygen intermediates. Macrophages and neutrophils can also form nitric oxide (NO) and other reactive nitrogen intermediates (RNI) that potentially also contribute to killing of the fungus. However, fungi can produce several enzymes involved in RNI detoxification. Based on genome analysis of A. fumigatus, we identified two genes encoding flavohemoglobins, FhpA, and FhpB, which have been shown to convert NO to nitrate in other fungi, and a gene encoding S-nitrosoglutathione reductase GnoA reducing S-nitrosoglutathione to ammonium and glutathione disulphide. To elucidate the role of these enzymes in detoxification of RNI, single and double deletion mutants of FhpA, FhpB, and GnoA encoding genes were generated. The analysis of mutant strains using the NO donor DETA-NO indicated that FhpA and GnoA play the major role in defense against RNI. By generating fusions with the green fluorescence protein, we showed that both FhpA-eGFP and GnoA-eGFP were located in the cytoplasm of all A. fumigatus morphotypes, from conidia to hyphae, whereas FhpB-eGFP was localized in mitochondria. Because fhpA and gnoA mRNA was also detected in the lungs of infected mice, we investigated the role of these genes in fungal pathogenicity by using a murine infection model for invasive pulmonary aspergillosis. Remarkably, all mutant strains tested displayed wild-type pathogenicity, indicating that the ability to detoxify host-derived RNI is not essential for virulence of A. fumigatus in the applied mouse infection model. Consistently, no significant differences in killing of ΔfhpA, ΔfhpB, or ΔgnoA conidia by cells of the macrophage cell line MH-S were observed when compared to the wild type.


Concise review: Deciphering the mechanism behind induced pluripotent stem cell generation.
Regenerative medicine using spluripotent/multipotent stem cells holds a great promise in developing therapies for treating developmental abnormalities, degenerative disorders, and aging-related illness. However, supply and safety of the stem cells are two major problems with today's regenerative medicine. Recent development of induced pluripotent stem cells (iPSCs) has overcome the supply shortages by allowing the reprogramming of patients' body cells to embryonic stem cell (ESC)-like pluripotent cells. Still, the potential tumorigenicity of iPSCs remains as an obstacle. During early embryogenesis ESCs can be generated without tumor formation; therefore, understanding the mechanisms underlying ESC generation may help us to prevent iPSC tumorigenicity. Previous studies have shown that an ESC-enriched noncoding RNA, miR-302, induces somatic cell reprogramming (SCR) to form iPSCs, suggesting its pivotal role in stem cell generation. Recent research further revealed that miR-302-induced SCR involves an epigenetic reprogramming mechanism similar to the natural zygotic reprogramming process in the two- to eight-cell-stage embryos. These findings indicate that miR-302, as a cytoplasmic gene silencer, inhibits the translation of multiple key epigenetic regulators, including AOF1/2, methyl-CpG binding proteins 1 and 2, and DNA (cytosine-5-)-methyltransferase 1, to induce global DNA demethylation, which subsequently triggers the activation of the previously defined factors Oct4, Sox2, and Nanog to complete the reprogramming process. The same mechanism was also found in the event of somatic cell nuclear transfer. Based on these advanced understandings, this review describes the currently established SCR mechanism--as compared to the natural process of early ESC formation--and demonstrates how stem cell researchers may use this mechanism to improve iPSC generation.


Immunization with cocktail of HIV-derived peptides in montanide ISA-51 is immunogenic, but causes sterile abscesses and unacceptable reactogenicity.
A peptide vaccine was produced containing B and T cell epitopes from the V3 and C4 Envelope domains of 4 subtype B HIV-1 isolates (MN, RF, CanO, & Ev91). The peptide mixture was formulated as an emulsion in incomplete Freund's adjuvant (IFA). Low-risk, healthy adult subjects were enrolled in a randomized, placebo-controlled dose-escalation study, and selected using criteria specifying that 50% in each study group would be HLA-B7+. Immunizations were scheduled at 0, 1, and 6 months using a total peptide dose of 1 or 4 mg. Adaptive immune responses in16 vaccine recipients and two placebo recipients after the 2nd immunization were evaluated using neutralization assays of sera, as well as ELISpot and ICS assays of cryopreserved PBMCs to assess CD4 and CD8 T-cell responses. In addition, (51)Cr release assays were performed on fresh PBMCs following 14-day stimulation with individual vaccine peptide antigens. 24 subjects were enrolled; 18 completed 2 injections. The study was prematurely terminated because 4 vaccinees developed prolonged pain and sterile abscess formation at the injection site-2 after dose 1, and 2 after dose 2. Two other subjects experienced severe systemic reactions consisting of headache, chills, nausea, and myalgia. Both reactions occurred after the second 4 mg dose. The immunogenicity assessments showed that 6/8 vaccinees at each dose level had detectable MN-specific neutralizing (NT) activity, and 2/7 HLA-B7+ vaccinees had classical CD8 CTL activity detected. However, using both ELISpot and ICS, 8/16 vaccinees (5/7 HLA-B7+) and 0/2 controls had detectable vaccine-specific CD8 T-cell responses. Subjects with moderate or severe systemic or local reactions tended to have more frequent T cell responses and higher antibody responses than those with mild or no reactions. The severity of local responses related to the formulation of these four peptides in IFA is clinically unacceptable for continued development. Both HIV-specific antibody and T cell responses were induced and the magnitude of response correlated with the severity of local and systemic reactions. If potent adjuvants are necessary for subunit vaccines to induce broad and durable immune responses, careful, incremental clinical evaluation is warranted to minimize the risk of adverse events. ClinicalTrials.gov NCT00000886.


Low-dose oxytocin delivered intranasally with Breath Powered device affects social-cognitive behavior: a randomized four-way crossover trial with nasal cavity dimension assessment.
Despite the promise of intranasal oxytocin (OT) for modulating social behavior, recent work has provided mixed results. This may relate to suboptimal drug deposition achieved with conventional nasal sprays, inter-individual differences in nasal physiology and a poor understanding of how intranasal OT is delivered to the brain in humans. Delivering OT using a novel 'Breath Powered' nasal device previously shown to enhance deposition in intranasal sites targeted for nose-to-brain transport, we evaluated dose-dependent effects on social cognition, compared response with intravenous (IV) administration of OT, and assessed nasal cavity dimensions using acoustic rhinometry. We adopted a randomized, double-blind, double-dummy, crossover design, with 16 healthy male adults completing four single-dose treatments (intranasal 8 IU (international units) or 24 IU OT, 1 IU OT IV and placebo). The primary outcome was social cognition measured by emotional ratings of facial images. Secondary outcomes included the pharmacokinetics of OT, vasopressin and cortisol in blood and the association between nasal cavity dimensions and emotional ratings. Despite the fact that all the treatments produced similar plasma OT increases compared with placebo, there was a main effect of treatment on anger ratings of emotionally ambiguous faces. Pairwise comparisons revealed decreased ratings after 8 IU OT in comparison to both placebo and 24 IU OT. In addition, there was an inverse relationship between nasal valve dimensions and anger ratings of ambiguous faces after 8-IU OT treatment. These findings provide support for a direct nose-to-brain effect, independent of blood absorption, of low-dose OT delivered from a Breath Powered device.


Laparoscopic Roux-en-Y versus mini-gastric bypass for the treatment of morbid obesity: a prospective randomized controlled clinical trial.
This prospective, randomized trial compared the safety and effectiveness of laparoscopic Roux-en-Y gastric bypass (LRYGBP) and laparoscopic mini-gastric bypass (LMGBP) in the treatment of morbid obesity. LRYGBP has been the gold standard for the treatment of morbid obesity. While LMGBP has been reported to be a simple and effective treatment, data from a randomized trial are lacking. Eighty patients who met the NIH criteria were recruited and randomized to receive either LRYGBP (n = 40) or LMGBP (n = 40). The minimum postoperative follow-up was 2 years (mean, 31.3 months). Perioperative data were assessed. Late complication, excess weight loss, BMI, quality of life, and comorbidities were determined. Changes in quality of life were assessed using the Gastro-Intestinal Quality of Life Index (GIQLI). There was one conversion (2.5%) in the LRYGBP group. Operation time was shorter in LMGBP group (205 versus 148, P < 0.05). There was no mortality in each group. The operative morbidity rate was higher in the LRYGBP group (20% versus 7.5%, P < 0.05). The late complications rate was the same in the 2 groups (7.5%) with no reoperation. The percentage of excess weight loss was 58.7% and 60.0% at 1 and 2 years, respectively, in the LPYGBP group, and 64.9% and 64.4% in the LMGBP group. The residual excess weight <50% at 2 years postoperatively was achieved in 75% of patients in the LRYGBP group and 95% in the LMGBP group (P < 0.05). A significant improvement of obesity-related clinical parameters and complete resolution of metabolic syndrome in both groups were noted. Both gastrointestinal quality of life increased significantly without any significant difference between the groups. Both LRYGBP and LMGBP are effective for morbid obesity with similar results for resolution of metabolic syndrome and improvement of quality of life. LMGBP is a simpler and safer procedure that has no disadvantage compared with LRYGBP at 2 years of follow-up.


Mortality of treated HIV-1 positive individuals according to viral subtype in Europe and Canada: collaborative cohort analysis.
To estimate prognosis by viral subtype in HIV-1-infected individuals from start of antiretroviral therapy (ART) and after viral failure. Collaborative analysis of data from eight European and three Canadian cohorts. Adults (N>20 000) who started triple ART between 1996 and 2012 and had data on viral subtype were followed for mortality. We estimated crude and adjusted (for age, sex, regimen, CD4 cell count, and AIDS at baseline, period of starting ART, stratified by cohort, region of origin and risk group) mortality hazard ratios (MHR) by subtype. We estimated MHR subsequent to viral failure defined as two HIV-RNA measurements greater than 500 copies/ml after achieving viral suppression. The most prevalent subtypes were B (15 419; 74%), C (2091; 10%), CRF02AG (1057; 5%), A (873; 4%), CRF01AE (506; 2.4%), G (359; 1.7%), and D (232; 1.1%). Subtypes were strongly patterned by region of origin and risk group. During 104 649 person-years of observation, 1172/20 784 patients died. Compared with subtype B, mortality was higher for subtype A, but similar for all other subtypes. MHR for A versus B were 1.13 (95% confidence interval 0.85,1.50) when stratified by cohort, increased to 1.78 (1.27,2.51) on stratification by region and risk, and attenuated to 1.59 (1.14,2.23) on adjustment for covariates. MHR for A versus B was 2.65 (1.64,4.28) and 0.95 (0.57,1.57) for patients who started ART with CD4 cell count below, or more than, 100 cells/μl, respectively. There was no difference in mortality between subtypes A, B and C after viral failure. Patients with subtype A had worse prognosis, an observation which may be confounded by socio-demographic factors.


Bone fluoride concentrations associated with fluoridated drinking water.
Recently published bone fluoride values from Iowa are very high compared to earlier reports, suggesting an increase in fluoride intake. Reanalysis of the Iowa specimens shows levels one-fourth those reported by the Iowa laboratory indicating an error in the original report. Seventeen bone specimens, collected from long-term residents of Rochester, New York, drinking 1 ppm F- water, had a mean value of 2085 +/- 270 ppm F- on an ashed-weight basis. This value is not significantly different from that predicted by the data of Zipkin et al. in 1958. These data, therefore, do not support the contention that there has been an increase in fluoride intake.


Next generation tools to accelerate the synthetic biology process.
Synthetic biology follows the traditional engineering paradigm of designing, building, testing and learning to create new biological systems. While such approaches have enormous potential, major challenges still exist in this field including increasing the speed at which this workflow can be performed. Here, we present recently developed microfluidic tools that can be used to automate the synthetic biology workflow with the goal of advancing the likelihood of producing desired functionalities. With the potential for programmability, automation, and robustness, the integration of microfluidics and synthetic biology has the potential to accelerate advances in areas such as bioenergy, health, and biomaterials.


Dendritic Polyglycerol Sulfate Inhibits Microglial Activation and Reduces Hippocampal CA1 Dendritic Spine Morphology Deficits.
Hyperactivity of microglia and loss of functional circuitry is a common feature of many neurological disorders including those induced or exacerbated by inflammation. Herein, we investigate the response of microglia and changes in hippocampal dendritic postsynaptic spines by dendritic polyglycerol sulfate (dPGS) treatment. Mouse microglia and organotypic hippocampal slices were exposed to dPGS and an inflammogen (lipopolysaccharides). Measurements of intracellular fluorescence and confocal microscopic analyses revealed that dPGS is avidly internalized by microglia but not CA1 pyramidal neurons. Concentration and time-dependent response studies consistently showed no obvious toxicity of dPGS. The adverse effects induced by proinflammogen LPS exposure were reduced and dendritic spine morphology was normalized with the addition of dPGS. This was accompanied by a significant reduction in nitrite and proinflammatory cytokines (TNF-α and IL-6) from hyperactive microglia suggesting normalized circuitry function with dPGS treatment. Collectively, these results suggest that dPGS acts anti-inflammatory, inhibits inflammation-induced degenerative changes in microglia phenotype and rescues dendritic spine morphology.


A sensitive molecularly imprinted polymer based quartz crystal microbalance nanosensor for selective determination of lovastatin in red yeast rice.
Lovastatin (LOV) is a statin, used to lower cholesterol which has been found as a hypolipidemic agent in commercial red yeast rice. In present study, a sensitive molecular imprinted quartz crystal microbalance (QCM) sensor was prepared by fabricating a self-assembling monolayer formation of allylmercaptane on QCM chip surface for selective determination of lovastatin (LOV) in red yeast rice. To prepare molecular imprinted quartz crystal microbalance (QCM) nanosensor, LOV imprinted poly(2-hydroxyethyl methacrylate-methacryloylamidoaspartic acid) [p(HEMA-MAAsp)] nanofilm was attached on the modified gold surface of QCM chip. The non-modified and improved surfaces were characterized by using contact angle, atomic force microscopy (AFM) and Fourier transform infrared (FTIR) spectroscopy. The imprinted QCM sensor was validated according to the ICH guideline (International Conference on Harmonisation). The linearity range was obtained as 0.10-1.25 nM. The detection limit of the prepared material was calculated as 0.030 nM. The developed QCM nanosensor was successfully used to examine red yeast rice. Furthermore, the stability and repeatability of the prepared QCM nanosensor were studied. The spectacular long-term stability and repeatability of the prepared LOV-imprinted QCM nanosensor make them intriguing for use in QCM sensors.


Depression and the risk of autoimmune disease: a nationally representative, prospective longitudinal study.
Autoimmune diseases are associated with substantial morbidity and mortality, yet the etiology remains unclear. Depression has been implicated as a risk factor for various immune-related disorders but little is known about the risk of autoimmune disease. This study examined the association between depression and the risk of autoimmune disease, and investigated the temporal and dose-response nature of these relationships. A prospective population-based study including approximately 1.1 million people was conducted using linked Danish registries. Depression and autoimmune diseases were diagnosed by physicians and documented in medical records. In total, 145 217 individuals with depression were identified between 1995 and 2012. Survival analyses were used to estimate the relative risk of autoimmune disease among those with, compared to without, depression. Analyses were adjusted for gender, age, and co-morbid mental disorders. Depression was associated with a significantly increased risk of autoimmune disease [incidence rate ratio (IRR) 1.25, 95% CI 1.19-1.31], compared to those without a history of depression. Results suggest a general increased risk of autoimmune diseases following the onset of depression during first year (IRR 1.29, 95% CI 1.05-1.58), which remained elevated for the ensuing 11 years and beyond (IRR 1.53, 95% CI 1.34-1.76). Findings did not support a dose-response relationship. Depression appears to be associated with an increased risk of a range of autoimmune diseases. Depression may play a role in the etiology of certain autoimmune conditions. If replicated, findings could highlight additional clinical implications in the treatment and management of depression. Future studies are needed to investigate the possible social, genetic, and neurobiological underpinnings of these relationships.


Adapted optimization model for planning regional wastewater systems: case study.
Wastewater systems are of crucial importance to the promotion of sustainable development. Through an integrated planning approach, the costs can be minimized and the resulting benefits maximized. A planning approach at regional level exploits the economies of scale, while achieving a better environmental performance. In this paper we set out a decision support approach for the planning of regional wastewater systems. Optimization models are used, aimed at finding optimal configurations for the location, type and size of the system's infrastructure: sewers, pump stations, and wastewater treatment plants. Solutions are evaluated in terms of the cost of installing, operating and maintaining the infrastructure, and the water quality in the river that receives the treated wastewater. The river water quality varies in accordance with the effluent discharges, and is assessed using environmental parameters. The models are solved with a simulated annealing algorithm complemented by a local improvement procedure. Its application is illustrated through a case study in the Una river basin region, in Brazil.


A new tool for the early diagnosis of carbon monoxide intoxication.
Invasive measurement of carboxyhemoglobin (COHb) by blood gas analysis (BGA) is accepted as the standard diagnostic procedure in diagnosis of inhalation injury and carbon monoxide (CO) intoxications. The main disadvantage of BGA with COHb testing is the unavailability in pre-hospital rescue conditions. The non-invasive SpCO analysis using pulse CO oximetry (Rad57, Masimo Corp., USA) represents an easy-to-handle device to facilitate the diagnosis of CO intoxication. Between January 2006 and August 2008, 20 patients who were admitted with CO intoxication to our burn centre were included in this study. Blood gas analysis including COHb testing was performed on the first day, hourly. At the same time, SpCO was determined using the Rad57 pulse CO oximeter. Patients received inhalative oxygen according to the parameters of blood gas analysis or hyperbaric oxygenation if COHb > 10%. Five young healthy volunteers served as control group. The SpCO of the volunteers was cross-checked against their COHb levels, which were measured by blood gas analysis. Results of pulse CO oximetry revealed a mean error of approximately 3.15% from the results achieved by blood gas analysis. If COHb resulted in values higher than 10%, the bias remained approximately the same (3.43%/precision 2.362%). When different blood gas analyzers in our department were tested with the same patient sample, a mean error of 2.4% was found. This is only 1% lower compared to the mean error of pulse CO oximetry. Therefore, pulse CO oximetry represents a reliable measurement technique that is easy to handle and could facilitate the early diagnosis of CO intoxication in pre-hospital rescue conditions.


Identification of differentially expressed genes in mouse Pax6 heterozygous lenses.
Pax6 is a critical regulator of the developing lens, other ocular tissues, central nervous system, and pancreas. Downstream targets of Pax6 are largely unknown. The present study was designed to identify differentially expressed genes in Pax6 heterozygous and normal mouse lenses. RNAs from 8-week-old normal and Pax6 heterozygous mouse lenses were analyzed by both RT-PCR differential display and a candidate-gene approach. The expression levels of identified genes were confirmed by semiquantitative RT-PCR. Eight transcripts encoding phosphatase inhibitor Pip-1 protein, heat shock protein Hsp40, Purkinje cell protein Pcp4, an expressed sequence tag (EST; AA331381) originally reported in a brain-specific library, Pitx3, and CBP, were confirmed to be downregulated in the Pax6 heterozygous mouse lenses. alphaB- and betaA3/A1-crystallin transcripts exhibited decreased expression in Pax6 heterozygous lenses, whereas the expression levels of other crystallins were virtually unchanged. The present data identify eight genes with expression levels that are decreased in Pax6 heterozygous lenses and provide evidence that four functional categories of transcripts-namely, small hsps (alphaB-crystallin and Hsp40), crystallins (alphaB- and betaA3/A1-crystallin), transcription factors (Pitx-3 and CBP), and components of signal transduction cascades (Pip-1) are under direct or indirect transcriptional control by Pax6.


Asian elephants (Elephas maximus) reassure others in distress.
Contact directed by uninvolved bystanders toward others in distress, often termed consolation, is uncommon in the animal kingdom, thus far only demonstrated in the great apes, canines, and corvids. Whereas the typical agonistic context of such contact is relatively rare within natural elephant families, other causes of distress may trigger similar, other-regarding responses. In a study carried out at an elephant camp in Thailand, we found that elephants affiliated significantly more with other individuals through directed, physical contact and vocal communication following a distress event than in control periods. In addition, bystanders affiliated with each other, and matched the behavior and emotional state of the first distressed individual, suggesting emotional contagion. The initial distress responses were overwhelmingly directed toward ambiguous stimuli, thus making it difficult to determine if bystanders reacted to the distressed individual or showed a delayed response to the same stimulus. Nonetheless, the directionality of the contacts and their nature strongly suggest attention toward the emotional states of conspecifics. The elephants' behavior is therefore best classified with similar consolation responses by apes, possibly based on convergent evolution of empathic capacities.


Rhenium(I) polypyridine biotin isothiocyanate complexes as the first luminescent biotinylation reagents: synthesis, photophysical properties, biological labeling, cytotoxicity, and imaging studies.
We report here the design of the first class of luminescent biotinylation reagents derived from rhenium(I) polypyridine complexes. These complexes [Re(N-N)(CO)(3)(py-biotin-NCS)](PF(6)) (py-biotin-NCS = 3-isothiocyanato-5-(N-((2-biotinamido)ethyl)aminocarbonyl)pyridine; N-N = 1,10-phenanthroline (phen) (1a), 3,4,7,8-tetramethyl-1,10-phenanthroline (Me(4)-phen) (2a), 4,7-diphenyl-1,10-phenanthroline (Ph(2)-phen) (3a)), containing a biotin unit and an isothiocyanate moiety, have been synthesized from the precursor amine complexes [Re(N-N)(CO)(3)(py-biotin-NH(2))](PF(6)) (py-biotin-NH(2) = 3-amino-5-(N-((2-biotinamido)ethyl)aminocarbonyl)pyridine; N-N = phen (1c), Me(4)-phen (2c), Ph(2)-phen (3c)). To investigate the amine-specific reactivity of the isothiocyanate complexes 1a-3a, they have been reacted with a model substrate ethylamine, resulting in the formation of the thiourea complexes [Re(N-N)(CO)(3)(py-biotin-TU-Et)](PF(6)) (py-biotin-TU-Et = 3-ethylthioureidyl-5-(N-((2-biotinamido)ethyl)aminocarbonyl)pyridine; N-N = phen (1b), Me(4)-phen (2b), Ph(2)-phen (3b)). All the rhenium(I) complexes have been characterized, and their photophysical properties have been studied. The avidin-binding properties of the thiourea complexes 1b-3b have been examined by the 4'-hydroxyazobenzene-2-carboxylic acid (HABA) assay. Titration results indicated that the complexes exhibited emission enhancement by ca. 1.4-1.5-fold upon binding to avidin, and the lifetimes were elongated to ca. 0.8-2.0 micros. Additionally, we have biotinylated bovine serum albumin (BSA) with the isothiocyanate complexes. All the resultant rhenium-BSA bioconjugates displayed intense and long-lived orange-yellow to greenish-yellow emission upon irradiation in aqueous buffer under ambient conditions. The avidin-binding properties of the bioconjugates have been investigated using the HABA assay. Furthermore, the cytotoxicity of the thiourea complexes 1b-3b toward the HeLa cells has been examined by the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyltetrazolium bromide (MTT) assay. The IC50 values were determined to be ca. 17.5-28.5 microM, which are comparable to that of cisplatin (26.7 microM) under the same conditions. The cellular uptake of complex 3b has been investigated by fluorescence microscopy, and the results showed that the complex was localized in the perinuclear region after interiorization.


Aerosol Filtration Efficiency of Common Fabrics Used in Respiratory Cloth Masks.
The emergence of a pandemic affecting the respiratory system can result in a significant demand for face masks. This includes the use of cloth masks by large sections of the public, as can be seen during the current global spread of COVID-19. However, there is limited knowledge available on the performance of various commonly available fabrics used in cloth masks. Importantly, there is a need to evaluate filtration efficiencies as a function of aerosol particulate sizes in the 10 nm to 10 μm range, which is particularly relevant for respiratory virus transmission. We have carried out these studies for several common fabrics including cotton, silk, chiffon, flannel, various synthetics, and their combinations. Although the filtration efficiencies for various fabrics when a single layer was used ranged from 5 to 80% and 5 to 95% for particle sizes of <300 nm and >300 nm, respectively, the efficiencies improved when multiple layers were used and when using a specific combination of different fabrics. Filtration efficiencies of the hybrids (such as cotton-silk, cotton-chiffon, cotton-flannel) was >80% (for particles <300 nm) and >90% (for particles >300 nm). We speculate that the enhanced performance of the hybrids is likely due to the combined effect of mechanical and electrostatic-based filtration. Cotton, the most widely used material for cloth masks performs better at higher weave densities (i.e., thread count) and can make a significant difference in filtration efficiencies. Our studies also imply that gaps (as caused by an improper fit of the mask) can result in over a 60% decrease in the filtration efficiency, implying the need for future cloth mask design studies to take into account issues of "fit" and leakage, while allowing the exhaled air to vent efficiently. Overall, we find that combinations of various commonly available fabrics used in cloth masks can potentially provide significant protection against the transmission of aerosol particles.


Cognitive zonal fusion biopsy of the prostate: Original technique between target and saturation.
We describe our experience in prostate biopsy using a new standardized cognitive fusion techniques, that we call "cognitive zonal fusion biopsy". This new technique is based on two operative options: the first based on target biopsies, the Cognitive Target Biopsy (CTB) if the same target was detected with transrectal ultrasound (TRUS) and multiparametric magnetic resonance (mpMRI); the second based on saturation biopsies, the Zonal Saturation Biopsy (ZSB) on anatomical zone/s containing the region of interest if the same target was not evident with TRUS and MRI. We evaluated results of our technique compared to standard biopsy in order to identify clinically relevant prostate cancer. This is a single-center prospective study conducted in 58 pts: 25 biopsy-naïve, 25 with previous negative biopsy and in 8 with cancer in active surveillance. Based on mpMRI and transrectal ultrasonography (TRUS), all patients were scheduled for standard 12-core TRUS-guided biopsy. If mpMRI was suggestive or positive (PI-RADS 3, 4 or 5): patients underwent additional targeted 2 to 6 cores using cognitive zonal fusion technique. 31/58 (53.4%) patients had a cancer. Our technique detected 80.6% (25 of 31) with clinically significant prostate cancer, leading to detection of insignificant cancer in 20%. Using standard mapping in MR negative areas we found 5 clinically significant cancer and 4 not significant cancers. MRI cancer detection rate was 18/31 (58.1%), and 9/18 (50%) in high grade tumors. Therefore MRI missed 50% of high grade cancers. The mean number of cores taken with cognitive zonal fusion biopsy was 6.1 (2-17), in addition biopsy sampling was done outside the ROI areas. Overall 15.4 cores (12-22) were taken. Cancer amount in Zonal Biopsy was larger than 7.3 mm (1-54.5) in comparison with 5.2 mm (1-23.5) in standard mapping. Largest percentage of cancer involvement with cognitive zonal fusion technique was detected in 19.4% vs 15.9%. Cognitive Zonal Saturation Biopsies should be used to reduce operator variability of cognitive fusion biopsy in addition to standard biopsy. Cognitive zonal biopsy based on mpMRI findings identifies clinically relevant prostate in 80%, has larger cancer extension in fusion biopsies than in random biopsies, and reduce the number of cores if compared to saturation biopsy.


Manganese superoxide dismutase and inducible nitric oxide synthase modify early oxidative events in acute adriamycin-induced mitochondrial toxicity.
In the present study, we used genetically engineered B6C3 mice [mice overexpressing manganese superoxide dismutase (TgM(+/+)), mice in which inducible nitric oxide synthase had been inactivated (iNOSKO(-/-)), and crosses of these two genotypes] to study the role of manganese superoxide dismutase (MnSOD) and inducible nitric oxide synthase (iNOS) in the development of acute Adriamycin-induced cardiotoxicity. Both nontransgenic and genetically engineered mice were treated with 20 mg/kg Adriamycin and cardiac left ventricular tissues studied at 0, 3, 6, and 24 hours. Ultrastructural damage and levels of 4-hydroxy-2-nonenal (4HNE) protein adducts and 3-nitrotyrosine (3NT) were determined in cardiomyocytes using immunogold ultrastructural techniques. Our previous results showed that Adriamycin caused mitochondrial injury without significant nuclear or cytoplasmic damage at early time points. Interestingly, overexpression of MnSOD protected against acute mitochondrial injury, whereas deficiency in iNOS potentiated mitochondrial injury in comparison with levels of injury present in cardiomyocyte mitochondria of nontransgenic mice. In TgM(+/+) mice, there was a significant inverse correlation between mitochondrial injury and 4HNE/3NT levels at all time points analyzed, suggesting that reactive oxygen species/reactive nitrogen species damage products directly regulated acute Adriamycin-induced mitochondrial injury in these mice. The present studies are the first to directly quantify the effects of MnSOD and iNOS on mitochondrial injury during acute Adriamycin-induced cardiotoxicity and show extensive and specific patterns of posttranslational modifications of mitochondrial proteins following Adriamycin treatment.


Anhedonia and its correlation with clinical aspects in Parkinson's disease.
Anhedonia is one of the non-motor symptoms observed in the Parkinson's disease (PD). However, there is no clear relationship between anhedonia and its correlation with other symptoms of PD. The aim of this study is to evaluate the characteristics of anhedonia and its correlation with clinical aspects of PD in a relatively large cohort. We enrolled 318 patients with PD and 62 control subjects for this study. Patients and subjects were tested using the Snaith-Hamilton Pleasure Scale Japanese version and the Beck Depression Inventory 2nd edition for the assessment of anhedonia and depression. We also investigated the correlation among clinical aspects of PD, anhedonia, and depression in patients with PD. The Snaith-Hamilton Pleasure Scale Japanese version and the Beck Depression Inventory 2nd edition scores were significantly higher in patients with PD than in control subjects (p=0.03 and p=0.0006, respectively). All PD patients with anhedonia had a significantly higher score on the unified Parkinson's disease rating scale (UPDRS) parts I and II compared to PD patients without anhedonia. Additionally, all PD patients with depression scored significantly higher on UPDRS part I-IV than PD patients without depression. The patients with anhedonia and without depression had mild motor severity and their treatment was relatively low dosage. These results suggest that anhedonia and depression are slightly linked, but not the same. PD patients with only anhedonia may be closely linked apathy found in untreated early stages of PD.


Trajectories of PTSD risk and resilience in World Trade Center responders: an 8-year prospective cohort study.
Longitudinal symptoms of post-traumatic stress disorder (PTSD) are often characterized by heterogeneous trajectories, which may have unique pre-, peri- and post-trauma risk and protective factors. To date, however, no study has evaluated the nature and determinants of predominant trajectories of PTSD symptoms in World Trade Center (WTC) responders. A total of 10835 WTC responders, including 4035 professional police responders and 6800 non-traditional responders (e.g. construction workers) who participated in the WTC Health Program (WTC-HP), were evaluated an average of 3, 6 and 8 years after the WTC attacks. Among police responders, longitudinal PTSD symptoms were best characterized by four classes, with the majority (77.8%) in a resistant/resilient trajectory and the remainder exhibiting chronic (5.3%), recovering (8.4%) or delayed-onset (8.5%) symptom trajectories. Among non-traditional responders, a six-class solution was optimal, with fewer responders in a resistant/resilient trajectory (58.0%) and the remainder exhibiting recovering (12.3%), severe chronic (9.5%), subsyndromal increasing (7.3%), delayed-onset (6.7%) and moderate chronic (6.2%) trajectories. Prior psychiatric history, Hispanic ethnicity, severity of WTC exposure and WTC-related medical conditions were most strongly associated with symptomatic trajectories of PTSD symptoms in both groups of responders, whereas greater education and family and work support while working at the WTC site were protective against several of these trajectories. Trajectories of PTSD symptoms in WTC responders are heterogeneous and associated uniquely with pre-, peri- and post-trauma risk and protective factors. Police responders were more likely than non-traditional responders to exhibit a resistant/resilient trajectory. These results underscore the importance of prevention, screening and treatment efforts that target high-risk disaster responders, particularly those with prior psychiatric history, high levels of trauma exposure and work-related medical morbidities.


Involvement of EphB1 receptors signalling in models of inflammatory and neuropathic pain.
EphB receptors tyrosine kinases and ephrinB ligands were first identified as guidance molecules involved in the establishment of topographical mapping and connectivity in the nervous system during development. Later in development and into adulthood their primary role would switch from guidance to activity-dependent modulation of synaptic efficacy. In sensory systems, they play a role in both the onset of inflammatory and neuropathic pain, and in the establishment of central sensitisation, an NMDA-mediated form of synaptic plasticity thought to underlie most forms of chronic pain. We studied wild type and EphB1 knockout mice in a range of inflammatory and neuropathic pain models to determine 1), whether EphB1 expression is necessary for the onset and/or maintenance of persistent pain, regardless of origin; 2), whether in these models cellular and molecular changes, e.g. phosphorylation of the NR2B subunit of the NMDA receptor, increased c-fos expression or microglial activation, associated with the onset of pain, are affected by the lack of functional EphB1 receptors. Differences in phenotype were examined behaviourally, anatomically, biochemically and electrophysiologically. Our results establish firstly, that functional EphB1 receptors are not essential for the development of normal nociception, thermal or mechanical sensitivity. Secondly, they demonstrate a widespread involvement of EphB1 receptors in chronic pain. NR2B phosphorylation, c-fos expression and microglial activation are all reduced in EphB1 knockout mice. This last finding is intriguing, since microglial activation is supposedly triggered directly by primary afferents, therefore it was not expected to be affected. Interestingly, in some models of long-term pain (days), mechanical and thermal hyperalgesia develop both in wild type and EphB1 knockout mice, but recovery is faster in the latter, indicating that in particular models these receptors are required for the maintenance, rather than the onset of, thermal and mechanical hypersensitivity. This potentially makes them an attractive target for analgesic strategies.


Improvements in health-related quality of life and function in middle-aged women with chronic diseases of lifestyle after participating in a non-pharmacological intervention programme: A pragmatic randomised controlled trial.
Musculoskeletal diseases consume a large amount of health and social resources and are a major cause of disability in both low- and high-income countries. In addition, patients frequently present with co-morbid chronic diseases of lifestyle. The area of musculoskeletal disease is restricted by a lack of epidemiological knowledge, particularly in low- and middle-income countries. This pragmatic randomised controlled trial assessed the benefits of a 6-week physiotherapy intervention for middle-aged women with musculoskeletal conditions compared to usual care. A weekly 2-h educational programme utilising a workbook, discussion group and exercise class was presented for the intervention group, while the control group received usual care. The primary outcome was health-related quality of life. Parametric and non-parametric data were used to determine the equivalence between the groups. Twenty-two participants were randomised to the intervention and 20 to the control group. The control group demonstrated no within-group improvement in health-related quality of life items, compared to significant improvements in two items in the intervention group. The change in median utility score within the intervention group was twice as large as the change in the control group. With regard to self-efficacy, the intervention group demonstrated significant within-group changes in perceived management of fatigue and discomfort. The positive impact of the intervention on the participants suggests that the programme should continue at the clinic in question, but should be presented at a more convenient time for participants who work, as recruitment to the study was less than anticipated. Primary health care systems in South Africa urgently need to put structures in place for effective management of the functional impact of chronic diseases of lifestyle and musculoskeletal conditions. It is time for physiotherapists and possibly other health care professionals to participate in the development of appropriate community level interventions to address the functioning and quality of life of individuals living with the diseases.


Optimal positioning for emergent needle thoracostomy: a cadaver-based study.
Needle thoracostomy is an emergent procedure designed to relieve tension pneumothorax. High failure rates because of the needle not penetrating into the thoracic cavity have been reported. Advanced Trauma Life Support guidelines recommend placement in the second intercostal space, midclavicular line using a 5-cm needle. The purpose of this study was to evaluate placement in the fifth intercostal space, midaxillary line, where tube thoracostomy is routinely performed. We hypothesized that this would result in a higher successful placement rate. Twenty randomly selected unpreserved adult cadavers were evaluated. A standard 14-gauge 5-cm needle was placed in both the fifth intercostal space at the midaxillary line and the traditional second intercostal space at the midclavicular line in both the right and left chest walls. The needles were secured and thoracotomy was then performed to assess penetration into the pleural cavity. The right and left sides were analyzed separately acting as their own controls for a total of 80 needles inserted into 20 cadavers. The thickness of the chest wall at the site of penetration was then measured for each entry position. A total of 14 male and 6 female cadavers were studied. Overall, 100% (40 of 40) of needles placed in the fifth intercostal space and 57.5% (23 of 40) of the needles placed in the second intercostal space entered the chest cavity (p < 0.001); right chest: 100% versus 60.0% (p = 0.003) and left chest: 100% versus 55.0% (p = 0.001). Overall, the thickness of the chest wall was 3.5 cm ± 0.9 cm at the fifth intercostal space and 4.5 cm ± 1.1 cm at the second intercostal space (p < 0.001). Both right and left chest wall thicknesses were similar (right, 3.6 cm ± 1.0 cm vs. 4.5 cm ± 1.1 cm, p = 0.007; left, 3.5 ± 0.9 cm vs. 4.4 cm ± 1.1 cm, p = 0.008). In a cadaveric model, needle thoracostomy was successfully placed in 100% of attempts at the fifth intercostal space but in only 58% at the traditional second intercostal position. On average, the chest wall was 1 cm thinner at this position and may improve successful needle placement. Live patient validation of these results is warranted.


Human smooth muscle myosin light chain-2 gene expression is repressed in ras transformed fibroblast cells.
We have previously characterized human smooth muscle myosin light chain (MLC)-2 isoform by complementary DNA cloning and have shown that this isoform is expressed in a number of nonmuscle cells such as fibroblast cells. In this report, we show that when human osteosarcoma derived clonal cells (TE 85 clone F-5) (HOS), which are immortalized and nontumorigenic, undergo transformation following infection by Kirsten murine sarcoma virus (K-HOS) or by a chemical carcinogen [N-methyl-N-nitro-N-nitrosoguanidine (MNNG-HOS)], the smooth muscle MLC-2 mRNA is repressed. Revertants of transformed K-HOS cells (K-HOS312H) show normal levels of smooth muscle MLC-2 mRNA. Transformation of HOS cells by Ha-ras oncogene sequences, either by retroviral infection or by transfection followed by selection for tumorigenic cells in nude mice, results in complete repression of smooth muscle MLC-2 mRNA level. Treatment of HOS cells with tumor promoting phorbol ester, 12-O-tetradecanoylphorbol-13-acetate, results in repression of smooth muscle MLC-2 mRNA. Smooth muscle MLC-2 mRNA level is repressed in many, but not all, transformed cell lines, suggesting that it is not an indirect consequence of transformation but is specific to the agent that brings about transformation. HOS cells synthesize three MLC-2 protein species resolved by the two-dimensional gel electrophoretic system. The identity of the smooth muscle MLC-2 isoform was established by coelectrophoresis of the in vitro synthesized MLC-2 protein corresponding to the cloned complementary DNA in the two-dimensional gel system along with total [35S]methionine labeled HOS cell proteins. Quantitative analysis of MLC-2 isoforms in different HOS cells indicates that the synthesis of smooth muscle MLC-2 isoform is specifically repressed to an undetectable level in ras transformed and MNNG transformed cells and also following treatment with 12-O-tetradecanoylphorbol-13-acetate.


Seasonal mesophotic coral bleaching of Stylophora pistillata in the Northern Red Sea.
Coral bleaching occurs when environmental stress induces breakdown of the coral-algae symbiosis and the host initiates algae expulsion. Two types of coral bleaching had been thoroughly discussed in the scientific literature; the first is primarily associated with mass coral bleaching events; the second is a seasonal loss of algae and/or pigments. Here, we describe a phenomenon that has been witnessed for repeated summers in the mesophotic zone (40-63 m) in the northern Red Sea: seasonal bleaching and recovery of several hermatypic coral species. In this study, we followed the recurring bleaching process of the common coral Stylophora pistillata. Bleaching occurred from April to September with a 66% decline in chlorophyll a concentration, while recovery began in October. Using aquarium and transplantation experiments, we explored environmental factors such as temperature, photon flux density and heterotrophic food availability. Our experiments and observations did not yield one single factor, alone, responsible for the seasonal bleaching. The dinoflagellate symbionts (of the genus Symbiodinium) in shallow (5 m) Stylophora pistillata were found to have a net photosynthetic rate of 56.98-92.19 µmol O2 cm(-2) day(-1). However, those from mesophotic depth (60 m) during months when they are not bleached are net consumers of oxygen having a net photosynthetic rate between -12.86 - (-10.24) µmol O2 cm(-2) day(-1). But during months when these mesophotic corals are partially-bleached, they yielded higher net production, between -2.83-0.76 µmol O2 cm(-2) day(-1). This study opens research questions as to why mesophotic zooxanthellae are more successfully meeting the corals metabolic requirements when Chl a concentration decreases by over 60% during summer and early fall.


Subepithelial connective tissue graft with and without the use of plasma rich in growth factors for treating root exposure.
The aim of this study was to evaluate the clinical efficiency of the subepithelial connective tissue graft (SCTG) with and without plasma rich in growth factor (PRGF) in the treatment of gingival recessions. Twenty bilateral buccal gingival Miller's Class I and II recessions were selected. Ten of the recessions were treated with SCTG and PRGF (test group). The rest ten of the recessions were treated with SCTG (control group). The clinical parameters including recession depth (RD), percentage of root coverage (RC), mucogingival junction (MGJ) position, clinical attachment level (CAL), and probing depth (PD) were measured at the baseline, and 1 and 3 months later. The data were analyzed using the Wilcoxon signed rank and Mann-Whitney U tests. After 3 months, both groups showed a significant improvement in all of the mentioned criteria except PD. Although the amount of improvement was better in the SCTG+PRGF group than the SCTG only group, this difference was not statistically significant. The mean RC was 70.85±12.57 in the test group and 75.83±24.68 in the control group. Both SCTG+PRGF and SCTG only result in favorable clinical outcomes, but the added benefit of PRGF is not evident.


Recent Advances in Antisense Oligonucleotide Therapy in Genetic Neuromuscular Diseases.
Genetic neuromuscular diseases are caused by defective expression of nuclear or mitochondrial genes. Mutant genes may reduce expression of wild-type proteins, and strategies to activate expression of the wild-type proteins might provide therapeutic benefits. Also, a toxic mutant protein may cause cell death, and strategies that reduce mutant gene expression may provide therapeutic benefit. Synthetic antisense oligonucleotide (ASO) can recognize cellular RNA and control gene expression. In recent years, advances in ASO chemistry, creation of designer ASO molecules to enhance their safety and target delivery, and scientific controlled clinical trials to ascertain their therapeutic safety and efficacy have led to an era of plausible application of ASO technology to treat currently incurable neuromuscular diseases. Over the past 1 year, for the first time, the United States Food and Drug Administration has approved two ASO therapies in genetic neuromuscular diseases. This overview summarizes the recent advances in ASO technology, evolution and use of synthetic ASOs as a therapeutic platform, and the mechanism of ASO action by exon-skipping in Duchenne muscular dystrophy and exon-inclusion in spinal muscular atrophy, with comments on their advantages and limitations.


Heading choices of flying Drosophila under changing angles of polarized light.
Many navigating insects include the celestial polarization pattern as an additional visual cue to orient their travels. Spontaneous orientation responses of both walking and flying fruit flies (Drosophila melanogaster) to linearly polarized light have previously been demonstrated. Using newly designed modular flight arenas consisting entirely of off-the-shelf parts and 3D-printed components we present individual flying flies with a slow and continuous rotational change in the incident angle of linear polarization. Under such open-loop conditions, single flies choose arbitrary headings with respect to the angle of polarized light and show a clear tendency to maintain those chosen headings for several minutes, thereby adjusting their course to the slow rotation of the incident stimulus. Importantly, flies show the tendency to maintain a chosen heading even when two individual test periods under a linearly polarized stimulus are interrupted by an epoch of unpolarized light lasting several minutes. Finally, we show that these behavioral responses are wavelength-specific, existing under polarized UV stimulus while being absent under polarized green light. Taken together, these findings provide further evidence supporting Drosophila's abilities to use celestial cues for visually guided navigation and course correction.


Audit of prescribing practices of topical corticosteroids in outpatient dermatology clinics in north Palestine.
To analyse the prescribing pattern of topical corticosteroids, 802 outpatient dermatology prescriptions were randomly collected during June 2003-September 2003 from all the 12 nongovernmental dermatological clinics in north Palestine. Of the 2458 medications prescribed, 616 were topical corticosteroids. In most prescriptions, information about strength, duration of treatment and quantity to be used was inadequate, while information regarding frequency, route and area of application was adequate. High efficacy and highest efficacy corticosteroids were prescribed for approximately 18% of patients; intermediate efficacy preparations were prescribed for approximately 50%.


Effect of different cooking methods on iodine losses.
Iodine Deficiency Disorders (IDD) is a public health problem in India. It is because of poor iodine availability to the body either due to loss of iodine from iodized salt or due to cooking. Since there is lack of scientific evidence on loss of iodine during different cooking methods, present study was undertaken to study the effect of different cooking methods on iodine losses. Methods used were boiling, roasting, shallow frying, deep frying, pressure cooking and microwave cooking. The loss of iodine ranged from 6.58% to 51.08%. Minimum losses were found during shallow frying where cooking time of salt was 1 min and 15 s and maximum during pressure cooking where cooking time of salt was 26 min. Losses during boiling, roasting, deep frying and microwave cooking were found to be 40.23%, 10.57%, 10.40% and 27.13% respectively. From the obtained results, authors have concluded that the loss of iodine depends upon type of cooking method and time of addition of salt during cooking.


Changes in perinatal care and outcomes in newborns at the limit of viability in Spain: the EPI-SEN Study.
Advances in perinatal care can influence morbidity and mortality in newborns at the limit of viability. Knowledge of these changes over time may help improve clinical decision making, optimize resource allocation and increase quality of care. To evaluate the influence on morbidity and mortality of changes introduced in the perinatal care of preterm infants (22-26 weeks' gestational age, GA) in Spain between two consecutive periods (2002-2006 and 2007-2011). An analysis of prospectively collected data in a national database network (SEN1500) was performed. All live newborn infants of 22-26 weeks' GA born in or transferred to referral centers of the SEN1500 network in the first 28 days of life were included. Perinatal interventions, clinical management, neonatal morbidity, and survival until hospital discharge were retrieved. A total of 5,470 newborns were included (2,533 and 2,937 in each period, respectively). The major changes introduced during the second period were as follows: (1) lower proportion of extramural births (11.0 vs. 8.9%, p = 0.01), (2) increase in antenatal steroids (69.5 vs. 80.8%, p < 0.001), (3) delivery by C-section (41.8 vs. 48.3%, p < 0.001) and (4) use of CPAP during resuscitation (7.8 vs. 20.7%, p < 0.001). Death in the delivery room decreased from 5.1 to 3.2% (p < 0.001). Survival increased from 49.9 to 57.9% (p < 0.001), and survival without major morbidity increased from 18.1 to 21.2% (p = 0.006). During the second period, a greater attachment to practices proven to have a beneficial impact on survival and reduction of morbidity in the extremely preterm infant was noted, and survival and survival without major morbidity increased. A more conservative approach was detected for newborns of 22 weeks' GA.


Neuroendocrine peptides stimulate adenyl cyclase in normal and malignant prostate cells.
Elevations of intracellular cAMP in human prostate cancer cells have been shown to increase invasiveness and to promote neuronal differentiation. Since neuroendocrine peptides capable of activating adenyl cyclase are present in prostatic nerves and epithelial neuroendocrine cells, we investigated normal and malignant human prostate cells for changes in intracellular cAMP in response to the prostatic peptides vasoactive intestinal peptide (VIP), calcitonin (CT), and calcitonin gene-related peptide (CGRP). Normal prostate epithelial cells and LNCaP prostate cancer cells exhibited, respectively, 6- and 30-fold increases in intracellular cAMP in response to VIP. ALVA-31 and PPC-1 prostate cancer cells demonstrated 20- to 200-fold increases in cAMP in response to CGRP, while normal epithelial cells and LNCaP cells exhibited smaller (2- to 6-fold) responses. Only DU-145 cells increased cAMP substantially in response to CT. VIP receptor mRNA was identified by Northern blot analysis only in those cells that responded to VIP. CT receptor mRNA was identified only in DU-145 cells by polymerase chain reaction and Southern blot analysis. These results suggest that VIP and possibly CGRP receptors are likely to be present in both normal and malignant prostate cells. VIP or CGRP may regulate secretion of proteases by normal or prostate cancer cells and may influence epithelial cell differentiation.


Variability in prostate and seminal vesicle delineations defined on magnetic resonance images, a multi-observer, -center and -sequence study.
The use of magnetic resonance (MR) imaging as a part of preparation for radiotherapy is increasing. For delineation of the prostate several publications have shown decreased delineation variability using MR compared to computed tomography (CT). The purpose of the present work was to investigate the intra- and inter-physician delineation variability for prostate and seminal vesicles, and to investigate the influence of different MR sequence settings used clinically at the five centers participating in the study. MR series from five centers, each providing five patients, were used. Two physicians from each center delineated the prostate and the seminal vesicles on each of the 25 image sets. The variability between the delineations was analyzed with respect to overall, intra- and inter-physician variability, and dependence between variability and origin of the MR images, i.e. the MR sequence used to acquire the data. The intra-physician variability in different directions was between 1.3 - 1.9 mm and 3 - 4 mm for the prostate and seminal vesicles respectively (1 std). The inter-physician variability for different directions were between 0.7 - 1.7 mm and approximately equal for the prostate and seminal vesicles. Large differences in variability were observed for individual patients, and also for individual imaging sequences used at the different centers. There was however no indication of decreased variability with higher field strength. The overall delineation variability is larger for the seminal vesicles compared to the prostate, due to a larger intra-physician variability. The imaging sequence appears to have a large influence on the variability, even for different variants of the T2-weighted spin-echo based sequences, which were used by all centers in the study.


Amphotericin B and anidulafungin directly interact with DNA and induce oxidative damage in the mammalian genome.
Amphotericin B and anidulafungin are widely used antifungal drugs for the treatment of systemic and serious mycoses. Amphotericin B is a relatively toxic drug which has long been established. This study is first of its kind to systematically investigate the nature of binding to DNA, and to evaluate intercalation of AMP-B or ANIDULA with the aid of UV-Vis, ITC, and CD spectroscopy. The binding affinity of AMP-B with exclusion sites of 4.68 base pairs (1.2 × 10(5) M(-1)) was found to be higher than that of ANIDULA with exclusion sites of 6.67 base pairs (3.78 × 10(4) M(-1)); consistent with the binding affinity values obtained for AMP-B (10(5) M(-1)) and ANIDULA (10(4) M(-1)). The binding of two drugs with double-stranded DNA was favoured by negative enthalpy as well as negative entropy changes. The intercalation of drugs to duplex polynucleotide induced changes in the intrinsic CD spectra and revealed comparatively higher affinity towards AMP-B than ANIDULA. Molecular docking studies revealed that the negative binding energy was higher in the case of AMP-B reflecting more affinity towards single-stranded DNA. The results of the cytotoxicity, immunoblotting, and gene specific LA-QPCR assay have indicated that ANIDULA is less genotoxic than AMP-B. Hence, the superiority of ANIDULA over AMP-B as a systemic antifungal drug has been established beyond doubt.


Association between interpersonal trust, reciprocity, and depression in South Korea: a prospective analysis.
A growing body of empirical evidence indicates that low-level social capital is related to poor mental health outcomes. However, the prospective association between social capital and depression remains unclear, and no published studies have investigated the association with longitudinal data in East-Asian countries. We analyzed data from the ongoing Korean Welfare Panel Study to prospectively investigate association between social capital and depression. Social capital was measured at the individual level by two items specific to interpersonal trust and reciprocity. Depression was annually assessed as a dichotomous variable using the Center for Epidemiologic Studies Depression Scale. After excluding participants who had depression in 2006, logistic regression models were applied to estimate the association between each social capital indicator and new-onset depression developed in 2007 or long-term depression in both 2007 and 2008. We also examined the association in a subpopulation restricted to healthy participants after excluding individuals with any pre-existing disability, chronic disease, or poor self-rated health condition. Compared to the high interpersonal trust group, the odds ratios of developing new-onset and long-term depression among the low interpersonal trust group were 1.22 (95% CI: 1.08∼1.38) and 1.23 (95% CI: 1.03∼1.50), respectively, and increased to 1.32 (95% CI: 1.10∼1.57) and 1.47 (95% CI: 1.05∼2.08) in the subpopulation analyses restricted to healthy individuals. Although the low and intermediate reciprocity group also had significantly higher odds of developing new-onset depression compared to the high reciprocity group, the effects were attenuated and statistically non-significant in the subpopulation analyses. Low interpersonal trust appears to be an independent risk factor for new-onset and long-term depression in South Korea.


CNN Explainer: Learning Convolutional Neural Networks with Interactive Visualization.
Deep learning's great success motivates many practitioners and students to learn about this exciting technology. However, it is often challenging for beginners to take their first step due to the complexity of understanding and applying deep learning. We present CNN Explainer, an interactive visualization tool designed for non-experts to learn and examine convolutional neural networks (CNNs), a foundational deep learning model architecture. Our tool addresses key challenges that novices face while learning about CNNs, which we identify from interviews with instructors and a survey with past students. CNN Explainer tightly integrates a model overview that summarizes a CNN's structure, and on-demand, dynamic visual explanation views that help users understand the underlying components of CNNs. Through smooth transitions across levels of abstraction, our tool enables users to inspect the interplay between low-level mathematical operations and high-level model structures. A qualitative user study shows that CNN Explainer helps users more easily understand the inner workings of CNNs, and is engaging and enjoyable to use. We also derive design lessons from our study. Developed using modern web technologies, CNN Explainer runs locally in users' web browsers without the need for installation or specialized hardware, broadening the public's education access to modern deep learning techniques.


Photoinitiator-Initiated Estrogenic Activity in Human Breast Cancer Cell Line MCF-7.
A recent in vitro study reported that the photoinitiator 2-isopropylthioxanthone (2-ITX) is an endocrine-disrupting compound (EDC). However, it is not clear whether other photoinitiators such as 1-hydroxycyclohexyl phenyl ketone (1-HCHPK) and 2-methyl-4'-(methylthio)-2-morpholinopropiophenone (MTMP) produce endocrine-disrupting effects. The purpose of this study was thus to assess the association between estrogenic activity and exposure to photoinitiators. For estimation of the proliferative effect of the photoinitiators, the E-screen assay was used. Six photoinitiators, 2,2-dimethoxy-2-phenylacetophenone (2,2-DMPAP), 2-ethylhexyl 4-(dimethylamino)benzoate (2-EHDAB), 1-HCHPK, 2-ITX, methyl-2-benzoylbenzoate (MBB), and MTMP, significantly increased number of MCF-7 cells, an estrogen-sensitive human breast cancer cell line. In addition, pretreatment with estrogen receptor (ER) antagonists such as clomiphene, tamoxifen, or fulvestrant, significantly reversed the proliferative effect of each photoinitiator. Data demonstrated that the six photoinitiators produced endocrine-disrupting effects and that these photoinitiators interacted with ER as agonists. Evidence indicates that the six photoinitiators demonstrated estrogenic activity via ER as agonists.


Integrin α9 regulates smooth muscle cell phenotype switching and vascular remodeling.
Excessive proliferation of vascular smooth muscle cells (SMCs) remains a significant cause of in-stent restenosis. Integrins, which are heterodimeric transmembrane receptors, play a crucial role in SMC biology by binding to the extracellular matrix protein with the actin cytoskeleton within the SMC. Integrin α9 plays an important role in cell motility and autoimmune diseases; however, its role in SMC biology and remodeling remains unclear. Herein, we demonstrate that stimulated human coronary SMCs upregulate α9 expression. Targeting α9 in stimulated human coronary SMCs, using anti-integrin α9 antibody, suppresses synthetic phenotype and inhibits SMC proliferation and migration. To provide definitive evidence, we generated an SMC-specific α9-deficient mouse strain. Genetic ablation of α9 in SMCs suppressed synthetic phenotype and reduced proliferation and migration in vitro. Mechanistically, suppressed synthetic phenotype and reduced proliferation were associated with decreased focal adhesion kinase/steroid receptor coactivator signaling and downstream targets, including phosphorylated ERK, p38 MAPK, glycogen synthase kinase 3β, and nuclear β-catenin, with reduced transcriptional activation of β-catenin target genes. Following vascular injury, SMC-specific α9-deficient mice or wild-type mice treated with murine anti-integrin α9 antibody exhibited reduced injury-induced neointimal hyperplasia at day 28 by limiting SMC migration and proliferation. Our findings suggest that integrin α9 regulates SMC biology, suggesting its potential therapeutic application in vascular remodeling.


Denitrosation of 1,3-bis(2-chloroethyl)-1-nitrosourea by class mu glutathione transferases and its role in cellular resistance in rat brain tumor cells.
1,3-Bis(2-chloroethyl)-1-nitrosourea (BCNU) is known to be detoxified by a denitrosation reaction catalyzed by glutathione-dependent enzymes in rat liver cytosol (R. E. Talcott and V. A. Levin, Drug Metab. Dispos., 11:175-176, 1983). Using a modification of their procedure, we have measured the ability of different purified rat glutathione transferase isoenzymes to denitrosate BCNU. The catalytic efficiencies of the isoenzymes for the denitrosation reaction expressed as the ratio of Vmax to Km were as follows (isoenzyme, Vmax/Km): 1-2, 2.3; 3-3, 12.2; 3-4, 29.2; and 4-4, 26.1. Thus, the class mu isoenzymes containing subunit 4 are by far the best catalysts of the BCNU denitrosation reaction. The class pi transferase 7-7 and class alpha transferases 1-1 and 1-2 demonstrated very weak catalytic activity with BCNU. Determination of the glutathione transferase isoenzyme profiles of 9L rat brain tumor cells and the BCNU-resistant 9L-2 subline by immunoblotting revealed that although the resistant 9L-2 cells contain lower total glutathione transferase activity than 9L cells, they have elevated levels of the class mu transferases. Also, the class pi transferases were found to be down-regulated in 9L-2 as compared with 9L cells. Thus, the increased resistance of 9L-2 cells to BCNU may, in part, be explained by up-regulation of class mu transferase expression with consequent increased capacity for BCNU detoxication. Further support for this hypothesis comes from the fact that pretreatment of 9L-2 cells with the glutathione transferase inhibitors ethacrynic acid or triphenyltin chloride enhanced the cytotoxic effects of BCNU. These results suggest that the class mu transferases play a role in the resistance of brain tumor cells to BCNU.