Pain Intensity and Sensory Perception of Tender Points in Female Patients with Fibromyalgia: A Pilot Study.
Fibromyalgia syndrome (FMS) is a condition that courses with chronic pain, fatigue, sleep disturbance, impaired quality of life and daily function. Due to the lack of blood, imaging or histological confirmatory tests, the diagnosis of FMS is based on the presence of widespread pain and presence of tender points (TPs). Our aim was to assess the pain pressure thresholds (PPTs) and subjective pain perception (SPP) of all 18 TPs while applying a normalized pressure in female patients with fibromyalgia. An exploratory descriptive pilot study was conducted in 30 female patients with FMS. Sociodemographic data (e.g., age, height, weight, and body mass index), clinical characteristics (e.g., years with diagnosis and severity of FMS), PPTs (assessed with an algometer), and SPP (assessed with a visual analogue scale) of all 18 TPs were collected. A comparative analysis side-to-side (same TP, left and right sides) and between TPs was conducted. No side-to-side differences were found (p < 0.05). Significant differences between all 18 TPs were found for PPTs (p < 0.0001), and SPP (p < 0.005) scores were found. The most mechanosensitive points were located in the second costochondral junction, the occiput, the trochanteric prominence; the most painful while applying a normalized pressure considering the TP and side were those located in the gluteus, trochanteric prominence, and supraspinatus. The current study describes PPTs and SPP, as assessed with algometry and visual analogue scale, respectively, of all 18 TPs in female patients with FMS. TPs exhibited significant PPTs and SPP differences between TP locations with no side-to-side differences.


Hydrogen bonding in the gas-phase: the molecular structures of 2-hydroxybenzamide (C7H7NO2) and 2-methoxybenzamide (C8H9NO2), obtained by gas-phase electron diffraction and theoretical calculations.
The structures of 2-hydroxybenzamide (C7H7NO2) and 2-methoxybenzamide (C8H9NO2) have been determined in the gas-phase by electron diffraction using results from quantum chemical calculations to inform restraints used on the structural parameters. Theoretical methods (HF and MP2/6-311+G(d,p)) predict four stable conformers for both 2-hydroxybenzamide and 2-methoxybenzamide. For both compounds, evidence for intramolecular hydrogen bonding is presented. In 2-hydroxybenzamide, the observed hydrogen bonded fragment is between the hydroxyl and carbonyl groups, while in 2-methoxybenzamide, the hydrogen bonded fragment is between one of the hydrogen atoms of the amide group and the methoxy oxygen atom.


A pilot study examining injuries in elite gaelic footballers.
To quantify injuries in elite gaelic footballers and to determine the nature, sites, and outcome of injuries and the possible risk factors involved. Information on injuries was collected from six elite gaelic football teams by a questionnaire. The footballers were asked to recall injuries over the preceding six month period. A total of 88 out of 107 subjects sustained injuries over the study period. Ninety five injuries were recorded, giving an incidence rate of 1.78 injuries per subject per year, of which 35% were recurring. It was found that 35% of injuries were sustained during training sessions. Lower body injuries predominated (77%), the ankle being the most commonly injured anatomic site. Most injuries were soft tissue in nature: muscle, 33%; ligament, 32%; tendon, 16%. The most common situations giving rise to injuries were collision (22%) and twist/turn (19%). Foul play only accounted for about 6% of injuries. Mean time off play as a result of injury was 17.3 days, and hospital admission was necessary for 15% of the injuries. Despite the limitations of a retrospective of this nature, the study provides useful and important information on injuries in gaelic footballers.


Novel pharmacotherapeutic approaches to prevention and treatment of GVHD.
Acute and chronic graft versus host disease (GVHD) remain the major barriers to successful hematopoietic cell transplantation. The induction of GVHD may be divided into three phases: recipient conditioning;donor T-cell activation; andeffector cells mediating GVHD. This review examines GVHD prevention and treatment using this conceptual model as framework. The various pharmacological agents discussed impact on different phases of the GVHD cascade. For example, keratinocyte growth factor and interleukin (IL)-11 are cytokines that may be useful in disrupting phase I of the GVHD cascade by blocking gastrointestinal tract damage, and lowering serum levels of lipopolysaccharide and tumour necrosis factor (TNF)-alpha. Cyclosporin, tacrolimus (FK-506) and sirolimus (rapamycin) are some of the main agents that disrupt phase II (donor T-cell activation). Mycophenolate mofetil and tresperimus probably act on this phase as well. Other novel drugs that affect phase II are tolerance-induction agents such as CTLA-4 and anti-CD40-ligand monoclonal antibodies, and preliminary results using CTLA-4 monoclonal antibody in GVHD prevention are encouraging. Examples of agents that disrupt phase III are the IL-2 receptor antagonist daclizumab and the anti-TNFalpha monoclonal antibody infliximab. These anti-cytokine antibodies have shown promising results in early studies. The most effective approach to GVHD prevention will probably be a combination regimen where the three phases of the GVHD cascade are disrupted. Once GVHD has occurred, all three phases of the cascade are activated. Developments of combination therapy for treatment of both acute and chronic GVHD are likely to yield better results than monotherapy. The numerous new treatment modalities presented should improve the outlook for patients with acute and chronic GVHD.


Landmarks for endoscopic approach to the parapharyngeal internal carotid artery: a radiographic and cadaveric study.
To define transnasal endoscopic surgical landmarks for the parapharyngeal segment of the internal carotid artery (ppICA) using radiographic analysis and cadaveric dissection. Cadaveric and radiographic study. One hundred seventy-nine computed tomography angiography studies of the head and neck were analyzed using Osirix third-party software (Pixmeo, Geneva, Switzerland). Dissection of a cadaveric specimen was used as a correlate to radiographic findings. The posterior aspect of the lateral pterygoid process and posterior border of the mandibular ramus were used as bony landmarks for the ppICA. At the level of the nasal floor, the distance from the ppICA to the posterolateral pterygoid process and to the posterior mandibular ramus was 2.36 cm and 1.94 cm, respectively, in males, and 2.37 cm and 1.99 cm, respectively, in females. At the level of the skull base, the distance from the ppICA to the posterolateral pterygoid process and to the posterior mandible was 2.33 cm and 1.49 cm, respectively, in males, and 2.20 cm and 1.57 cm, respectively, in females. Cadaver dissection demonstrated the utility of identifying these landmarks. The posterior border of the mandibular ramus and the posterolateral aspect of the pterygoid process may serve as consistent bony landmarks for identification of the ppICA.


GRP78 mediates the therapeutic efficacy of curcumin on colon cancer.
Glucose-regulated protein 78 (GRP78) is the key regulator of endoplasmic reticular (ER) function. Expression of GRP78 was correlated with malignancy in different cancers. However, the role of GRP78 in the cytotoxic effect of curcumin on colon cancer cells is still unclear. A silencing RNA (siRNA) technique was used to knock down GRP78 expression. The anticancer effects of curcumin were assessed by a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, a flow cytometric cell cycle analysis, and a terminal dexynucleotidyl transferase-mediated nick end labeling (TUNEL) assay. HT-29 cells expressed lower GRP78 compared with DLD-1 cells. The MTT assay revealed that HT-29 cells were more resistant to curcumin treatment than DLD-1 cells. GRP78KD cells showed more resistance to curcumin treatment compared with scrambled control cells. Overexpressed GRP78 in HT-29 cells increased the sensitivity to curcumin treatment. According to the cell cycle analysis and TUNEL assay, we found that apoptosis dramatically increased in scrambled control cells compared to GRP78KD DLD-1 cells after curcumin treatment. Finally, we evaluated levels of Bcl-2, BAX, and Bad and found that an increase of Bcl-2 level was observed in GRP78KD cells treated with curcumin. Those results were consistent with the increasing of resistance to curcumin after silencing of GRP78. The levels of GRP78 expression might determine the therapeutic efficacy of curcumin against colon cancer cells.


Surgical pathology of the tricuspid valve: a study of 363 cases spanning 25 years.
Surgical pathologic features of the tricuspid valve were reviewed in 363 patients who had undergone tricuspid valve replacement at our institution during the period 1963 through 1987. Valves were purely regurgitant in 74%, stenotic and regurgitant in 23%, and purely stenotic in 2%; two valves were neither stenotic nor regurgitant. Among 269 purely insufficient tricuspid valves, the four most common causes were postinflammatory disease (41%), congenital disorder (32%), pulmonary venous hypertension (21%), and infective endocarditis (4%). Of 92 cases of tricuspid stenosis, with or without regurgitation, postinflammatory disease was observed in 92%. Female patients accounted for 66% of the 363 cases, including 84% of those with postinflammatory disease and 64% of those with pulmonary venous hypertension. In contrast, male patients accounted for 73% of cases with endocarditis and 61% with congenital heart disease. Although postinflammatory disease accounted for 53% of the 363 cases, its relative frequency diminished from 79% during 1963 through 1967 to only 24% during 1983 through 1987. This trend may reflect the decreasing incidence of acute rheumatic fever reported in Western countries. During the same time interval, the relative frequency of congenital heart disease as a cause of tricuspid dysfunction increased from 7% to 53%, and it is currently the most common cause in our surgical population. This finding apparently reflects changes in patient referral practices and the development of new operative procedures.


Surgical procedures involving cardiopulmonary bypass in patients aged 70 or older.
Cardiac surgery was performed in 27 patients whose ages ranged from 70 to 78 years (mean, 72). In 17 of these patients, the operation was coronary artery bypass grafting without other procedures. There were 3 operative deaths (17.6 percent) but no late deaths during a mean follow-up period of 14 months, and all the 14 surviving patients were improved symptomatically. In the other 10 of the 27 patients, the operation was valve replacement. There was no operative mortality among the 6 aortic valve patients and 1 operative death among the 4 mitral valve patients; the corresponding late deaths were 2 and 1, respectively, during a mean follow-up period of 41.3 months. Improvements in operative management and improved criteria for the selection of patients should afford benefits and risks for elderly cardiac patients similar to those for younger cardiac patients.


Ambient nitrogen dioxide in 47 187 neighbourhoods across 326 cities in eight Latin American countries: population exposures and associations with urban features.
Health research on ambient nitrogen dioxide (NO2) is sparse in Latin America, despite the high prevalence of NO2-associated respiratory diseases in the region. This study describes within-city distributions of ambient NO2 concentrations at high spatial resolution and urban characteristics associated with neighbourhood ambient NO2 in 326 Latin American cities. We aggregated estimates of annual surface NO2 at 1 km2 spatial resolution for 2019, population counts, and urban characteristics compiled by the SALURBAL project to the neighbourhood level (ie, census tracts). We described the percentage of the urban population living with ambient NO2 concentrations exceeding WHO air quality guidelines. We used multilevel models to describe associations of neighbourhood ambient NO2 concentrations with population and urban characteristics at the neighbourhood and city levels. We examined 47 187 neighbourhoods in 326 cities from eight Latin American countries. Of the roughly 236 million urban residents observed, 85% lived in neighbourhoods with ambient annual NO2 above WHO guidelines. In adjusted models, higher neighbourhood-level educational attainment, closer proximity to the city centre, and lower neighbourhood-level greenness were associated with higher ambient NO2. At the city level, higher vehicle congestion, population size, and population density were associated with higher ambient NO2. Almost nine out of every ten residents of Latin American cities live with ambient NO2 concentrations above WHO guidelines. Increasing neighbourhood greenness and reducing reliance on fossil fuel-powered vehicles warrant further attention as potential actionable urban environmental interventions to reduce population exposure to ambient NO2. Wellcome Trust, National Institutes of Health, Cotswold Foundation.


A novel mutation ApoE2 Kurashiki (R158P) in a patient with lipoprotein glomerulopathy.
Lipoprotein glomerulopathy (LPG) is a rare glomerulopathy caused by lipoprotein thrombi. In almost all cases of LPG, several apolipoprotein (apo) E mutations were reported. Here, we present a case of LPG caused by a novel mutation that we named ApoE2 Kurashiki, which substitutes arginine with proline at apoE codon 158. ApoE2 polymorphism is well known for its relationship to type III hyperlipoproteinemia, and the common apoE2 isoform is encoded by the R158C allele. ApoE2 Kurashiki substitutes at the same codon and cannot be distinguished from common apoE2 by stan-dard apoE genotyping or phenotyping.


Linear ubiquitin chains: enzymes, mechanisms and biology.
Ubiquitination is a versatile post-translational modification that regulates a multitude of cellular processes. Its versatility is based on the ability of ubiquitin to form multiple types of polyubiquitin chains, which are recognized by specific ubiquitin receptors to induce the required cellular response. Linear ubiquitin chains are linked through Met 1 and have been established as important players of inflammatory signalling and apoptotic cell death. These chains are generated by a ubiquitin E3 ligase complex called the linear ubiquitin chain assembly complex (LUBAC) that is thus far the only E3 ligase capable of forming linear ubiquitin chains. The complex consists of three subunits, HOIP, HOIL-1L and SHARPIN, each of which have specific roles in the observed biological functions of LUBAC. Furthermore, LUBAC has been found to be associated with OTULIN and CYLD, deubiquitinases that disassemble linear chains and counterbalance the E3 ligase activity of LUBAC. Gene mutations in HOIP, HOIL-1L and OTULIN are found in human patients who suffer from autoimmune diseases, and HOIL-1L mutations are also found in myopathy patients. In this paper, we discuss the mechanisms of linear ubiquitin chain generation and disassembly by their respective enzymes and review our current understanding of their biological functions and association with human diseases.


Application of Accelerated Predictive Stability Studies in Extemporaneously Compounded Formulations of Chlorhexidine to Assess the Shelf Life.
Industrially fabricated medicines have a well-defined shelf life supported by rigorous studies before their approval for commercialization. However, the shelf life of extemporaneous compounding topical formulations prepared at hospitals tends to be shorter, especially when no data are available to prove a longer stability period. Also, the storage conditions are unknown in many circumstances. Accelerated Predictive Stability (APS) studies have been shown to be a useful tool to predict in a faster and more accurate manner the chemical stability of extemporaneously compounded formulations requiring a minimum amount of formulation, thereby reducing the chemical drug waste per study. Shelf life will be allocated based on scientific data without compromising drug efficacy or safety. In this work, the APS approach was applied to the commercially available Cristalmina® (CR) and an extemporaneously compounded formulation of chlorhexidine (DCHX). A different degradation kinetic was found between DCHX and CR (Avrami vs. zero-order kinetics, respectively). This can explain the different shelf life described by the International Council for Harmonisation of Technical Requirements Registration Pharmaceuticals Human Use (ICH) conditions between both formulations. A predicted stability for the DCHX solution was obtained from the extrapolation of the degradation rate in long-term conditions from the Arrhenius equation. The estimated degradation from the Arrhenius equation for DCHX at 5 °C, 25 °C, and 30 °C at 365 days was 3.1%, 17.4%, and 25.9%, respectively. The predicted shelf life, in which the DCHX content was above 90%, was 26.67 months under refrigerated conditions and 5.75 and 2.24 months at 25 and 30 °C, respectively. Currently, the Spanish National Formulary recommends a shelf life of no longer than 3 months at room temperature for DCHX solution. Based on the predicted APS and confirmed by experimental long-term studies, we have demonstrated that the shelf life of DCHX extemporaneously compounded formulations could be prolonged by up to 6 months.


Update on cystic fibrosis-related diabetes.
The aim is to provide a detailed review of recent publications on cystic fibrosis-related diabetes (CFRD) with a particular focus on the interplay between cystic fibrosis (CF) lung disease and diabetes. CFRD is a form of diabetes that is distinct from type 1 or type 2 diabetes. CFRD remains very common and increases in prevalence with increasing age so that one in two middle-aged CF persons have CFRD. People with CFRD have lower lung function, worse nutrition, more frequent hospitalization, and worse mortality than CF people without diabetes. The excess mortality previously noted in women with CFRD compared with CF women without diabetes or CF men is much less apparent. CFRD is due to insulin deficiency and peripheral insulin resistance is much less a factor. Genetic susceptibility and oxidant stress are key risk factors for developing CFRD. The lung is the prime end organ target in CFRD and mortality is due to respiratory failure, not vascular complications. Insulin is the mainstay of therapy and early recognition and institution of therapy appear to improve health outcomes. CFRD remains one of the most important co-morbidities in CF. Early recognition of the disease and therapeutic intervention may diminish the negative impact that diabetes has on lung health in CF. Although a clearer understanding of the role of oxidant stress and genetics in the pathogenesis of CFRD is being elucidated, much needs to be learned before more targeted, specific therapies can be developed for this distinct form of diabetes.


Trends in Bone Morphogenetic Protein Usage since the U.S. Food and Drug Administration Advisory in 2008: What Happens to Physician Practices When the Food and Drug Administration Issues an Advisory?
Study Design Retrospective cross-sectional study of spinal procedures from 2002 to 2010 using the Nationwide Inpatient Sample database. Objective To determine the patterns of bone morphogenetic protein (BMP) usage in fusion surgery before and after the U.S. Food and Drug Administration (FDA) 2008 advisory for the anterior cervical spine to understand how advisories affect U.S. physician practices. Methods Procedures were identified through International Classification of Diseases, Ninth Revision procedure codes and were plotted over time based on fusion procedure type, site, and area of fusion. U.S. national trends were approximated by polynomial regression analysis. Results The majority of the data trends of BMP usage reflect a second-order polynomial model. BMP usage in anterior cervical spine fusion procedures plateaued during the fourth quarter of 2007. The most apparent change in trend was noted in BMP usage pre- and postadvisory in the analysis of anterior cervical spine fusions. BMP percentage of use decreased in this area by 5% from the time of the FDA advisory to the fourth quarter of 2010. Conclusions The decrease in BMP usage in anterior cervical spinal fusion procedures coincided with the timing of the FDA advisory. The fact that BMP continued to be used in cervical spine fusion procedures, even at lower rates, despite the advisory, may reflect the availability of new clinical information that could lessen complications (i.e., lower BMP dose, perioperative steroids, BMP containment). Furthermore, factors like the natural ceiling effect of use or demand for new technology, complications, prohibitive institutional costs, access to information, and insurance compensation may have all contributed to the BMP usage trends observed.


Insight into the process of product expulsion in cellobiohydrolase Cel6A from Trichoderma reesei by computational modeling.
Glycoside hydrolase cellulase family 6 from Trichoderma reesei (TrCel6A) is an important cellobiohydrolase to hydrolyze cellooligosaccharide into cellobiose. The knowledge of enzymatic mechanisms is critical for improving the conversion efficiency of cellulose into ethanol or other chemicals. However, the process of product expulsion, a key component of enzymatic depolymerization, from TrCel6A has not yet been described in detail. Here, conventional molecular dynamics and steered molecular dynamics (SMD) were applied to study product expulsion from TrCel6A. Tyr103 may be a crucial residue in product expulsion given that it exhibits two different posthydrolytic conformations. In one conformation, Tyr103 rotates to open the -3 subsite. However, Tyr103 does not rotate in the other conformation. Three different routes for product expulsion were proposed on the basis of the two different conformations. The total energy barriers of the three routes were calculated through SMD simulations. The total energy barrier of product expulsion through Route 1, in which Tyr103 does not rotate, was 22.2 kcal·mol-1. The total energy barriers of product expulsion through Routes 2 and 3, in which Tyr103 rotates to open the -3 subsite, were 10.3 and 14.4 kcal·mol-1, respectively. Therefore, Routes 2 and 3 have lower energy barriers than Route 1, and Route 2 is the thermodynamically optimal route for product expulsion. Consequently, the rotation of Tyr103 may be crucial for product release from TrCel6A. Results of this work have potential applications in cellulase engineering.


A Mobile Social Networking App for Weight Management and Physical Activity Promotion: Results From an Experimental Mixed Methods Study.
Smartphone apps, fitness trackers, and online social networks have shown promise in weight management and physical activity interventions. However, there are knowledge gaps in identifying the most effective and engaging interventions and intervention features preferred by their users. This 6-month pilot study on a social networking mobile app connected to wireless weight and activity tracking devices has 2 main aims: to evaluate changes in BMI, weight, and physical activity levels in users from different BMI categories and to assess user perspectives on the intervention, particularly on social comparison and automated self-monitoring and feedback features. This was a mixed methods study involving a one-arm, pre-post quasi-experimental pilot with postintervention interviews and focus groups. Healthy young adults used a social networking mobile app intervention integrated with wireless tracking devices (a weight scale and a physical activity tracker) for 6 months. Quantitative results were analyzed separately for 2 groups-underweight-normal and overweight-obese BMI-using t tests and Wilcoxon sum rank, Wilcoxon signed rank, and chi-square tests. Weekly BMI change in participants was explored using linear mixed effects analysis. Interviews and focus groups were analyzed inductively using thematic analysis. In total, 55 participants were recruited (mean age of 23.6, SD 4.6 years; 28 women) and 45 returned for the final session (n=45, 82% retention rate). There were no differences in BMI from baseline to postintervention (6 months) and between the 2 BMI groups. However, at 4 weeks, participants' BMI decreased by 0.34 kg/m2 (P<.001), with a loss of 0.86 kg/m2 in the overweight-obese group (P=.01). Participants in the overweight-obese group used the app significantly less compared with individuals in the underweight-normal BMI group, as they mentioned negative feelings and demotivation from social comparison, particularly from upward comparison with fitter people. Participants in the underweight-normal BMI group were avid users of the app's self-monitoring and feedback (P=.02) and social (P=.04) features compared with those in the overweight-obese group, and they significantly increased their daily step count over the 6-month study duration by an average of 2292 steps (95% CI 898-3370; P<.001). Most participants mentioned a desire for a more personalized intervention. This study shows the effects of different interventions on participants from higher and lower BMI groups and different perspectives regarding the intervention, particularly with respect to its social features. Participants in the overweight-obese group did not sustain a short-term decrease in their BMI and mentioned negative emotions from app use, while participants in the underweight-normal BMI group used the app more frequently and significantly increased their daily step count. These differences highlight the importance of intervention personalization. Future research should explore the role of personalized features to help overcome personal barriers and better match individual preferences and needs.


Staff's awareness of abuse in health care varies according to context and possibilities to act.
The aim of this study was to explore awareness of abuse in health care (AHC) from a staff perspective. Patient evaluation studies often focus on patient satisfaction, and serious negative experiences might therefore be obscured. In our research, we have found that abuse in health care (AHC) is commonly reported by male and female patients, when asked for in a strait way, but so far no intervention studies against AHC have been published. Investigating staff's awareness of AHC is our first step toward developing interventions against AHC. Data were collected at a Swedish clinic of obstetrics and gynecology. Qualitative interviews with 21 informants were analysed with constant comparative analyses. The core category - 'Staff's awareness of AHC varies according to context and possibilities to act' - was derived from the interaction between five categories; Moral imagination, Relativism, Explanations, Dissociation from AHC and Acting against AHC. Awareness of AHC was not a permanent state that did/did not exist as all participants displayed both high and low awareness; depending on the context. Staff's awareness depends on more than personal characteristics; therefore, AHC interventions have to target individual behavior as well as cultures and structures in health care.


Maternal hemodynamics and uteroplacental blood flow throughout gestation in conscious rats.
The present studies were conducted to develop experimental methods for obtaining cardiovascular measurements in conscious, pregnant rats. Methods were then used to establish key quantitative measurements of (a) placental and fetal development, (b) maternal hemodynamics and (c) uteroplacental blood flow throughout gestation. A progressive and significant enhancement in fetal weight occurs during the later one-third of gestation, commencing at day 15 of pregnancy. Fetal mass increases from 100 mg to 6,500 mg over this time period. Placental weight increases concurrently; however, over the last one-third of gestation, fetal growth and development outstrips placental augmentation such that each placental unit supports 10 fetal units near-term. As late gestation proceeds, a progressive reduction in mean arterial blood pressure is accompanied by enhancement in cardiac output. Total peripheral resistance is significantly reduced. Starting at day 15 of gestation, progressive and significant enhancement in blood flow to uterine tissue occurs. Moreover, significantly greater percentage of cardiac output is directed toward uterine tissue, especially near term. Percentage uterine blood flow directed to placenta is less than 10% at day 15 gestation, but placental perfusion is preferentially enhanced as late gestation continues. Near-term, 90% of uterine blood flow perfuses the placenta. Blood flows to nonreproductive visceral organs (kidney, liver, gut and spleen) and skeletal muscles (gastrocnemius, plantaris, tibialis anterior and soleus) are unaltered by pregnancy and gestation. Therefore, late gestational rat fetal development is supported by cardiovascular adaptations, including specific regional control mechanisms, qualitatively similar to those occurring during human gestation.


Low post-operative mortality after surgery on patients with screening-detected abdominal aortic aneurysms: a Swedvasc registry study.
Screening for abdominal aortic aneurysms (AAAs) substantially reduces aneurysm-related mortality in men and is increasing worldwide. This cohort study compares post-operative mortality and complications in men with screening-detected vs. non-screening-detected AAAs. Data were extracted from the Swedish National Registry for Vascular Surgery (Swedvasc) for all screening-detected men treated for AAA (n = 350) and age-matched controls treated for non-screening-detected AAA (n = 350). There were no differences in baseline characteristics besides age, which was lower in the screening-detected group than in the non-screening-detected group (median 66 vs. 68, p < .001). Open repair was used more frequently than endovascular aortic repair (EVAR) in patients with screening-detected AAAs than in non-screening-detected controls (56% vs. 45% p = .005). No differences in major post-operative complications at 30 days were observed between the groups. In patients treated with open repair there were no differences in 30-day, 90-day or 1-year mortality in screening-detected patients compared to non-screening-detected controls (1.0% vs. 3.2% p = .25, 2.1% vs. 4.5% p = .23, 4.1% vs. 5.8% p = .61). None of the patients treated with EVAR in either group died within 30 days. The 90-day mortality after EVAR was lower in patients with screening-detected AAA than in those with non-screening-detected AAAs (0.0% vs. 3.1%, p = .04). No difference in the 1-year mortality was detected in the EVAR-patients between the two groups (1.4% vs. 4.7%, p = .12). The contemporary post-operative mortality after AAA surgery was low in this national audit of patients with screening-detected AAAs and age-matched controls. Patients with screening-detected AAAs have the same frequency of complications at 30 days as patients with non-screening-detected AAA. This study gives further support to national screening programs for the detection of AAA in men.


Remediation by chemical reduction in laboratory mesocosms of three chlordecone-contaminated tropical soils.
Chlordecone (CLD), a highly persistent organochlorine pesticide commonly encountered in French West Indies (FWI) agricultural soils, represents a major source of contamination of FWI ecosystems. The potential of chemical reduction for remediation of CLD-contaminated soil has been investigated in laboratory pilot-scale 80 kg mesocosms for andosol, ferralsol, and nitisol from FWI banana plantations. Six cycles consisting of a 3-week reducing phase followed by a 1-week oxidizing phase were applied, with 2 % (dw/dw) Daramend® (organic plant matter fortified with zero valent iron) added at the start of each cycle. Complementary amendments of zero valent iron and zinc (total of 3 % dw/dw) were added at the start of the first three cycles. After the 6-month treatment, the CLD soil concentration was lowered by 74 % in nitisol, 71 % in ferralsol, and 22 % in andosol. Eleven CLD-dechlorinated transformation products, from mono- to penta-dechlorinated, were identified. None of them accumulated over the duration of the experiment. Six of the seven ecotoxicological tests applied showed no difference between the control and treated soils. The treatment applied in this study may offer a means to remediate CLD-contaminated soils, especially nitisol and ferralsol.


Physical restraint usage at a teaching hospital: a pilot study.
This mixed method study examines the prevalence of restraint usage; perception of nurses and doctors about the practice and whether they were trained to apply physical restraints. The physical restraint prevalence tools were used to observe 172 adult patients and conduct 47 chart audits in the medical-surgical wards and a psychiatric unit in November 2011. Focus group discussions with nurses and doctors were conducted. Quantitative data were analyzed using the SPSS and focus group discussions thematically analyzed. The prevalence of physical restraints between the medical-surgical wards was 75%. Nurses and medical doctors were not formally trained to apply restraint, and had learnt from peer observation. They expressed sadness, guilt, and fear when restraints are used and identified that inadequate institutional support existed. Restraint usage was high, and nurses and doctors experienced moral dilemma when they perceived that lack of formal training and inadequate institutional support may contribute to patient injury.


Cholesterol, a modulator of membrane-associated Abeta-fibrillogenesis.
One of the major pathological features of Alzheimer's disease is the presence of extracellular amyloid plaques that are predominantly composed of the amyloid-beta peptide (Abeta). Characterisation of plaques demonstrated the predominance of two peptides differing at the carboxyl terminus by 2 hydrophobic amino acids, Abeta40 and Abeta42. Diffuse plaques associated with AD are composed predominantly of Abeta42, whereas senile plaques contain both Abeta40 and Abeta42. Recently, it has been suggested that diffuse plaque formation is initiated as a plasma membrane bound Abeta species and that Abeta42 is the critical component. In order to investigate this hypothesis, we have examined Abeta40/42-lipid interactions using in situ atomic force microscopy, electron microscopy and fluorescence anisotropy. While the association of Abeta42 with planar bilayers resulted in peptide aggregation but no fibre formation, this was not the case for Abeta40 where we observed preferential fibre formation. Cholesterol, a key membrane component and modulating factor in AD, is inversely correlated with the extent of Abeta40/42-bilayer interaction. These results were confirmed using fluorescence anisotropy to evaluate the effect of Abeta on membrane fluidity and fluorimetry to confirm membrane integrity. Our results suggest that the enhanced amyloidogenic properties of Abeta42 are not correlated with fibril formation but aggregation on bilayer surfaces.


Statistical Mediation Analysis for Models with a Binary Mediator and a Binary Outcome: the Differences Between Causal and Traditional Mediation Analysis.
Mediation analysis is an important statistical method in prevention research, as it can be used to determine effective intervention components. Traditional mediation analysis defines direct and indirect effects in terms of linear regression coefficients. It is unclear how these traditional effects are estimated in settings with binary variables. An important recent methodological advancement in the mediation analysis literature is the development of the causal mediation analysis framework. Causal mediation analysis defines causal effects as the difference between two potential outcomes. These definitions can be applied to any mediation model to estimate natural direct and indirect effects, including models with binary variables and an exposure-mediator interaction. This paper aims to clarify the similarities and differences between the causal and traditional effect estimates for mediation models with a binary mediator and a binary outcome. Causal and traditional mediation analyses were applied to an empirical example to demonstrate these similarities and differences. Causal and traditional mediation analysis provided similar controlled direct effect estimates, but different estimates of the natural direct effects, natural indirect effects, and total effect. Traditional mediation analysis methods do not generalize well to mediation models with binary variables, while the natural effect definitions can be applied to any mediation model. Causal mediation analysis is therefore the preferred method for the analysis of mediation models with binary variables.


Neutrophils: Novel Contributors to Estrogen-Dependent Intracranial Aneurysm Rupture Via Neutrophil Extracellular Traps.
Background Intracranial aneurysms (IAs) are more prevalent in women than men, and aneurysmal subarachnoid hemorrhage disproportionately affects postmenopausal women. These sex differences suggest estrogen protects against IA progression that can lead to rupture, but the underlying mechanisms are not fully understood. Although studies have demonstrated estrogen regulates inflammatory processes that contribute to IA pathogenesis, the role of neutrophils remains to be characterized. Using a murine model, we tested our hypothesis that neutrophils contribute to IA pathophysiology in an estrogen-dependent manner. Methods and Results We compared neutrophil infiltration in C57BL/6 female mice that develop IAs to those with a normal circle of Willis. Next, we investigated the estrogen-dependent role of neutrophils in IA formation, rupture, and symptom-free survival using a neutrophil depletion antibody. Finally, we studied the role of neutrophil extracellular trap formation (NETosis) as an underlying mechanism of aneurysm progression. Mice that developed aneurysms had increased neutrophil infiltration compared with those with a normal circle of Willis. In estrogen-deficient female mice, both neutrophil depletion and NETosis inhibition decreased aneurysm rupture. In estrogen-deficient female mice treated with estrogen rescue and estrogen-intact female mice, neither neutrophil depletion nor NETosis inhibition affected IA formation, rupture, or symptom-free survival. Conclusions Neutrophils contribute to aneurysm rupture in an estrogen-dependent manner. NETosis appears to be an underlying mechanism for neutrophil-mediated IA rupture in estrogen deficiency. Targeting NETosis may lead to the development of novel therapeutics to protect against IA rupture in the setting of estrogen deficiency.


LPN perspectives of factors that affect nurse mobility in Canada.
Although the licensed practical nurse (LPN) workforce represents an ever-growing and valuable human resource, very little is known about reasons for practical nurse mobility. The purpose of this study was to describe LPN perspectives regarding motives for inter-provincial/territorial (P/T) movement in Canada. Participants included 200 LPNs from nine P/T, and data were analyzed using a qualitative descriptive approach. Three primary themes were identified regarding motivators for LPN migration, including (a) scope of practice, (b) education and advancement opportunities and (c) professional respect and recognition. Although current economic forces have a strong influence on nurse mobility, these findings emphasize that there are other equally important factors influencing LPNs to move between jurisdictions. As such, policy makers, administrators and researchers should further explore and address these themes in order to strengthen Canada's nursing workforce.


Ancestral Information Analysis of Chinese Korean Ethnic Group via a Novel Multiplex DIP System.
Deletion/insertion polymorphism (DIP) is one of the more promising genetic markers in the field of forensic genetics for personal identification and biogeographic ancestry inference. In this research, we used an in-house developed ancestry-informative marker-DIP system, including 56 autosomal diallelic DIPs, three Y-chromosomal DIPs, and an Amelogenin gene, to analyze the genetic polymorphism and ancestral composition of the Chinese Korean group, as well as to explore its genetic relationships with the 26 reference populations. The results showed that this novel panel exhibited high genetic polymorphism in the studied Korean group and could be effectively applied for forensic individual identification in the Korean group. In addition, the results of multiple population genetic analyses indicated that the ancestral component of the Korean group was dominated by northern East Asia. Moreover, the Korean group was more closely related to the East Asian populations, especially to the Japanese population in Tokyo. This study enriched the genetic data of the Korean ethnic group in China and provided information on the ancestry of the Korean group from the perspective of population genetics.


The development of a DNA microarray-based assay for the characterization of commercially formulated microbial products.
Commercially formulated bioproducts containing a complex consortia of bacteria as an active ingredient pose a significant challenge for regulatory agencies and companies seeking to assess the safety and efficacy of these bioproducts. The main challenge stems from how to characterize the bacterial composition of these products, for which there is presently a lack of suitable methods. A prototype DNA microarray composed of oligonucleotide probes for functional genes, virulence factors, and taxonomic genes for a number of bacterial species was developed to examine the utility of microarray technology as a molecular tool for characterizing consortia bioproducts. The genomic DNA from four different products was extracted by two methods and examined with the microarray prototype and by denaturing gradient gel electrophoresis (DGGE). Although the identity of the consortial species remains unknown, the microarray assay provided unique and reproducible hybridization patterns for all four products, and agreed with the fingerprints generated by DGGE. The ability to differentiate between a variety of consortia products demonstrates that DNA microarrays have the potential to be a powerful tool in monitoring complex microbial communities.


Using models to establish the financially optimum strategy for Irish dairy farms.
Determining the effect of a change in management on farm with differing characteristics is a significant challenge in the evaluation of dairy systems due to the interacting components of complex biological systems. In Ireland, milk production is increasing substantially following the abolition of the European Union milk quota regime in 2015. There are 2 main ways to increase the milk production on farm (within a fixed land base): either increase the number of animals (thus increasing the stocking rate) or increase the milk production per animal through increased feeding or increased lactation length. In this study, the effect of increased concentrate feeding or an increase in grazing intensity was simulated to determine the effect on the farm system and its economic performance. Four stocking rates (2.3, 2.6, 2.9, and 3.2 cow/ha) and 5 different concentrate supplementation strategies (0, 180, 360, 600, and 900 kg of dry matter/lactation) resulting in 20 different scenarios were evaluated across different milk, concentrate, and silage purchase prices. Each simulation was run across 10 yr of meteorological data, which had been recorded over the period 2004 to 2013. Three models-the Moorepark and St Gilles grass growth model, the pasture-based herd dynamic milk model, and the Moorepark dairy systems model-were integrated and applied to simulate the different scenarios. Overall, this study has demonstrated that the most profitable scenario was a stocking rate of 2.6 cow/ha with a concentrate supplementation of 600 kg of dry matter/cow. The factor that had the greatest influence on profitability was variability of milk price.


Crossed cerebellar diaschisis in acute stroke detected by dynamic susceptibility contrast MR perfusion imaging.
Crossed cerebellar diaschisis (CCD), the decrease in blood flow and metabolism in the cerebellar hemisphere contralateral to a supratentorial stroke, is frequently reported on positron-emission tomography (PET) and single-photon emission CT (SPECT) but is rarely described with MR perfusion techniques. This study was undertaken to determine the frequency of CCD observed in acute stroke by retrospective review of a research data base of patients with acute stroke evaluated by diffusion-weighted (DWI) and dynamic contrast susceptibility perfusion MR imaging (PWI). PWI scans of 301 consecutive patients with acute stroke and positive DWI abnormality from a research data base were reviewed. Contralateral cerebellar hypoperfusion was identified by inspection of time-to-peak (TTP) maps for asymmetry with an absence of cerebellar abnormalities on T2-weighted scans, DWI, or disease of the vertebrobasilar system on MR angiography. In a subset of the cases, quantitative analysis of perfusion scans was performed using an arterial input function and singular value decomposition (SVD) to generate cerebral blood flow (CBF) maps. A total of 47 of 301 cases (15.61%) met the criteria of CCD by asymmetry of cerebellar perfusion on TTP maps. On quantitative analysis, there was corresponding reduction of CBF by 22.75 +/- 10.94% (range, 7.45% to 52.13%) of the unaffected cerebellar hemisphere). MR perfusion techniques can be used to detect CCD, though the frequency presented in this series is lower than that commonly reported in the PET/SPECT literature. Nevertheless, with its role in acute stroke and noninvasive nature, MR perfusion may be a viable alternative to PET or SPECT to study the phenomenon and clinical consequences of supratentorial stroke with CCD.


Efficacy and safety of one intravitreal injection of bevacizumab in diabetic macular oedema.
To assess the efficacy, duration of effect and safety of one intravitreal injection of bevacizumab in diabetic macular oedema (DMO). Bevacizumab (1 mg/0.04 ml) was injected intravitreally into eyes with DMO (29 with and nine without previous treatments). Best corrected visual acuity (BCVA), intraocular pressure and central retinal thickness (CRT) were measured; slit-lamp examination, macular biomicroscopy, optical coherence tomography and fluorescein angiography were performed before and at 2-4, 8 and 12 weeks post-injection. Best corrected VA and CRT were analysed in both groups. In the non-pretreated group, mean BCVA improved from 0.76 +/- 0.33 (baseline) to 0.57 +/- 0.30 and 0.54 +/- 0.27 at 2-4 weeks and 8 weeks post-injection, respectively (p = 0.02, p = 0.014, paired t-test). Mean CRT decreased from 632.4 +/- 196.0 microm (baseline) to 392.3 +/- 113.6 microm and 370.4 +/- 141.7 microm at the same time-points, respectively (p = 0.01, p = 0.01). There was no difference in BCVA or CRT at 12 weeks. In the pretreated group, mean BCVA improved from 0.62 +/- 0.30 (baseline) to 0.53 +/- 0.33 at 2-4 weeks post-injection (p = 0.01), and mean CRT decreased from 583.9 +/- 180.7 microm (baseline) to 404.1 +/- 197.9 microm at 2-4 weeks post-injection (p < 0.001). Mean BCVA was unchanged at 8 weeks and 12 weeks post-injection, although mean CRT remained lower at 8 weeks (p = 0.004). No ocular or systemic side-effects developed during follow-up. One intravitreal injection of bevacizumab for DMO seems to be effective and safe in both eyes that have been treated previously and eyes that have not. The therapeutic effect is temporary and repeat treatment may be needed.


Neurocognitive outcome in survivors of pediatric cancer.
There are more than 11 million survivors of pediatric cancers living in the US. The largest proportion had leukemia and the group most severely impacted by their cancer and their therapies are the survivors of central nervous system (CNS) tumors. This review describes the neurocognitive outcome for these groups and outlines work aimed at understanding the pathophysiology of and approach to ameliorating neurocognitive dysfunction. The impact of chemotherapy on children treated for leukemia without radiation has been elucidated and the differential impact of different radiation fields and doses among children with CNS malignancies has been described. Newer imaging techniques may predict damage earlier and animal models of chemotherapy-induced neurotoxicity may prove valuable in designing less toxic therapies or finding protective agents. Cognitive training programs, notably computerized programs that can be accessed at home, may be part of successful programs for minimizing neurotoxicity. This review seeks to describe the neurocognitive consequences of cancer and its therapy among pediatric patients treated for leukemia or a CNS tumor. The consequences of therapy with and without cranial radiation are described and information on potentially valuable animal models and imaging techniques are presented. The impact of host pharmacogenomics is outlined.


[Effects of induction of anesthesia on hemodynamics in children with deformities of the spinal cord when turning to the position lying on the belly].
The investigation was devoted to assessment of the reaction of blood circulation to turning to the position "lying on the belly" in different variants of induction of anesthesia to children aged from 7 to 17 years having deformities of the spinal cord. The following combinations were compared: Ketamin, Fentanyl, and inhalation with nitrous oxide; Propofol and Fentanyl; Thiopental, Clofelin, Fentanyl and inhalation with nitrous oxide; Propofol, Clofelin and Fentanyl. The minimal changes in blood circulation were found to occur when using the combination of Thiopental, Clofelin and Fentanyl.


Standard versus prosocial online support groups for distressed breast cancer survivors: a randomized controlled trial.
The Internet can increase access to psychosocial care for breast cancer survivors through online support groups. This study will test a novel prosocial online group that emphasizes both opportunities for getting and giving help. Based on the helper therapy principle, it is hypothesized that the addition of structured helping opportunities and coaching on how to help others online will increase the psychological benefits of a standard online group. A two-armed randomized controlled trial with pretest and posttest. Non-metastatic breast cancer survivors with elevated psychological distress will be randomized to either a standard facilitated online group or to a prosocial facilitated online group, which combines online exchanges of support with structured helping opportunities (blogging, breast cancer outreach) and coaching on how best to give support to others. Validated and reliable measures will be administered to women approximately one month before and after the interventions. Self-esteem, positive affect, and sense of belonging will be tested as potential mediators of the primary outcomes of depressive/anxious symptoms and sense of purpose in life. This study will test an innovative approach to maximizing the psychological benefits of cancer online support groups. The theory-based prosocial online support group intervention model is sustainable, because it can be implemented by private non-profit or other organizations, such as cancer centers, which mostly offer face-to-face support groups with limited patient reach. ClinicalTrials.gov: NCT01396174.


Individual aging and mortality rate: how are they related?
Many researchers working in the area of aging and longevity base their conclusions on the behavior of empirical age trajectories of mortality rates. In such analyses, changes in the slope of the logarithm of the mortality curve are often associated with changes in the rate of individual aging. We show that such interpretation may be incorrect: the changes in the slope of this curve do not necessarily correspond to the changes in the rate of individual aging. We use three models of mortality and aging to illustrate this statement. The first one is based on the idea of frailty. We show that changes in frailty distribution alone may be responsible for changes in the slope. The second model exploits the idea of saving lives. It evaluates changes in mortality rate after elimination of lethal stressful events. The third model uses the idea of Strehler and Mildvan (1960). It shows that changes in the rate of individual aging may take place without changes in the slope of the logarithm of the mortality curve.


Mast cell-derived interleukin 10 limits skin pathology in contact dermatitis and chronic irradiation with ultraviolet B.
Allergic contact dermatitis, such as in response to poison ivy or poison oak, and chronic low-dose ultraviolet B irradiation can damage the skin. Mast cells produce proinflammatory mediators that are thought to exacerbate these prevalent acquired immune or innate responses. Here we found that, unexpectedly, mast cells substantially limited the pathology associated with these responses, including infiltrates of leukocytes, epidermal hyperplasia and epidermal necrosis. Production of interleukin 10 by mast cells contributed to the anti-inflammatory or immunosuppressive effects of mast cells in these conditions. Our findings identify a previously unrecognized function for mast cells and mast cell-derived interleukin 10 in limiting leukocyte infiltration, inflammation and tissue damage associated with immunological or innate responses that can injure the skin.


Organization and expression of the lambda-like genes that contribute to the mu-psi light chain complex in human pre-B cells.
Lambda-like genes encode a polypeptide chain that associates with VpreB and mu chain in the so-called mu-psi light chain complex specifically expressed in pre-B cells. In humans, the lambda-like gene cluster contains three genes, termed 14.1, 16.1, and F lambda 1. The 14.1 gene contains three exons and was previously sequenced. The 16.1 and F lambda 1 have been isolated from cosmid libraries. They both contain only the exons 2 and 3 that appear highly homologous to their 14.1 counterparts. The lambda-like gene cluster has been mapped on chromosome 22, close and distal to the BCR gene, in the order (14.1; F lambda 1) and 16.1. Hybridization with the 14.1 exon 1 probe did not detect an equivalent on 16.1 and F lambda 1 genes, but instead, only revealed the X6 gene, that was previously identified 5 kb upstream of the IGLC locus. It appears, therefore, that the gene organization of the lambda and lambda-like loci is strikingly similar, with a three-exon-containing gene 5' of a series of J lambda-C lambda or J lambda-C lambda-like tandemly organized genes. Analysis of the transcripts in a 8 week old human fetal liver clearly indicated that 14.1 was the only functional gene of the lambda-like cluster. Various forms of transcripts resulting from alternate splicing have been characterized. The major component consisted of a full-length (exons 1-2-3) mRNA, whereas a minor (1-3) transcript was identified. Only the full-length transcript could encode a functional polypeptide chain corresponding to the 22 kDa light chain surrogate.


Using ChIP-seq technology to identify targets of zinc finger transcription factors.
Half of all human transcription factors are zinc finger proteins and yet very little is known concerning the biological role of the majority of these factors. In particular, very few genome-wide studies of the in vivo binding of zinc finger factors have been performed. Based on in vitro studies and other methods that allow selection of high affinity-binding sites in artificial conditions, a zinc finger code has been developed that can be used to compose a putative recognition motif for a particular zinc finger factor (ZNF). Theoretically, a simple bioinformatics analysis could then predict the genomic locations of all the binding sites for that ZNF. However, it is unlikely that all of the sequences in the human genome having a good match to a predicted motif are in fact occupied in vivo (due to negative influences from repressive chromatin, nucleosomal positioning, overlap of binding sites with other factors, etc). A powerful method to identify in vivo binding sites for transcription factors on a genome-wide scale is the chromatin immunoprecipitation (ChIP) assay, followed by hybridization of the precipitated DNA to microarrays (ChIP-chip) or by high throughput DNA sequencing of the sample (ChIP-seq). Such comprehensive in vivo binding studies would not only identify target genes of a particular zinc finger factor, but also provide binding motif data that could be used to test the validity of the zinc finger code. This chapter describes in detail the steps needed to prepare ChIP samples and libraries for high throughput sequencing using the Illumina GA2 platform and includes descriptions of quality control steps necessary to ensure a successful ChIP-seq experiment.


An Anisotropic Model for Magnetostriction and Magnetization Computing for Noise Generation in Electric Devices.
During the manufacturing process and use of ferromagnetic sheets, operations such as rolling, cutting, and tightening induce anisotropy that changes the material's behavior. Consequently for more accuracy in magnetization and magnetostriction calculations in electric devices such as transformers, anisotropic effects should be considered. In the following sections, we give an overview of a macroscopic model which takes into account the magnetic and magnetoelastic anisotropy of the material for both magnetization and magnetostriction computing. Firstly, a comparison between the model results and measurements from a Single Sheet Tester (SST) and values will be shown. Secondly, the model is integrated in a finite elements code to predict magnetostrictive deformation of an in-house test bench which is a stack of 40 sheets glued together by the Vacuum-Pressure Impregnation (VPI) method. Measurements on the test bench and Finite Elements results are presented.


Adaptive will: the evolution of attention deficit disorder.
The increasing prevalence of attention-deficit disorder among American school children was a source of significant controversy in the 1990s. This paper looks at the social and historical contexts in which ADD evolved in order to understand its emergence as a coherent and widespread entity. Changes in expert models of child behavior interacted with the formation of new identities around disability to shape a milieu in which the disorder could thrive. The pattern of affect control, of what must and what must not be restrained, regulated, and transformed, is certainly not the same in this stage as in the preceding one of court aristocracy. In keeping with its different interdependencies, bourgeois society applies stronger restrictions to certain impulses, while in the case of others aristocratic restrictions are simply continued and transformed to suit the changed situation (Elias, 1994, p. 125).


Modeling and updating the occurrence of Aedes aegypti in its southern limit of distribution in South America.
Aedes aegypti is the main vector of arboviruses in the world. This mosquito species is distributed from tropical to temperate regions. In Argentina, it has been reported in 20 out of 23 provinces and reaches its southernmost distribution in the world. Its distribution and persistence are affected by meteorological, demographic and environmental factors, such as temperature, precipitation, and population. The aim of this study was to update and model the occurrence of Aedes aegypti in its southern limit of distribution in Argentina. To this end, a total of 37 sites were inspected in La Pampa and Río Negro provinces. Generalized Linear Models were used to explain the occurrence of Aedes aegypti based on meteorological, environmental and demographic variables. Aedes aegypti was found in 11 cities of La Pampa province where it had not been previously reported, but was not found in any of the cities evaluated in Río Negro province. The averaged model explaining the occurrence of Aedes aegypti included the minimum temperature, precipitation and interactions between maximum temperature and precipitation as explanatory variables. Although precipitation was statistically significant, other factors such as minimum temperature are also important in modeling the occurrence of Aedes aegypti in its southernmost distribution limit.


Animal toxins and the kidney.
Envenomation or poisoning by toxins from animals poses an important health hazard in the tropics. Animal toxins are complex mixtures of proteins, peptides, enzymes and chemicals. These toxins exert their effects through modulation of ion channels and receptors, and via direct enzyme action. Depolarization or hyperpolarization of ion channels--caused by most marine toxins, and some snake and insect venoms--results in neuromuscular symptoms that can be associated with hemodynamic changes. Toxin enzymes, especially proteases and phospholipase A2, initiate inflammatory processes that involve the generation of proinflammatory cytokines and vasoactive mediators, resulting in systemic and renal hemodynamic alterations. Toxin enzymes also have direct effects on erythrocytes, myocytes, blood coagulation factors, vascular endothelium and epithelial cells. As a result, disseminated intravascular coagulation, bleeding diathesis, intravascular hemolysis and rhabdomyolysis are common after exposure to animal toxins. The renal manifestations of animal toxin envenomation, which are usually acute, result mainly from these enzymatic effects. All renal structures can be affected by animal toxins, and tubular necrosis is common. Acute kidney injury is attributed to decreased renal blood flow (associated with intravascular hemolysis or rhabdomyolysis), disseminated intravascular coagulation or direct tubular toxicity. Immunologic mechanisms have a minor role in the pathophysiology of nephropathy caused by animal toxins.


Discovery and development of first in class antifungal caspofungin (CANCIDAS®)--a case study.
Covering: 1985 to 2001.This paper describes a fifteen year journey from concept to clinical discovery and development of the first in class caspofungin acetate (CANCIDAS®) a parenteral antifungal agent. Caspofungin is a semisynthetic derivative of pneumocandin B0, a naturally occurring, lipophilic cyclic peptide isolated from the fungus, Glarea lozoyensis. While the echinocandins had been previously studied for antifungal activity by several organizations, the class was dropped for a variety of reasons. Merck subsequently initiated a research program leading to the discovery and development of caspofungin. The multitude of challenges that ensued during the discovery and development process and which were successfully resolved by multi-disciplinary teams constitute the content of this article. The article consists of five sections that describe the discovery and development of caspofungin in chronological order: (i) discovery of the natural product pneumocandin B0 from fungal fermentations, (ii) fermentation development to improve the titer of pneumocandin B0 to make it commercially viable, (iii) semisynthetic modification by medicinal chemistry to successfully improve the properties of pneumocandin B0 leading to the discovery of caspofungin, (iv) development of commercial semisynthesis and purification and formulation development to improve stability and (v) clinical development and approval of CANCIDAS® as an antifungal drug which subsequently saved thousands of lives.


Acute coronary syndromes in young patients: presentation, treatment and outcome.
Acute coronary syndromes (ACS) in very young patients have been poorly described. We therefore evaluate ACS in patients aged 35 years and younger. In this prospective cohort study, 76 hospitals treating ACS in Switzerland enrolled 28,778 patients with ACS between January 1, 1997, and October 1, 2008. ACS definition included ST-segment elevation myocardial infarction (STEMI), non-ST-segment elevation myocardial infarction (NSTEMI), and unstable angina (UA). 195 patients (0.7%) were 35 years old or younger. Compared to patients>35 years, these patients were more likely to present with chest pain (91.6% vs. 83.7%; P=0.003) and less likely to have heart failure (Killip class II to IV in 5.2% vs. 23.0%; P<0.001). STEMI was more prevalent in younger than in older patients (73.1% vs. 58.3%; P<0.001). Smoking, family history of CAD, and/or dyslipidemia were important cardiovascular risk factors in young patients (prevalence 77.2%, 55.0%, and 44.0%). The prevalence of overweight among young patients with ACS was high (57.8%). Cocaine abuse was associated with ACS in some young patients. Compared to older patients, young patients were more likely to receive early percutaneous coronary interventions and had better outcome with fewer major adverse cardiac events. Young patients with ACS differed from older patients in that the younger often presented with STEMI, received early aggressive treatment, and had favourable outcomes. Primary prevention of smoking, dyslipidemia and overweight should be more aggressively promoted in adolescence.


Unusual Stress Fracture in a CrossFit Athlete: A Case Report.
This is a case of a 28-year-old CrossFit athlete who was observed at the emergency department after a competition with acute right shoulder pain. After investigation, she claimed of some posterior shoulder tightness for the past month, without any trauma associated. After the imaging study, we diagnosed a scapula stress fracture. After 8 weeks of rest, she was pain free and returned to sports. Stress fracture of the scapula should be considered in the differential diagnosis of shoulder pain in overhead activities athletes. This case illustrates an excellent prognosis with conservative treatment and the potencial for full return to sports.


Retrospective Comparison of Preoperative and Postoperative Foot Width in Minimally Invasive Hallux Valgus Surgery.
Minimally invasive surgery (MIS) has gained popularity for hallux valgus correction in the adult population. The advantage of reproducibility of this procedure can aid in lower operating room costs, quicker recovery, and fewer complications. The purpose of this retrospective study was to compare preoperative versus postoperative foot widths in patients that underwent MIS hallux valgus correction. The average preoperative foot width was 101.1 ± 5.67 mm and postoperatively the foot width measured at 12-month follow-up was 95.9 ± 4.92 mm, which was statistically significant (p < .001). Overall, there was a 5.03 ± 3.71% reduction in foot width, with a statistically significant linear relationship between preoperative foot width and percent change in width following the procedure (R = -0.46; p = .003). Based on our results, we can conclude that MIS bunion surgery can effectively narrow the foot postoperatively, particularly in patients with a wider forefoot, adding cosmetic benefit to the procedure.


[History of surgical treatment of goiter].
Struma has called for treatment very early in medical history due to its appearance. At the beginning of our calendar, the physicians dealt with this problem already. This paper gives a historical review about the surgical treatment of struma.


Acute abdomen caused by a small bowel perforation due to a clinically unsuspected fish bone.
We report the case of a 78-year-old woman with a three-day history of abdominal pain and vomiting. An abdominal plain film showed a distended small bowel loop and no signs of free intra-abdominal gas. An abdominal ultrasound revealed a mass containing a linear, hyperechoic structure. The mass was connected through a sinus tract to an adjacent aperistaltic small bowel loop. A laparotomy revealed a jejunal perforation and an omental granuloma containing a fish bone. Accidentally ingested foreign bodies should always be suspected in cases of acute abdomen, and ultrasonography remains a firstline examination tool for preoperative diagnoses of unsuspected foreign bodies and their complications.


Traits of a mussel transmissible cancer are reminiscent of a parasitic life style.
Some cancers have evolved the ability to spread from host to host by transmission of cancerous cells. These rare biological entities can be considered parasites with a host-related genome. Still, we know little about their specific adaptation to a parasitic lifestyle. MtrBTN2 is one of the few lineages of transmissible cancers known in the animal kingdom. Reported worldwide, MtrBTN2 infects marine mussels. We isolated MtrBTN2 cells circulating in the hemolymph of cancerous mussels and investigated their phenotypic traits. We found that MtrBTN2 cells had remarkable survival capacities in seawater, much higher than normal hemocytes. With almost 100% cell survival over three days, they increase significantly their chances to infect neighboring hosts. MtrBTN2 also triggered an aggressive cancerous process: proliferation in mussels was ~ 17 times higher than normal hemocytes (mean doubling time of ~ 3 days), thereby favoring a rapid increase of intra-host population size. MtrBTN2 appears to induce host castration, thereby favoring resources re-allocation to the parasites and increasing the host carrying capacity. Altogether, our results highlight a series of traits of MtrBTN2 consistent with a marine parasitic lifestyle that may have contributed to the success of its persistence and dissemination in different mussel populations across the globe.


A patterned human primitive heart organoid model generated by pluripotent stem cell self-organization.
Pluripotent stem cell-derived organoids can recapitulate significant features of organ development in vitro. We hypothesized that creating human heart organoids by mimicking aspects of in utero gestation (e.g., addition of metabolic and hormonal factors) would lead to higher physiological and anatomical relevance. We find that heart organoids produced using this self-organization-driven developmental induction strategy are remarkably similar transcriptionally and morphologically to age-matched human embryonic hearts. We also show that they recapitulate several aspects of cardiac development, including large atrial and ventricular chambers, proepicardial organ formation, and retinoic acid-mediated anterior-posterior patterning, mimicking the developmental processes found in the post-heart tube stage primitive heart. Moreover, we provide proof-of-concept demonstration of the value of this system for disease modeling by exploring the effects of ondansetron, a drug administered to pregnant women and associated with congenital heart defects. These findings constitute a significant technical advance for synthetic heart development and provide a powerful tool for cardiac disease modeling.


The use of fluorescent quenching in studying the contribution of evaporation to tear thinning.
The purpose of our study was to test the prediction that if the tear film thins due to evaporation, rather than tangential flow, a high concentration of fluorescein in the tear film would show a greater reduction in fluorescent intensity compared to a low concentration of fluorescein due to self-quenching at high concentrations. Tear film thickness, thinning rate, and fluorescent intensity were measured continuously and simultaneously with a modified spectral interferometer in 30 healthy subjects with two different concentrations (2% followed by 10%) of 1 μL of liquid fluorescein on the eye. Measurements of fluorescein self-quenching (fluorescent efficiency as a function of fluorescein concentration) are described in an Appendix and are reported in arbitrary units. Under low and high fluorescein concentration conditions, there were no differences in tear film thickness (P = 0.09) or thinning rates (P = 0.76). While the mean initial fluorescent intensity was similar between groups (637.47 ± 381.47 vs. 672.09 ± 649.72, P = 0.55), the mean rate of fluorescent decay was 4-fold faster in the high (16.57 ± 29.34) than in the low (4.11 ± 6.78) concentration group (P < 0.01). The large difference in the rate of fluorescent decay between groups can be explained by the effects of evaporation and self quenching of fluorescein; the latter is expected to be greater for high than for low fluorescein concentration. Fluorescence decay due to tangential flow would be expected to be similar at high and low fluorescein concentrations. This supports previous evidence that evaporation has the primary role in normal tear thinning between blinks.


A multi-site randomized controlled trial of a cognitive skills programme for male mentally disordered offenders: social-cognitive outcomes.
Cognitive skills programmes have been associated with improvements on psychometric measures and reductions in antisocial behaviour in mentally disordered offenders (MDOs). However, to date there have been no randomized controlled trials (RCTs) of such programmes with this population. In the first RCT of a cognitive skills programme with MDOs we aimed to determine if participation in the Reasoning and Rehabilitation (R&R) programme was associated with improvements in social-cognitive skills and thinking styles. A total of 84 men with a primary diagnosis of psychotic disorder and a history of violence were recruited from medium-secure forensic units and allocated to receive R&R (n=44) or treatment as usual (TAU; n=40). At baseline and post-treatment interviews, participants completed questionnaires to assess social problem-solving, criminal attitudes, anger experience, blame externalizing and perspective-taking. Researchers were not blind to group status. The R&R group demonstrated significant improvements on measures of social problem-solving relative to the TAU group, some of which were maintained at 12 months post-treatment. Only half of those allocated to receive R&R completed the full programme. In post-hoc analyses programme completers showed improvements in social problem-solving at the end of treatment and changes in criminal attitudes at 12 months post-treatment. Among male MDOs, R&R participation was associated with improvements in social-cognitive skills, some of which were maintained for up to 12 months post-treatment. Our finding that programme completers do better may reflect pre-treatment patient characteristics. This study establishes that multi-site RCTs can be conducted in medium-secure forensic units.


Nuclear isoform of RAPH1 interacts with FOXQ1 to promote aggressiveness and radioresistance in breast cancer.
Radioresistance limits the efficacy of radiotherapy against breast cancer, especially the most lethal subtype of breast cancer, triple-negative breast cancer (TNBC). Epithelial-to-mesenchymal transition (EMT) is closely related to tumor radioresistance. In this work, we attempted to identify the key EMT-related transcription factor(s) that can induce radioresistance in breast cancer cells. A set of 44 EMT transcription factors were analyzed in parental and radioresistant TNBC cell lines. The function of FOXQ1, a differentially expressed transcription factor, was determined in TNBC radioresistance. FOXQ1-interacting proteins were identified by co-immunoprecipitation and mass spectrometry. Compared with parental cells, FOXQ1 was significantly upregulated in radioresistant TNBC cells. Silencing of FOXQ1 increased the radiosensitiviy of radioresistant TNBC cells both in vitro and in vivo. FOXQ1 associated with a nuclear isoform of RAPH1 (named RAPH1-i3) in radioresistant TNBC cells. Overexpression of RAPH1-i3 enhanced TNBC cell proliferation and migration, and most interestingly, induced radioresistance in parental TNBC cells when co-expressed with FOXQ1. Similar findings were observed in estrogen receptor-positive breast cancer cell lines that had co-expression of RAPH1-i3 and FOXQ1. Mechanistically, co-expression of RAPH1-i3 and FOXQ1 activated STAT3 signaling and increased the expression of CCND1, MCL1, Bcl-XL, and MMP2. Depletion of RAPH1-i3 impaired the radioresistance of radioresistant TNBC cells. Additionally, RAPH1-i3 upregulation was associated with advanced tumor stage and reduced disease-free survival in TNBC patients. These results collectively show that RAPH1-i3 interacts with FOXQ1 to promote breast cancer progression and radioresistance. RAPH1-i3 and FOXQ1 represent therapeutic targets for the treatment of breast cancer including TNBC.


Factors affecting the outcomes of modified tension band wiring techniques in transverse patellar fractures.
Modified tension band wiring has been widely used to treat transverse patellar fractures. However, few studies have evaluated the clinical outcomes using different methods of Kirschner wire bending, location of the tension band, and depths of Kirschner wires. Thus, we tried to clarify these factors according to our clinical outcomes. This retrospective cohort study recruited consecutive patients underwent surgical fixation for patellar fractures using modified tension band technique between January 2010 and December 2015. Different factors in this procedure, including the bending manner of the Kirschner wires, their depth, and location of the tension band with respect to the superior and inferior border of the patella were recorded and analysed. The primary outcome was early loss of fixation. The secondary outcomes were minor loss of reduction, implant breakage, deep infection, and the need for implant removal. This study included 170 patients with patellar fractures. Regarding the bending method, similar results were obtained with bilaterally or proximally bent Kirschner wires. Regarding length, the tension band was placed closely (within 25% of the patella length) in 124 patients and distantly in 46 patients. The rates of loss of reduction and implant breakage were significantly higher in the distantly placed tension bands. Regarding depth, 37 patellar fractures were fixed with the Kirschner wires at the superficial one third of the patellae while the K- wires at the middle layer of patella were used in the remaining 133 patellar fractures. A significantly higher rate of minor loss of reduction was obtained using the superficial Kirschner wires. The modified tension band technique for transverse patella fractures provides favourable clinical outcomes, with low failure (5%) and infection (2%) rates. Implant irritation is the major complication, and almost half of cases require implant removal. The location of the tension band with respect to the superior and inferior border of the patella plays an important role in clinical outcomes. Placing the wire close to the patella may prevent major loss of reduction and implant breakage. Superficially placed Kirschner wires also affect clinical outcomes by increasing the rate of minor loss of reduction.


Case fatality rate for Ebola disease, 1976-2022: A meta-analysis of global data.
An up-to-date pooled case fatality rate (CFR) for Ebola disease (EBOD) at the global level is lacking. We abstracted EBOD data from 1976 to 2022 for 16 countries and 42 outbreaks to conduct a meta-analysis. The pooled CFR was 60.6% (95% confidence interval (CI) 51.6-69.4; 95% prediction interval 12.9-99.1). Of the four ebolaviruses, Zaire virus was the most lethal (CFR = 66.6%, 95% CI 55.9-76.8), then Sudan virus (CFR=48.5%, 95% CI 38.6-58.4), Bundibugyo virus (CFR=32.8%, 95% CI 25.8-40.2) and Tai Forest virus (CFR= 0%, 95% CI 0.0-97.5). The CFR in sub-Saharan Africa was 61.3% (95% CI 52.8-69.6) and for the rest of the world was 24.5% (95% CI 0.0-67.9%). CFR declined over time but stabilized at 61.0% (95% CI, 52.0-69.0) between 2014 and 2022. Overall, the EBOD CFR is still high and heterogeneous. Accordingly, early diagnosis, early treatment if available, and supportive care are important to prevent significant morbidity and mortality.


An Assessment of Primary Care and Pulmonary Provider Perspectives on Lung Cancer Screening.
Lung cancer screening has a mortality benefit to high-risk smokers, but implementation remains suboptimal. Providers represent the key entry point to screening, and an understanding of provider perspectives on lung cancer screening is necessary to improve referral and overall implementation. The objective of this study was to understand knowledge, beliefs, attitudes, barriers, and facilitators to screening in a diverse group of referring pulmonologists and primary care providers. We conducted an electronic survey of primary care and pulmonary providers within a tertiary care medical center across different practice sites. The survey covered the following domains: 1) beliefs and assessment of evidence, 2) knowledge of lung cancer screening and guidelines, 3) current screening practices, 4) barriers and facilitators, and 5) demographic and practice characteristics. The 196 participants included 80% primary care clinicians and 19% pulmonologists (1% others). Forty-one percent practiced at university-based or affiliated clinics, 47% at county hospital-based clinics, and 12% at other or unidentified sites. The majority endorsed lung cancer screening effectiveness (74%); however, performance on knowledge-based assessments of screening eligibility, documentation, and nodule management was suboptimal. Key barriers included inadequate time (36%), inadequate staffing (36%), and patients having too many other illnesses to address screening (38%). Decision aids, which are used at the point of referral, were commonly identified both as important lung cancer screening clinical facilitators (51%) and as provider knowledge facilitators (59%). There were several differences by provider specialty, including primary care providers more frequently reporting time constraints and their patients having too many other illnesses to address screening as significant barriers to lung cancer screening. Providers endorsed the benefits of lung cancer screening, but there are limitations in provider knowledge of key screening components. The most frequently reported barriers to screening represent a lack of clinical time or resources to address lung cancer screening in clinical practice. Facilitators for nodule management as well as point-of-care referral materials may be helpful in reducing knowledge gaps and the clinical burden of referral. These are all modifiable factors, which could be addressed to increase screening referral. Differences in attitudes and barriers by specialty should also be considered to optimize screening implementation.


Statin drugs and dietary isoprenoids as antithrombotic agents.
Statin drugs and various isoprenoids from plant origins inhibit mevalonic acids, cholesterol, and other isoprenoid products. Among these, reduction of farnesyl and geranylgeranyl prenylated proteins impedes signal transduction at the cellular level. The authors envision that limiting such prenylated proteins downregulates thrombin-stimulated events, including decreasing the expression and availability of protease-activated receptor-1 mitigating thrombin stimulation of cells, tissue factor preventing additional thrombin generation, and plasminogen activator inhibitor-1 allowing thrombosis. Additional processes may enhance nitric oxide production and induce other processes. Downregulation of thrombin-stimulated events should promote hypothrombotic or quiescent conditions that reduce cardiovascular disease, thus contributing to longevity.


Description of two new nomogram/calculators for categorising oxygenation status.
Presentation of blood gas results requires knowledge of the position of the oxygen dissociation curve (ODC) to give a complete indication of oxygenation status. Many computations rely on the shift of the ODC occurring with a constant proportional value throughout its length, with no change of shape. If this consistency is accepted it permits geometric manipulation of the curve and the construction of accurate hand held mechanical calculators. Two examples of such calculators are presented. From the measured values of oxygen partial pressure, saturation and haemoglobin concentration they will present many of the new proposed units.


A novel model system for studying the double-edged roles of nitric oxide production in pancreatic cancer growth and metastasis.
In the present study, a model system for studying the role of nitric oxide (NO) in tumor growth and metastasis was reported. Incubation of Panc02 murine pancreatic adenocarcinoma cells in vitro with cytokines and interferon led to heterogeneous expression of NO synthase II (NOS II) protein. Clonal sublines expressing different levels of NOS II were then established using a limited dilution technique. After orthotopical implantation into the pancreas of syngeneic C57BL/6 mice, clones with a low level of NOS II expression produced tumors in pancreas, metastasized to the liver, and formed ascites, whereas those having a high level of NOS II expression did not. Liver-metastasis variants having low to high metastatic ability were also established using in vivo/in vitro passage. Compared with parental Panc02 cells exhibiting a high level of NOS II expression, these variants had a decreased level of NOS II expression. Furthermore, the heterogeneous Panc02 cells were injected intravenously into a large number of syngeneic mice. Variants that metastasized to the liver, lung, skin, peritoneum, ovary, and lymph nodes were established. All of the metastatic variants exhibited a lower level of NOS II expression than the parental Panc02 cell line did. However, the phenotypes of NOS II induction and metastatic ability were unstable. Multiple in vitro/in vivo selection led to stable low NOS II expression and high metastatic potential. Finally, to further confirm the role of NOS II expression derived from tumor cells in metastasis, poorly metastatic Panc02-H0 and highly metastatic Panc02-H7 cells were injected into the pancreas of syngeneic NOS II(-/-) mice, and groups of mice received i.p. injections of either phosphate-buffered saline or L-N(6)-(1-iminoethyl) lysine. Inhibition of NOS II activity in vivo significantly promoted distant liver metastasis. Collectively, these data show that NOS II expression is highly heterogeneous and dynamically regulated, which can directly influence tumor growth and metastasis.


Genome-wide systematic characterization of bZIP transcription factors and their expression profiles during seed development and in response to salt stress in peanut.
Plant basic leucine zipper (bZIP) transcription factors play crucial roles in plant growth, development, and abiotic stress responses. However, systematic investigation and analyses of the bZIP gene family in peanut are lacking in spite of the availability of the peanut genome sequence. In this study, we identified 50 and 45 bZIP genes from Arachis duranensis and A. ipaensis genomes, respectively. Phylogenetic analysis showed that Arachis bZIP genes were classified into nine groups, and these clusters were supported by several group-specific features, including exon/intron structure, intron phases, MEME motifs, and predicted binding site structure. We also identified possible variations in DNA-binding-site specificity and dimerization properties among different Arachis bZIPs by inspecting the amino acid residues at some key sites. Our analysis of the evolutionary history analysis indicated that segmental duplication, rather than tandem duplication, contributed greatly to the expansion of this gene family, and that most Arachis bZIPs underwent strong purifying selection. Through RNA-seq and quantitative real-time PCR (qRT-PCR) analyses, the co-expressed, differentially expressed and several well-studied homologous bZIPs were identified during seed development stages in peanut. We also used qRT-PCR to explore changes in bZIP gene expression in response to salt-treatment, and many candidate bZIPs in groups A, B, and S were proven to be associated with the salt-stress response. This study have conducted a genome-wide identification, characterization and expression analysis of bZIP genes in Arachis genomes. Our results provide insights into the evolutionary history of the bZIP gene family in peanut and the funcntion of Arachis bZIP genes during seed development and in response to salt stress.


Does MALT lymphoma of the lung require immediate treatment? An analysis of 11 untreated cases with long-term follow-up.
Mucosa-associated lymphoid tissue lymphoma (MALT lymphoma) of the lung is a relatively rare disease. As little is known about the natural clinical course if left untreated, all patients undergoing a watch-and-wait policy at our institution were investigated. A retrospective analysis identified a total of 11 patients with MALT lymphoma of the lung who did not undergo treatment following initial diagnosis. All patients had undergone extensive staging and were closely observed with restaging every three months. Histological assessment included immunhistochemistry for demonstration of the immunphenotype CD20+/CD5-/ CD10-/cyclinD1-/CD23-. Genetic aberrations were assessed, using RT-PCR for t(11;18) (q21;21) and fluorescence in situ hybridisation for the evaluation of t(14;18)(q32;q21), t(1;14) (p22;q32), trisomies 3 and 18. Five patients had MALT lymphoma restricted to the lung, while the remaining six had additional extrapulmonary sites detected during staging. The median time of observation without therapy was 28.1 months (inter-quartile range: 5 to 60 months); within this time, all 11 patients showed at least stable disease. Six of these 11 patients, however, had spontaneous regressions and wax-and-wane phenomena of the pulmonary lesions, but not of extrapulmonary manifestations. Three of these patients had evidence of t(11;18)(q21;q21), while the remaining three had no evidence of genetic aberrations. One patient was referred for treatment after progression in the lung, while two patients experienced progression outside the lung. Currently, all patients are alive, with 8 patients still only being watched. Our findings suggest that MALT lymphoma of the lung is a very indolent disease with the potential for spontaneous regression. In view of this, patients diagnosed with pulmonary MALT lymphoma might not require immediate treatment in the absence of symptoms and a watch-and-wait policy could be adopted.


The microbicidal agent C31G inhibits Chlamydia trachomatis infectivity in vitro.
Safe and effective vaginal microbicidal compounds are being sought to offer women an independent method for protection against transmission of sexually acquired pathogens. The purpose of this study was to examine the efficacy of two formulations of one such compound, C31G, against Chlamydia trachomatis serovar E alone, its host epithelial cell (HEC-1B) alone, and against chlamydiae-infected HEC-1B cells. Preexposure of isolated, purified infectious chlamydial elementary bodies (EB) to C31G, at pHs 7.2 and 5.7, for 1 h at 4 degrees C resulted in reduced infectivity of EB for HEC-1B cells. Examination of the C31G-exposed 35S-EB on sodium dodecyl sulfate-polyacrylamide gel electrophoresis autoradiographs and by Western blotting revealed a C31G concentration-dependent and pH-dependent destabilization of the chlamydial envelope, resulting in the release of chlamydial lipopolysaccharide and proteins. Interestingly, when the host human genital columnar epithelial cells were infected with chlamydiae and then exposed to dilute concentrations of C31G which did not alter epithelial cell viability, chlamydial infectivity was also markedly reduced. C31G gained access to the developing chlamydial inclusion causing damage to or destruction of metabolically active reticulate bodies as well as apparent alteration of the inclusion membrane, which resulted in premature escape of chlamydial antigen to the infected epithelial surface. These studies show that the broad-spectrum antiviral and antibacterial microbicide C31G also has antichlamydial activity.


Stabilized nanoparticles of phytosterol by rapid expansion from supercritical solution into aqueous solution.
The basic objective of this work was to form stable suspensions of submicron particles of phytosterol, a water-insoluble drug, by rapid expansion of supercritical solution into aqueous solution (RESSAS). A supercritical phytosterol/CO2 mixture was expanded into an aqueous surfactant solution. In these experiments 4 different surfactants were used to impede growth and agglomeration of the submicron particles resulting from collisions in the free jet. The concentration of the drug in the aqueous surfactant solution was determined by high-performance liquid chromatography, while the size of the stabilized particles was measured by dynamic light scattering. Submicron phytosterol particles (<500 nm) were stabilized and in most cases a bimodal particle size distribution was obtained. Depending on surfactant and concentration of the surfactant solution, suspensions with drug concentrations up to 17 g/dm3 could be achieved, which is 2 orders of magnitude higher than the equilibrium solubility of phytosterol. Long-term stability studies indicate modest particle growth over 12 months. Thus, the results demonstrate that RESSAS can be a promising process for stabilizing submicron particles in aqueous solutions.


Three distinct families of GABAergic neurons in rat visual cortex.
In the cortex inhibition is mediated predominantly by GABAergic interneurons. Although all of these neurons use the same neurotransmitter, studies in the rat frontal cortex have shown that they are molecularly and physiologically diverse. It is not known whether similar subgroups of GABAergic neurons exist in primary visual cortex and how these different inhibitory neurons are inserted into specific cortical circuits. We have used immunostaining with antibodies against gamma aminobutyric acid (GABA), parvalbumin (PV), calretinin (CR), somatostatin (SOM), calbindin (CB) and nitric oxide synthase (NOS) to probe for colocalization of known markers of GABAergic interneurons. The results show that the majority of PV (100%), SOM (89.8%) and CR (93.9%) staining neurons are GABA positive. PV immunoreactive neurons constitute a distinct group that show no overlap with CR, SOM and NOS expressing cells and only a minor overlap (5.3%) with CB. PV immunoreactive cells account for 50.8% of GABAergic neurons. A second group of SOM expressing neurons accounts for 16.9% of GABAergic cells. None of these cells colocalize PV or CR, but 1.7% of SOM neurons stain for NOS and 86.3% show CB immunoreactivity. The third distinct group of CR expressing cells accounts for 17.0% of GABAergic neurons. All of these are PV, CB, SOM and NOS negative. CB expressing neurons represent a heterogeneous group that includes GABAergic and non-GABAergic cells. Our findings indicate that GABAergic neurons in rat area 17 are organized in at least three separate families that can be identified by the expression of PV, CR and SOM. These cells account for 84.9% of GABAergic neurons. These results extend previous observations in rat frontal agranular cortex and suggest that in visual cortex the inhibitory network is composed of similar cell types.


Synergistic anti-proliferative effect of metformin and sorafenib on growth of anaplastic thyroid cancer cells and their stem cells.
Sorafenib, a multikinase inhibitor has recently been approved for the treatment of radio-iodine refractory thyroid carcinoma. However, toxic side effects may lead to dose reduction. In the present study, we analyzed whether a combined therapy with metformin may allow a dose reduction of sorafenib without loss of effectiveness at the same time. In HTh74 anaplastic thyroid carcinoma (ATC) cells and its derived doxorubicin-resistant HTh74Rdox cell line, the growth inhibitory effect of sorafenib with or without metformin was investigated. Furthermore, an analysis of cell cycle arrest in response to sorafenib was performed and the ability of a combined treatment to induce apoptosis was analyzed. In addition, the effects on clonal growth and formation of stem cell-derived spheres were assayed. The influence of sorafenib and metformin on MAP kinase pathway was investigated by analysis of ERK phosphorylation. Sorafenib and metformin synergistically inhibited growth of the two thyroid cancer cell lines, with a more pronounced effect on the doxorubicin-resistant HTh74Rdox cell line. The two drugs also synergistically decreased sphere formation, which suggested a specific effect on thyroid cancer stem cells. The addition of metformin enabled a 25% dose reduction of sorafenib without loss of its growth inhibitory efficacy. Sorafenib and metformin synergistically decreased the proliferation of ATC cell lines and the outgrowth of their derived cancer stem cells. A combined treatment enabled a significant dose reduction of sorafenib. In respect to frequent toxic side effects, clinical studies in future should demonstrate whether the addition of metformin may be an advantage in the chemotherapy of patients with radio-iodine‑resistant thyroid cancer.


Synaptic short-term plasticity in auditory cortical circuits.
The auditory system must be able to adapt to changing acoustic environment and still maintain accurate representation of signals. Mechanistically, this is a difficult task because the responsiveness of a large heterogeneous population of interconnected neurons must be adjusted properly and precisely. Synaptic short-term plasticity (STP) is widely regarded as a viable mechanism for adaptive processes. Although the cellular mechanism for STP is well characterized, the overall effect on information processing at the network level is poorly understood. The main challenge is that there are many cell types in auditory cortex, each of which exhibit different forms and degrees of STP. In this article, I will review the basic properties of STP in auditory cortical circuits and discuss the possible impact on signal processing.